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    You are here : Home » MS Research News » Drugs » Gilenya® (fingolimod)

    Gilenya® (fingolimod)

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    Gilenya® (fingolimod) is the first in a new class of disease-modifying treatments called sphingosine 1-phosphate receptor (S1P-R) modulators and has a novel mode of action different from all currently marketed MS therapies.

    Read fellow MSers experiences on Gilenya® on the MSRC Gilenya® User Diaries

    Encouraging data from oral MS drug Gilenya study analysis

    GilenyaNovartis AG has announced new data that reinforce the generally early and sustained efficacy benefit and long-term safety profile for Gilenya, the first once-daily oral therapy approved to treat relapsing forms of multiple sclerosis, or MS.

    Analysis shows significant early treatment effect with Gilenya. A new post hoc analysis of two large Phase III studies shows treatment with Gilenya 0.5 mg led to significant benefits on relapse-related outcomes within the first three months and on brain volume loss by six months compared to placebo.

    There was a significant (p<0.05) Gilenya treatment effect on time to first confirmed relapse within three months in both the pivotal FREEDOMS study (n=1272), and FREEDOMS II, the second large Phase III placebo-controlled study (n=1083). The differences between Gilenya and placebo became persistently significant by Day 82 in FREEDOMS and Day 64 in FREEDOMS II, respectively.

    Furthermore, in the FREEDOMS study, patients-treated with Gilenya 0.5 mg had on average a 35% reduction in brain volume loss compared with placebo at the first MRI evaluation after six months of treatment (mean percent brain volume change of -0.22 for Gilenya vs. -0.34 for placebo; p=0.006). In FREEDOMS II, there was a 39% reduction in brain volume loss (mean percent volume change of - 0.23 for Gilenya vs. - 0.38 for placebo; p=0.012) at six months.

    First results from the PANGAEA observational study in Germany indicate that 90% of investigators and 91% of patients rated Gilenya treatment success, defined as efficacy and tolerability, as Good or Very Good. PANGAEA is a German registry study aimed to enroll a total of 4,000 patients with a follow-up of five years designed to investigate the efficacy and safety of Gilenya in everyday clinical practice. As of May 2012, one year after initiation of the registry, more than 1,850 patients were enrolled in 475 participating centers. These results also showed an overall safety profile in line with previously reported data.

    In addition, a separate analysis of time to discontinuation of therapy among MS patients receiving Gilenya and other disease modifying treatments (DMTs) using pharmacy claims in the US (n=1891) show Gilenya-treated patients were significantly less likely to discontinue treatment over the 12 month observation period (Gilenya: 27.8%, other DMT cohorts: 42.7-54.5%; p<0.01) and discontinued later than patients using injectable DMTs.

    A new integrated analysis of safety data from Phase II, Phase III and study extensions for fingolimod (all doses, n=3553) show a safety profile generally consistent with previous results. The total fingolimod exposure was 9,070 patient years, with 1,510 patients treated for more than three years and some for more than seven years.

    As of August 2012, more than 49,000 patients have been treated with fingolimod in clinical trials and in the post-marketing setting, and there is approximately 52,000 patient years of exposure.

    Gilenya, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of compounds called sphingosine 1-phosphate receptor (S1PR) modulators. It has demonstrated superior efficacy compared to Avonex, a commonly prescribed treatment, showing a 52% relative reduction in annualized relapse rate (primary endpoint) and a 40% relative reduction in the rate of brain atrophy (secondary endpoint) at one year in a pivotal head-to-head trial in patients with relapsing-remitting multiple sclerosis.
    In a recent post hoc sub-group analysis, Gilenya showed a 61% relative reduction in annualized relapse rate compared to interferon-beta-1a (IM) at one year in subgroups of patients with highly active relapsing-remitting MS not responding to interferon treatment.

    "As the first once-daily oral MS therapy, growing real-world experience reinforces Gilenya's high efficacy and long-term safety profile," said David Epstein, head of the pharmaceuticals division of Novartis Pharma AG. "With data showing an early treatment effect on relapses and brain volume loss, Gilenya continues to show positive outcomes for patients and Novartis remains committed to addressing the significant remaining unmet medical need in the MS community."

    "Understanding the onset of efficacy is an important consideration in the treatment of MS as early effective treatment may improve patient outcomes," said Professor Ludwig Kappos, chair of neurology, University Hospital, Basel, Switzerland. "The new analysis of Phase III data shows a significant early effect of Gilenya on relapses and MRI measures, and further supports its role as a valuable treatment option for relapsing-remitting MS."

    Source: equities.com Copyright © 2012 equities.com (17/10/12)

    Gilenya reduces brain loss in Multiple Sclerosis patients

    GilenyaPooled data from two large Phase III studies have demonstrated a significant early treatment effect of Novartis' multiple sclerosis pill Gilenya on relapses and MRI outcomes, including brain volume loss.

    The data, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress in Lyons, France, shows that treatment with Gilenya (fingolimod) led to significant benefits on relapse-related outcomes within the first three months and on brain volume loss by six months compared to placebo. Specifically, in the FREEDOMS study, treatment with the once-daily pill resulted in, on average, a 35% reduction in brain volume loss compared with placebo after six months of treatment. In FREEDOMS II, there was a 39% reduction.

    David Epstein, head of Novartis Pharma, said that "as the first once-daily oral MS therapy, growing real-world experience reinforces Gilenya's high efficacy and long-term safety profile". The company also quoted Ludwig Kappos, chair of neurology at University Hospital, Basel, Switzerland, as saying that "understanding the onset of efficacy is an important consideration in the treatment of MS as early effective treatment may improve patient outcomes".

    Other Novartis data presented at ECTRIMS includes first results from 1850 patients enrolled in the PANGAEA observational study in Germany. This shows that 90% of investigators and 91% of patients rated Gilenya treatment success, defined as efficacy and tolerability, as 'good' or 'very good'.

    In addition, a separate analysis of time to discontinuation of therapy among MS patients receiving Gilenya and other disease modifying treatments (DMTs) using pharmacy claims in the US (n=1891) show Gilenya-treated patients were significantly less likely to discontinue treatment over the 12 month observation period (Gilenya: 27.8%, other DMT cohorts: 42.7-54.5%) and discontinued later than patients using injectable DMTs.

    Source: PharmaTimes Copyright 2012 (15/10/12)

    Battle lines drawn in the MS oral drugs market

    Oral MS DrugsFor years, patients with multiple sclerosis had to endure injection therapies to stave off the horrible disease. Oral medications have finally emerged from development recently, and it turns out the competition is heating up fast: Results arrived on two major clinical trials for Biogen Idec's own oral MS drug, BG-12, and the data looks rock-solid. With the MS market suddenly red-hot, will Biogen's latest success propel the company to higher heights?

    Mopping up the competition

    Biogen's two phase 3 trials for BG-12 came out in Wednesday's New England Journal of Medicine with promising results. The two trials demonstrated strong efficacy for BG-12, with chronic relapses falling 44% to 51% at the two-year mark. Given that drugs currently used to combat MS relapses typically demonstrate only a 30% improvement, BG-12's success looks sharp.

    While the FDA won't rule on BG-12's approval until later in the year, Biogen's drug looks to become just the third oral medication for MS on the market. Sanofi's Aubagio received the green light from the FDA earlier this month, following Novartis's Gilenya, the first oral MS treatment launched in 2010.

    Unfortunately for Biogen's two competitors, their drugs come with serious questions over efficacy and side effects. Gilenya has caused numerous headaches for Novartis, with the FDA issuing a restrictive label for the drug after a patient died soon after beginning treatment. While the connections between the death and the drug were unclear, the fact that Gilenya also can slow patient heart rates -- and that patients are recommended to stay in a hospital for six hours after the first dose -- aren't helping Novartis' PR department.

    Sanofi might not face the same sort of lethal problems with Aubagio, but regardless of Aubagio's warm reception around projected future sales, early signs show that BG-12 is simply a better product. In one trial, Aubagio failed to beat the Rebif injection treatment offered by Pfizer with Aubagio sporting only a 30% relapse reduction. BG-12 leads with a considerable advantage in a head-to-head matchup of efficacy.

    Concerns and answers

    Ironically, the hurdles hit by these two drugs -- Gilenya in particular -- could come back to haunt Biogen. With doctors used to effective injection medications for MS, the problems of the past could make individual practitioners hesitant to dole out a third oral treatment. National MS Society Chief Research Officer Timothy Coetzee cautioned BG-12's spread on this very issue, stating, "My guess is that the injectables will remain an important treatment option." He warned that a wide-scale replacement of injection treatments with oral drugs is still up in the air.

    Still, BG-12 is a potent drug. The twice-daily treatment in one clinical trial proved to reduce new MS-linked brain lesions by 71%. The drug also lacks the problematic side effects of Gilenya, with the most common problems being digestive issues such as abdominal pain and diarrhea. Such side effects also diminished in number in the clinical trials after the first treatment month.

    Additionally, Biogen has plenty of ways to combat MS on the market already. Its MS injection therapy developed jointly with Elan Tysabri, is prescribed for first-line MS treatment in Europe. Tysabri still recorded 69,000 patients as of July and grew year-over-year annual revenue by more than 10% in 2011 for Biogen.

    BG-12's U.S. patents won't expire until 2019 at the earliest, so if it's approved, Biogen will have plenty of time to make inroads on a lucrative and growing MS market. Biogen further estimates that BG-12 would hold eight years of data exclusivity and an additional two years of market exclusivity in the European Union, effectively stringing out maximum sales in the Western world's most powerful consumer markets until the next decade.

    Biogen's steady stream of optimism

    Biogen's still a solid company with a strong financial future on top of all that. It boasts a steady pipeline of 12 drugs and therapies in phase 2 trials or later, including BG-12. The company's best-selling drug, Avonex, took in more than 50% of the company's revenues, and Biogen holds exclusive rights on the drug until 2026.

    The strong majority of Biogen's $5 billion in annual revenues stemmed from MS treatments in 2011 -- a market that will reward Biogen and its shareholders even more as it grows from a current $9.6 billion market last year to an estimated $14 billion by 2015, according to JPMorgan Chase projections. If medical professionals sign on to the prescription of oral MS treatments, it's common sense to think that patients would go for the hassle-free therapies over painful injections -- allowing BG-12 and Biogen to further tighten the company's grip on this market.

    Don't bet the farm on Biogen before the FDA rules on BG-12's approval, but for right now, everything's looking optimistic for this MS drug. It's up for debate whether BG-12 will hit superstar status, but with Gilenya already selling reasonably well and projections for Aubagio high, BG-12 could take the lead in a promising market. Biogen may be trading at all-time highs, but the coming returns could soundly trump what we've seen so far from this booming biotech stock.

    Source: Daily Finance © Copyright 2012 AOL Inc.

    Scottish MS patients finally given access to oral MS drug Gilenya®

    GilenyaThe Scottish Medicines Consortium (SMC) has today announced that Gilenya® (fingolimod), the world’s first pill for the treatment of highly active relapsing-remitting multiple sclerosis (RRMS), has now been approved for restricted use within NHS Scotland.

    Today’s decision means that people with highly active RRMS not responding to treatment with first-line interferon injections now have the option of switching to fingolimod as their next step, bringing Scotland in line with the rest of the UK. Until now, people with MS in Scotland have had to self-inject at least weekly or travel to hospital for infusions to manage their condition.

    As part of today’s landmark decision, SMC clinical experts recognised the significant unmet need for an effective oral treatment for those people failing on first-line interferon injections, highlighting the important patient and service benefits an oral treatment would bring.

    Having reviewed a wealth of data, including sub-group data, the SMC acknowledged the clinical effectiveness of fingolimod as part of its decision. The SMC recognised that fingolimod significantly reduced relapse rates (by 52%) when compared to a standard injection (interferon β-1a IM). Furthermore, they noted that fingolimod showed broadly similar efficacy and demonstrated cost-savings when compared to infusion therapy (natalizumab).

    Dr Belinda Weller, a consultant neurologist who took part in the clinical trials for fingolimod in Scotland, commented, “Scotland has the highest incidence of MS in the world, so the availability of an effective oral treatment for people whose injections are no longer working is fantastic news. Not only is fingolimod very effective, but also more convenient, which is very important considering the geography of Scotland.”

    Until today’s decision, the Scottish were the only people in the UK not to have access to fingolimod on the NHS, despite having the highest incidence of MS in the world with 10,000 people affected. Fingolimod has been approved by the National Institute of Health and Clinical Excellence (NICE) since April 2012 and over 41,000 people have been treated worldwide to date. Importantly, there is no limit on the duration of time for which fingolimod can be taken.

    In March 2012, the SMC initially rejected the use of fingolimod on NHS Scotland. Key to the positive decision was the involvement of patient and professional groups, including the MS Society Scotland, MSPs and the MS medical community, who recognised the unmet clinical need for an effective oral treatment for those people failing on injections.

    Commenting on the decision, Dr Mark Bechter, Medical Director ad interim at Novartis UK, said: “This is a landmark day for the Scottish MS community and we are delighted that our continued collaboration with the SMC has resulted in a positive decision. We are looking forward to working with the Scottish NHS Boards to ensure appropriate people with MS have access to fingolimod as soon as possible.”

    Source: Novartis (10/09/12)

    Rethink on MS pill Gilenya gives hope to Scots sufferers

    GilenyaMultiple sclerosis sufferers in Scotland will learn today if the world’s first oral pill to alleviate symptoms of the condition is to be prescribed on the NHS.

    The drug, Fingolimod, is already available to MS patients in England and Wales after being approved by the National Institute for Clinical Excellence in March. But the Scottish Medicines Consortium, which evaluates drugs for use in Scotland and ruled earlier this year that it did not provide value for money, has now reconsidered its decision.

    The earlier judgment sparked anger among campaigners in Scotland, which is believed to have the highest rate of MS in the world, with approximately 10,500 diagnosed cases.

    At present people with MS have to receive a weekly injection of interferon to slow progress of the disease of a monthly infusion of Tysabri.

    Those who receive regular injections claim they have a “six day week”, with one day wiped out by the debilitating effects of the treatment.

    Patients claim that taking a daily pill would improve their quality of life and avoid unnecessary doctors’ appointments. For those who live in remote island communities, where there are significant numbers of MS sufferers, it would put an end to lengthy journeys to and from mainland hospitals.

    MS damages the central nervous system, leading to a range of disabilities including co-ordination difficulties and visual impairment. The reasons for Scotland’s high rates of the condition remain unknown, although it is thought a lack of sunshine and Vitamin D may trigger the illness.

    Fingolimod, also know as Gilenya, is said to reduce relapse rates among MS sufferers by around 50%. It has been approved for use in 35 countries including the United States and Germany.

    Campaigners says as well as improving quality of life, Fingolimod is also cost effective. The annual bill for treating one patient with the pill is estimated at around £19,665 while the cost for Natalizumab, the drug used in monthly infusions, is around £21,257.

    Hospital stays for patients who suffer a relapse cost the NHS more than £30,000 per admission. Only a small number of Scots have been prescribed the drug after their GPs requested funding for consideration on a “case by case” basis from health trusts.

    Gillian Rafferty, 48, from Moffat, is one who has been taking part in a trial for Fingolimod after her GP referred her to specialist MS nurses in Carlisle. “I started taking the drug in 2007 and since then I’ve had no relapses or MS symptoms. Before that I had to take steroids to manage the symptoms when I had relapses,” said Rafferty.

    “I had one when my daughter Sarah was 11 months and I couldn’t feel anything down my right side. I was terrified of dropping her and couldn’t do up her BabyGro.”

    Rafferty added: “It’s not really fair that people are getting Fingolimod in England and Wales. I’d always thought that the attitude here in Scotland was usually more go-ahead in health matters, especially since we’ve got more people with MS in the world as a percentage of the population. I’m hoping that injectables will become a thing of the past.”

    Becky Duff, head of policy and communications at MS Society Scotland, which expressed disappointment at the SMC decision in March, said: “We would welcome any decision that would increase the treatment options for people with highly active MS.

    “For the past 10 years, people with MS have needed to inject to receive their medicines – a pill represents a significant step forward and will greatly improve quality of life.”

    Announcing their decision not to make Fingolimod available in Scotland, the SMC acknowledged there was evidence of a reduction in relapse rates. But they claimed it had not been compared to another drug available in Scotland and that it could be responsible for a short-term decrease in heartbeat, swelling of the retina inside the eye and that about half of the patients monitored went on to develop infections.

    A spokesperson for the SMC said: “We were disappointed not to be in a position to accept Fingolimod as a value for money medicine for use within the NHS in Scotland when we assessed the manufacturer’s evidence in March of this year.

    “Unfortunately there were weaknesses in the economic case presented by the manufacturer that meant that it was not considered cost-effective. However, we’re pleased that the manufacturer has been quick to come back to us with a revised submission. We will be making a new announcement on Monday.”

    Source: Scotsman.com © 2012 Johnston Publishing Ltd (10/09/12)

    Oral MS drug piloted in North East is available on the NHS

    GilenyaNHS funding for a groundbreaking drug piloted in the North East for patients with multiple sclerosis is now mandatory.

    The National Institute for Clinical Excellence (Nice) has stipulated that adults with relapsing remitting MS not responding to treatment with first-line interferon injections should have access to fingolimod, an oral pill that cuts relapses by more than half compared to a standard injection.

    Clinical trials that began in 2004 at the regional centre for the treatment of MS at Newcastle’s Royal Victoria Infirmary (RVI) has meant patients in the North East were among the first worldwide to try fingolimod.

    Now all eligible patients should have access to the daily pill, which is proven to be twice as effective as a standard injection. Dr Martin Duddy, consultant neurologist at the RVI said: “A number of patients at our centre have already started treatment with fingolimod and we anticipate these numbers will increase over the coming months.

    “Our patients are keen to get started on treatment and we are delighted to be one of the first centres in the UK to have our service up and running.

    “It is an important step forward and it gives us another option in the treatment for MS patients.”

    Fingolimod, which is also known by the brand name Gilenya, has taken many years to develop and 38,000 patients worldwide are already using the treatment.

    In April this year, Nice approved it for use on the NHS, confirming it is a valuable, innovative and cost-effective therapy.

    Following publication of final Nice guidance, the NHS is obliged to provide funding and resources for recommended treatments within three months.

    Within the last month eight patients at the RVI have been prescribed fingolimod, and it is anticipated that an extra eight to 10 patients a month will be given the medication.

    It is hoped that access to the treatment will help reverse the current trend highlighted by a 2010 report from leading expert Prof Mike Richards.

    This showed that the UK is ranked 13th out of 14 countries when it comes to access to new treatments for MS.

    MS is the most common neurological condition affecting young adults.

    It is estimated that more than 100,000 people in the UK have the illness and it can occur at any age but is usually diagnosed between the ages of 20 to 40.

    In MS, white blood cells attack the coating of the nerve cells which help messages from the brain travel to the rest of the body.

    As these cells are damaged, people experience symptoms such as numbness and tingling, blurred vision, mobility and balance problems, and muscle weakness and tightness.

    Fingolimod works by preventing the white blood cells from attacking nerve cells in the brain and spinal cord.

    Angela Hamilton has suffered with the condition for 15 years and experiences pain and fatigue.

    The 45-year-old, of South Shields, said the development to make NHS funding mandatory for fingolimod offered hope to those living with the debilitating condition.

    “It is really brilliant news and it’s an excellent decision by Nice,” explained the policy and information officer.

    “It’s helping to take away patient’s anxiety about the condition as you know that there is a treatment option available if you relapse.

    “Anything that’s a step forward and a development in the type of medication and treatment offered is welcomed.”

    We are delighted to be one of the first centres in the UK to have our service up and running

    Source: The Journal © 2012 ncjMedia Limited (26/07/12)

    MS drug Gilenya prescriptions slowing due to lack of monitoring facilities

    GilenyaNovartis’ multiple sclerosis (MS) pill Gilenya faces slowing prescriptions in New York because of a lack of facilities to perform first-dose observations, neurologists told Biopharm Insight. However, Novartis has been in contact with a number of clinicians and is working on increasing the number of sites.

    A US Food and Drug Administration (FDA) review was initiated after a patient died within 24 hours of taking the first dose of Gilenya. Regulatory authorities also re-evaluated study data regarding the drug’s effect on heart rate and blood pressure.

    Gilenya is now contraindicated for use in patients with certain pre-existing or recent heart conditions or stroke, or those taking certain antiarrhythmic drugs, according to FDA. Extended monitoring is recommended in patients with QT prolongation and in patients who are already taking medication that slows heart rate. Observation includes continuous overnight electrocardiography (ECG) monitoring.

    A Novartis spokesperson said via email the company is committed to helping healthcare providers implement the updated prescribing information recommendations.

    Gilenya sales in 2011 reached USD 494m.

    Monitoring requirements and set up
    There is no official Novartis-arranged facility in Manhattan to perform first-dose observations at this time, but this is likely to change in the very near term, according to Dr Stephen Krieger, assistant professor of neurology, Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, New York. Dr David Snyder, director of the Multiple Sclerosis Center at New York Hospital Queens, added there is no facility available in New York City. “There is a facility in Secaucus, New Jersey, where one [of my] patients in New York is going,” he noted.

    At his hospital, Snyder noted that he is not in a position to do an ECG. He noted that patients need to be referred to a cardiologist to assess if the patient can take Gilenya. “We don’t repeat the ECGs in our office, but now the new guidelines indicate that you do need to get ECGs before and after dosing. We cannot do that,” Synder explained.

    He said the same issue is likely to affect other private practice neurologists. Dr Aaron Miller, professor of neurology at the Mount Sinai School of Medicine, said there are one or more sites in New York that have been identified to conduct monitoring. “We work directly with Novartis to find a site,” he said.

    Novartis currently has a system in place with a “nurse navigator” to facilitate arranging monitoring and first dosing, Krieger noted. He said he believed this program is being updated to arrange first-dose centers that meet the new, heightened requirements.

    If a neurologist wishes to arrange the first-dose observation themselves, then either hospital admission or contracting with a facility that can perform continuous monitoring can be done, Krieger added.

    This would likely be akin to Biogen Idec’s “TOUCH-certified” infusion centers for Tysabri administration in the US, he added. The TOUCH program monitors deaths, and physicians know the risks with Tysabri, stated Dr Karen Blitz-Shabbir, director of the North Shore MS Care Center in East Meadow, New York.

    Physicians can stratify risks with Tysabri, while Gilenya is more difficult because we do not know how people are dying, she said. Blitz-Shabbir said two of the 11 deaths associated with Gilenya were from drowning and appear to be cardiac-related. There has been no information given to physicians about the cause of these patients’ deaths, she noted.

    Novartis needs to expand its Gilenya Go program to a more comprehensive case-management system for doctors and patients to be able to efficiently use the drug, said Dr Daniel Kantor, president of the Florida Society of Neurology, who was an investigator on Gilenya. Kantor said he is currently trying to figure out what to do for patients who need hospitalization. In the US, Novartis continues to offer pre-tests and first-dose observation capabilities at a network of clinical centers that provide assessments and screenings, but not 23 hour observations, that may be needed by patients taking Gilenya called the Gilenya Assessment Network (GAN), the spokesperson said. It currently comprises close to 250 sites around the country, and sites are accessible within 30 miles of Novartis’ customers and growing rapidly, the spokesperson added.

    Gilenya’s efficacy is still great, but it’s really the logistical factors associated with the drug, Kantor noted. The safety data suggests that despite some questions in clinical practice, Gilenya is overall associated with a very low chance of cardiac signs or symptoms, noted Kantor. Because of recent events, Snyder said his prescribing process has slowed down somewhat. If patients are doing well on the current injectables, Snyder said he would not switch to an oral drug just because of patient convenience. In terms of the number of unexplained deaths, one US patient who was on Tysabri and then was switched to Gilenya, developed progressive multifocal leukoencephalopathy (PML) shortly after the change, Snyder said.

    Declining use
    MS centers are using it less frequently, and it’s mostly used by general neurologists rather than MS specialists, Blitz-Shabbir said.
    Gilenya’s efficacy is still great, but it’s really the hassle factor associated with the drug, Kantor noted.

    Some of the unexplained deaths were due to inappropriate patient selection by the physicians involved, Snyder stated. “I emphasized that the patients that we select for Gilenya use are young, free of any CV disease, and are not on any medications that would affect the heart.”

    As neurologists refine the concept of the “appropriate patient” for Gilenya, with limitations regarding cardiac history and concomitant medicines that can impact heart rhythm, there may be a modest slowing of prescriptions, said Krieger.

    The likely approval of Sanofi’s teriflunomide and Biogen’s BG-12 in the coming year may also impact use of Gilenya, as it may cause neurologists to hold off on switching a patient to this oral medication in anticipation of additional options, said Krieger.

    Gilenya is a very interesting drug and it affects the S1P receptor, which is on every cell, and every organ in the body, Blitz-Shabbir explained.

    A neurologist on background said one concern when Gilenya was approved was the fact that the circulating white cells decrease, so nobody really knows the long-term effects.

    The reason why patients are willing to go on Tysabri is because it’s the most efficacious drug on the market, Blitz-Shabbir claimed. She said she was unsure whether Gilenya is the best drug, adding it doesn’t warrant the risk. Dr Samuel Hunter, a neurologist at the Advanced Neurosciences Institute in Tennessee, said Gilenya will be a “huge pain” for the majority of patients. Costs have been increased and inconvenience thousands of people for the benefit of rare individuals who are easily identified as being at risk by history and ECG, he said. Physicians do not want to take the time or trouble to screen these issues, especially unnecessarily, he added.

    Source: The Financial Times Copyright The Financial Times Limited 2012 (04/07/12)

    Oral MS drug Gilenya slows brain inflammation

    GilenyaThe multiple sclerosis medication fingolimod (Gilenya) led to "rapid and sustained" reductions in MRI-documented inflammatory lesion activity, researchers reported.

    In a two-year randomized trial, the medication also slowed the rate of brain volume loss compared with placebo, according to Ernst-Wilhelm Radue, MD, of University Hospital Basel in Basel, Switzerland, and colleagues.

    Changes in lesion volume over time also favoured the medication rather than placebo, Radue and colleagues reported online in Archives of Neurology.

    Combined with previously reported improvements in relapse rates and disability progression, the findings suggest that the drug -- a sphingosine 1–phosphate receptor (S1PR) modulator -- has a "positive impact on long-term disease evolution," the researchers argued.

    Fingolimod inhibits migration of T cells out of lymph nodes, preventing them from attacking the protective myelin sheaths surrounding nerve fibers. The drug, in an oral formulation of 0.5 milligrams, was approved in 2010 on the basis of its effects on relapse and disability.

    The current study looks at magnetic resonance imaging (MRI) of the 1,272 patients who were part of the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial.

    Participants were randomly assigned to get once-daily fingolimod capsules of 0.5 mg or 1.25 mg, or to placebo and had standardized MRI scans at screening and at 6, 12, and 24 months.

    The scans were evaluated for the number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions, Radue and colleagues reported, as well as for the percentage of change in brain volume.

    They found:

    Both fingolimod doses significantly reduced (P<0.001) the number of new or newly enlarged T2 lesions over 24 months compared with placebo.

    The reductions reached significance by month 6 and remained significant for the rest of the study.

    Fingolimod patients at either dose also had fewer gadolinium-enhancing lesions and lower lesion volumes at 6, 12 and 24 months than patients treated with placebo (P<0.001 for all).

    Over the 24 months, 21% of placebo patients were completely free from new or newly enlarged T2 lesions, gadolinium-enhancing lesions, or both, compared with 52% and 50.7% of those treated with the high and low doses of fingolimod, respectively (P<0.001).
    Changes in T2 hyperintense and T1 hypointense lesion volume also favored fingolimod over placebo, (P<0.05 for all).

    Both doses of the drug slowed the loss of brain volume compared with placebo (P<0.001) over the whole study period. The improvement was significant by month 6 and was sustained, with relative reductions in brain volume loss, compared with placebo, of 23% to 45% at the various intervals.

    The findings "confirm that the efficacy of fingolimod therapy is robust across all MRI end points," the authors argued.

    The study was supported by Novartis Pharma AG. Radue reported financial links with Bayer Schering, Biogen Idec, Novartis, Merck Serono, Actelion, and Basilea Pharmaceutica.

    Primary source: Archives of Neurology
    Source reference:
    Radue E-W, et al "Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis" Arch Neurol 2012; DOI: 10.1001/archneurol.2012.105.

    Source: MedPage Today © 2012 Everyday Health, Inc (03/07/12)

    Gilenya® shows long-term efficacy and safety in extension of phase III head-to-head study

    GilenyaNew long-term data for Gilenya® (fingolimod), the only oral therapy approved to treat people with relapsing forms of multiple sclerosis (MS), show a sustained efficacy benefit and a consistent safety profile with up to 4.5 years of continuous treatment. These results, from an extension of the phase III head-to-head TRANSFORMS study, also showed improved efficacy for patients switched to Gilenya from Avonex® (interferon-beta-1a IM), a commonly prescribed MS treatment.

    "These data further reinforce our confidence in Gilenya's long-term effectiveness and safety profile. The TRANSFORMS extension study shows that MS patients treated continuously with Gilenya for up to four and a half years demonstrated sustained low levels of clinical and MRI activity," said Tim Wright, Global Head of Development, Novartis Pharma. "Furthermore, patients who switched to Gilenya from interferon beta-1a IM showed a reduction in relapses and improvements in MRI measures in the extension compared to the core study."

    In the core TRANSFORMS study, Gilenya demonstrated superior efficacy to interferon-beta- 1a IM, reducing the annualized relapse rate (ARR) by 52% at one year (Gilenya 0.5 mg, ARR = 0.16; interferon-beta- 1a IM, ARR = 0.33; p<0.001. The extension study showed that this low relapse rate was sustained in patients receiving continuous treatment with Gilenya (n=356) for up to 4.5 years (Gilenya 0.5 mg, ARR core study = 0.16; ARR extension study = 0.16). The data from the extension study also showed that patients treated with Gilenya continuously maintained a low brain atrophy rate throughout the study as measured by assessing brain volume loss, which is valued as a predictor of long-term disability.

    For patients who switched to Gilenya for the open-label extension study (n=167), their ARR was 0.33 in the core study when treated with interferon-beta-1a IM and 0.20 in the extension phase when treated with Gilenya (n.s.). Patients in the switch group also displayed a slowing of brain atrophy following the switch to Gilenya.

    These extension data from up to 4.5 years also showed long-term treatment with Gilenya was generally well tolerated with a safety profile consistent with pivotal trials. In line with previous studies, including the core TRANSFORMS study, the most common adverse events were nasopharyngitis, headache, and upper respiratory tract infections. Switching therapy from IFN beta-1a to Gilenya did not reveal any new or unexpected safety concerns. On treatment initiation, a low incidence of asymptomatic transient bradycardia was observed in patients who switched from interferon-beta-1a IM to Gilenya (IFN-0.5 mg [0.6%]), which resolved without treatment. Overall cardiac events were similar across all patient groups.

    In addition, all patients treated with Gilenya in the extension phase, regardless of original treatment in the core study, showed comparable percentage of patients free from MRI disease activity by the end of the study. (free from gd enhanced t1 lesions:77.4% in switch group vs. 74.7% Gilenya 0.5mg)(free from new/newly enlarged t2 lesions:45.0% in switch group vs. 42.0% Gilenya 0.5mg). The continuous and switch groups did not significantly differ with respect to disability progression at the end of the study.

    "This extension study data provide deeper insight into the efficacy and safety profile of fingolimod", said Dr. Xavier Montalban, Director of the Multiple Sclerosis Center of Catalonia and of the Unit of Clinical Neuroimmunology, Vall d'Hebron University Hospital, Barcelona, Spain. "The results, which are consistent with the pivotal phase III studies, confirm that fingolimod is highly effective in treating relapsing forms of MS, and as the first available oral MS treatment, continues to be a valuable treatment option for appropriate patients."

    TRANSFORMS was a large phase III double-blind, double-dummy, head-to-head study that involved 1,292 patientswith relapsing-remitting MS that was conducted over one year, comparing the efficacy and safety of Gilenya to interferon-beta-1a IM. At the end of the 12-month core study, eligible patients could enroll in the extension study, which ran for an additional 3.5 years. Patients on once-daily oral Gilenya remained on drug and those who had been treated with interferon-beta-1a (IM) switched to Gilenya for the duration of the extension study.

    These data were presented at the 22nd Annual Meeting of the European Neurological Society (ENS), taking place 9-12 June 2012 in Prague, Czech Republic.

    As of February 2012, approximately 36,000 patients have been treated with fingolimod in clinical trials and in the post-marketing setting, some up to seven years, and currently there is approximately 34,000 patient years of exposure.

    Source: MarketWatch Copyright © 2012 MarketWatch, Inc (11/06/12)

    Multiple Sclerosis: the disease of a thousand faces

    GilenyaA new drug for treating multiple sclerosis (MS) has yet to be made available by the state, forcing sufferers to buy at their own expense, according to the Cyprus Multiple Sclerosis Association.

    “The approval of the first pill for MS, called Fingolimod (trade name Gilenya), which is a ray of hope for MS sufferers, has taken us one step back, because this medication has still not been incorporated into our national formulary,” said the Association’s head Lenia Takoushi.
    She was speaking at a news conference yesterday to mark World MS Day, under the banner: ‘The disease of a thousand faces’.

    Fingolimod is a drug approved to reduce the rate of relapses and progression of the disease in cases of relapsing MS.

    MS is an autoimmune disease that affects the brain and central nervous system. Symptoms, including loss of balance, muscle spasms and problems walking, vary because the location and severity of each attack can be different. Episodes can last for days, weeks or months and these episodes alternate with periods of reduced or no symptoms.

    Takoushi said that in a meeting the Association had with the Health Minister, he promised that over the next few weeks the drug would be added to the list of those available from the state, provided that parliament releases the funds needed.

    She said the sooner the funds were released the better, as some sufferers had been paying for the medication themselves.

    Takoushi also raised the issue of employment of MS sufferers and disabled people in general. “We congratulate the ministry and government for adopting the law (new legislation allows for 10 per cent of public sector positions to be filled by people with disabilities) but there are weaknesses (in the system) when it comes to MS sufferers, due to the uniqueness of the disease,” she said.
    She explained that a sufferer may not fulfil the criteria if they happen to be present before the medical board on one of their ‘good days,’ and may therefore not be hired.

    Up till now no MS sufferer has been hired (under the legislation), added Takoushi.

    Labour Minister Sotiroulla Charalambous said the ratification of the UN convention on the rights of disabled persons was a milestone for the hiring of disabled persons in the public sector and the reorganisation of vocational training and rehabilitation of people with disabilities.

    With a view to making the public more aware of the disease Takoushi said: “As a society we must learn to understand and respect this diversity and this uniqueness of MS…….and we have to admit that in Cyprus we still have a long road ahead of us.”

    We’re not talking about feeling sorry (for them) but about equal rights and equal opportunities, she added.

    Source: Cyprus Mail 2012 Cyprus mail Ltd (31/05/12)

    FDA issues new advice on oral MS drug Gilenya

    Gilenya As their European counterparts did last month, the FDA has recommended continued use of the Gilenya multiple sclerosis pill sold by Novartis, but did say the drug should carry stronger warnings about heart risks and that some patients should undergo increased monitoring. The move was largely expected after the European Medicines Agency issued a similar alert, despite arguments by a non-profit safety watchdog that further restrictions are needed.

    Although cardiovascular risks were known at the time of approval two years ago, the regulatory review was undertaken in response to patient deaths, including an unexplained sudden death of one person within 24 hours after taking Gilenya for the first time (back story). The back-to-back regulatory decisions will likely ease investor concerns over the prospects for the pill, which Novartis continues to hope will generate blockbuster sales.

    The drugmaker has been counting on Gilenya to help compensate for the loss of patent protection on such big-selling drugs as the Diovan blood pressure pill. Meanwhile, competition in the MS market looms as Biogen Idec plans to seek FDA approval for an oral pill shortly.

    Last month, Novartis execs maintained that between just 4 percent and 7 percent of MS patients may be at risk for the sort of cardiovascular issues that prompted the FDA and EMA reviews.

    The FDA advised doctors not to prescribe Gilenya to patients with a history of cardiovascular and cerebrovascular disease or those on heart-rate lowering meds. If Gilenya is considered needed, heart rates should be monitored at least overnight following the first dose. But all patients should have an electrocardiogram and blood pressure measured before a first dose and for six hours after treatment. And continuous ECG monitoring is recommended.

    In reaching its decision, the FDA noted data show the maximum heart rate lowering effect usually occurs within six hours of the first dose, but the maximum effect may occur as late as 20 hours after the first dose in some patients (read the FDA statement and data summary here and the EMA report here). Despite these warnings, the FDA did not suggest that all Gilenya patients should be monitored overnight, which Wall Street viewed as a worst-case scenario because such a step would likely have inhibited more widespread usage.

    Last month, the Institute for Safe Medicine Practices called on the agency to substantially restrict Gilenya usage and enhance patient monitoring after reviewing adverse events that were reported to the FDA during the second quarter of 2011, shortly after the drug was approved. The watchdog group also criticized the agency for placing Gilenya in its fast-track approval process.

    Source: Pharmalot ©2012 UBM Canon Pharmaceutical Media Group (15/05/12)

    New MS oral drug, Gilenya, still not available in Eire

    GilenyaA new oral drug to treat the symptoms of Multiple Sclerosis, which has been licensed and deemed cost-effective here, remains unavailable to sufferers.

    The final stage in the HSE’s process before which it could be prescribed was “neither fair nor transparent”, a leading neurologist has said.

    Prof Orla Hardiman, consultant neurologist at Beaumont Hospital in Dublin, said the MS drug Gilenya had been assessed and deemed cost-effective at the National Centre for Pharmacoeconomics (NCPE) in St James’s Hospital, Dublin.

    Any pharmacological company seeking to have a new drug reimbursed for patients under the Community Drugs Schemes must first have its cost-effectiveness assessed by the centre.

    Speaking on RTÉ radio yesterday, Prof Hardiman said the new drug was the first of a new generation of MS drugs that could be taken orally. “It looks like it’s going to be very effective.”

    It would be prescribed to people already on injectable drugs for relapsing and remitting MS and for whom the drugs were not working effectively. Prof Hardiman said about 1,000 of the 6,000 or so MS sufferers here would benefit.

    “It has been approved across Europe actually and we are one of the last countries where funding is a problem,” she said.

    “There is a kind of a go-slow across the sector in terms of anything that might cost money.”

    She said Gilenya would replace another drug so the extra cost would be “minimal”. There had to be a system that was “fair and transparent”.

    “But the point at which drugs become available, when they reach the queue post the analysis, that’s not transparent . . . It’s not clear how the drug progresses from the top of the list into becoming available, and that’s a thing of grave concern to many of us in practice.”

    There seemed to be another process, “whereby if you have an advocate, if you have a condition that generates a certain amount of sympathy through advocacy, that that’s the system to get the drug through”.

    A spokeswoman for the HSE said there were a number of drugs, including for the treatment of MS, going through the process of approval. She said the assessment process was “well-established and has been in place for a number of years”.

    Source: Irishtimes.com © 2012 irishtimes.com (08/05/12)

    Gilenya positive benefit-risk profile following CHMP review, Europe

    GilenyaAccording to Novartis, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has confirmed a positive benefit-risk profile for their once-a-day orally administered drug Gilenya (fingolimod).

    In agreement with the CHMP, the company has updated their E.U. product information after the Article 20 review the EMA announced in January 2012, in order to offer further guidance to healthcare providers who want to initiate using Gilenya in MS patients. In the E.U., Gilenya is approved for the treatment of individuals with highly active relapsing-remitting MS, regardless of treatment with beta interferon, or in patients with rapidly evolving severe relapsing-remitting MS.

    Gilenya is the first in a new class of sphingosine 1-phosphate receptor (S1PR) modulating compounds and has demonstrated superior efficacy over Avonex (interferon-beta-1a IM), a commonly prescribed treatment. In a pivotal head-to-head trial in patients with relapsing- remitting multiple sclerosis at one year, Gilenya achieved both its primary and secondary endpoints, i.e. a 52% relative reduction of the yearly relapse rate and a 40% relative reduction in the rate of brain atrophy.

    A recent sub-analysis at one year revealed that in comparison to interferon-beta-1a (IM), Gilenya achieved a 61% relative reduction in the rate of yearly relapses in patient subgroups with highly active relapsing-remitting MS patients who previously received interferon therapy.

    Gilenya has no label restrictions specific to treatment duration and was generally well tolerated during clinical trials with a manageable safety profile. Since February 2012, over 36,000 patients have been treated with Gilenya in clinical trials and in the post-marketing setting, which confirms Gilenya's long- term effectiveness and safety profile. 2,400 patients have been taking the drug for longer than two years.

    The most common adverse events reported were cough, diarrhea, headache, liver enzyme elevations and back pain, whilst other side effects included a mild increase in blood pressure, transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, macular edema, and mild bronchoconstriction.

    Overall, the rates of infections, including serious events were similar in all treatment groups. However, patients treated with Gilenya reported a slightly higher rate of respiratory tract infections that consisted mainly of bronchitis. There were only a small number of reported malignancies in the clinical trial, with similar rates between the Gilenya and control groups.

    All MS patients who start Gilenya therapy in the E.U. should have an electrocardiogram (ECG) and a blood pressure measurement before taking the first dose and after the six-hour first-dose monitoring period, in addition to having hourly measurements of their blood pressure and heart rate taken during this period. It is also recommended that patients' with symptomatic bradycardia (low heart rate) receive continuous ECG monitoring for at least six hours after taking the first dose, with those who had ECG abnormalities during the 6-hour monitoring period requiring extended monitoring, as well as those who had very low or their lowest measured heart rate at the six-hour time point.

    The recommended label update in the E.U. also warns that Gilenya should not be used in patients who may be less tolerant of or tend to have a higher risk of developing a substantially slower or abnormal heart rate, due to certain underlying conditions or other medications taken at the same time.

    Previous clinical trials have revealed insufficient knowledge about using Gilenya in such patients, but if these patients are to be treated, they would require overnight monitoring.

    Patients who are already taking Gilenya are not affected by the new first-dose observation recommendations. However, should therapy be interrupted for longer than two weeks, patients should undergo the new recommended monitoring upon re-initiation of the treatment. Patients should not make any changes to any medications, including Gilenya, without first consulting with their doctor.

    David Epstein, Division Head of Novartis Pharmaceuticals declares:

    "We believe that Gilenya is a valuable treatment option for many patients with relapsing remitting MS, and we welcome the confirmation of the positive benefit-risk profile of the drug which also supports our continued belief of the blockbuster potential of Gilenya. MS is a devastating chronic disease that affects more than 2.1 million people worldwide, and patients need effective treatment options."

    The EU will review the CHMP labeling recommendations, with a final decision expected in June 2012. In terms of any changes to the EU product information, Novartis will notify EU physicians via a Direct Healthcare Provider Communication (DHPC) by end of April 2012.

    Source: Medical News Today © MediLexicon International Ltd 2004-2012 (24/04/12)

    Updated prescribing data in USA for oral MS therapy Gilenya

    GilenyaNovartis says it has updated prescribing data for multiple sclerosis therapy Gilenya (Fingolimod) after a review by the Food and Drug Administration (FDA). The prescribing information includes new parameters for selecting patients, based on specific cardiovascular considerations. Novartis emphasizes that the prescribing information does not alter treatment management of MS patients currently taking Gilenya, unless treatment is stopped, and then a need to reinitiate occurs.

    Gilenya (fingolimod) is an oral medication, taken once a day, which has been proven to reduce relapse numbers, as well as slowing down disability progression in patients with relapsing forms of MS (multiple sclerosis). Fingolimod, a sphingosine 1-phosphate receptor modulator, sequesters lymphocytes in lymph nodes, stopping them from becoming involved in an autoimmune reaction.

    The prescribing information (PI) changes follow an FDA review, announced in December 2011.

    The updated PI advises doctors to have patients who are being considered for Gilenya therapy to undergo an ECG (electrocardiogram) beforehand, and at the end of the six-hour observation period, as well as hourly heart rate and blood pressure measurements.

    Novartis reiterates that patients currently already on Gilenya treatment are not affected by this update, unless they came off the medication and the doctor is considering restarting Gilenya therapy.

    Novartis explains that new recommendations have been issued on how to reinitiate Gilenya therapy if it had been discontinued. If you are an MS patient, you should not make any changes to your current medication regime, even if you are on Gilenya, without checking with your doctor first.

    The prescribing information also recommends that those with some pre-existing heart conditions, as well as patients on concomitant heart rate lowering drugs, be checked by a doctor before going on the first dose of Gilenya. If these patients then do go on to receiving Gilenya, they should be monitored overnight with continuous ECG in a clinic after the first dose. Novartis wrote on its US website today "Experience with the use of Gilenya in such patients is limited."

    Gilenya contraindications

    The term contraindications refers to when a treatment is inadvisable. The updated PI includes new contraindications.

    Gilenya therapy is contraindicated in those with the presence of, or a history of:
    Heart attack (during the last six months)

    Stroke (during the last six months)

    2nd and 3rd degree AV (atrioventricular) block

    Other severe cardiac rhythm disturbances

    As well as those taking certain anti-arrhythmic medications
    Novartis informs that 36,000 patients globally have been treated with Gilenya in human studies in the post-marketing setting (as of February 2012).

    Barry Singer, MD, Director, MS Center for Innovations in Care, Missouri Baptist Medical Center, said:

    "Gilenya represents an important treatment option for relapsing forms of MS. Choosing appropriate patients for Gilenya therapy and patient safety is essential."

    Novartis says it will be informing US doctors and patients through established field force and patient communication channels.

    Source: Medical News Today MediLexicon International Ltd © 2004-2012 (23/04/12)

    EU supports oral MS drug, Gilenya, with stronger warning

    Gilenya European regulators have endorsed the continued use of Novartis AG's multiple sclerosis pill Gilenya, one of the Swiss firm's top new drug hopes, but said on Friday the drug needed to carry stronger warnings on heart risks.

    Novartis said the decision meant the drug remained on-track to be a "blockbuster" - one with annual sales above $1 billion.

    Prospects for Gilenya, the first multiple sclerosis (MS) pill of its kind, have been clouded by reports of its association with serious heart problems.

    The European Medicines Agency (EMA), which had initially aimed to give an update on Gilenya last month, said doctors should not prescribe it to patients with a history of cardiovascular and cerebrovascular disease or those on heart-rate lowering medication.

    If treatment with Gilenya was considered necessary in these patients, however, their heart activity should be monitored at least overnight following the first dose of the drug, it said.

    All patients getting the drug should have an electrocardiogram (ECG) and a blood pressure measurement prior to the first dose and after a six-hour initial period, during which continuous ECG monitoring is recommended.

    A committee of EMA experts said the possible risk of heart problems could be limited by these stronger warnings.

    "With these risk-minimization measures in place, the committee concludes that the benefits of Gilenya continue to outweigh the risks," the agency said in a statement.

    David Epstein, head of Novartis Pharmaceuticals, said he welcomed EMA's confirmation of Gilenya's positive benefit-risk profile "which also supports our continued belief of the blockbuster potential of Gilenya".

    WORST CASE AVOIDED

    Analysts said there would be relief that the drug had not been pulled off the market but safety concerns would linger.

    Martin Voegtli at Kepler Capital Markets said the strengthened warnings against prescribing in patients with cardiovascular risk factors would restrict the patient population and hit sales forecasts.

    But Tim Race of Deutsche Bank viewed the EMA verdict more positively, since it ruled out the worse-case scenarios of either product removal or overnight monitoring for all patients.

    Shares in Novartis were 0.6 percent higher at 1000 GMT, broadly in line with the European drugs sector.

    Gilenya is still seen by analysts as a big seller, with annual sales of $1.7 billion by 2015, according to consensus forecasts collected by Thomson Reuters Pharma. But that is down on the $2.2 billion forecast in late 2011, due to safety fears.

    In recent months, doctors have grown more cautious about the drug following reports of heart problems in some patients and the death of one person in the United States within 24 hours of starting treatment.

    Those cases prompted the EMA to start its review in January, when it first advised doctors to continuously monitor patients for six hours after giving them a first dose. The U.S. Food and Drug Administration (FDA) is also looking into the drug.

    Gilenya represents a significant change in MS treatment, since existing medicines like beta interferons and Elan and Biogen Idec's Tysabri must be injected.

    Rival oral MS treatments in development include BG-12 from Biogen, teriflunomide from Sanofi and laquinimod from Teva.

    Source: Reuters (c) Thomson Reuters 2012 (20/04/12)

    Extension study data for Gilenya® shows patients successfully treated for up to 7 years

    GilenyaNew data will be presented at the 64th annual meeting of the American Academy of Neurology (AAN) that support the efficacy and safety profile of Gilenya® (fingolimod), the only oral therapy approved to treat relapsing forms of multiple sclerosis (MS).

    "The data being presented reinforce our confidence in the sustained efficacy and safety profile of Gilenya," said David Epstein, Head of the Pharmaceuticals Division of Novartis Pharma AG.

    New data presented on long-term efficacy and safety profile of Gilenya.

    New results from the phase III FREEDOMS extension study showed significant improvements in clinical and MRI measures in patients who switched from placebo (administered during the 24-month core study) to Gilenya (administered during the extension).

    1033 patients completed the two-year, double-blind FREEDOMS 24 month core study. Of these, 90% of patients completed 3 years observation and 45% were followed for 4 years in this study before being transferred to the umbrella follow-up study (LONGTERMS).

    Patients who switched from placebo to Gilenya saw a 55% decrease in their annualized relapse rate (ARR) during the extension phase compared to the core phase (ARR [core] = 0. 29 vs. ARR [extension] 0.13; p<0.001). Significantly more patients on continuous fingolimod treatment compared to those first randomized to placebo remained relapse-free (59% vs. 37%) and free from three-month confirmed disability progression (74 % vs. 66 %).

    MRI measures continued to show significant effects in favor of fingolimod treatment, including a significantly reduced rate of brain atrophy in the patients treated continuously as compared to switch patients (mean (%) change in brain volume -1.67% vs. -2.24%; p = 0.001) at the end of the observation. In the core FREEDOMS study, Gilenya reduced the rate of brain atrophy by 38% versus placebo at two years (0-24 months).

    The phase III FREEDOMS extension showed a safety profile consistent with that of the pivotal phase III trials. The most common adverse events were nasopharyngitis, low lymphocyte counts (to be expected from the mode of action), upper respiratory tract infections and influenza.

    "This extension study confirms the efficacy shown in the published phase III studies and supports the positive long term impact of continuous treatment. The favorable longer term safety profile is consistent with results from the phase III studies," said Ludwig Kappos, Department of Neurology, University of Basel, Switzerland. "These observations in a large group of patients, now for four and more years, confirm that fingolimod is a valuable treatment option for patients with relapsing remitting MS."

    Additionally, new data for up to 7 years of treatment from the phase II extension study demonstrated patients treated with Gilenya (n=122) had sustained low MRI and clinical disease activity. The overall ARR for the continuous Gilenya treatment group was 0.16, which can be expressed as one relapse every 6 years. Of patients on continuous Gilenya treatment since study start and who completed the long-term extension, over half had remained free of relapses throughout the study.

    The phase III registration program for Gilenya included the two-year FREEDOMS study and a head-to-head study in which Gilenya showed a 52% relative reduction in annualized relapse rate (primary endpoint) compared to Avonex® (interferon-beta-1a IM), a commonly prescribed treatment, at one year.

    Low incidence of ECG abnormalities and symptomatic heart rate reduction at treatment initiation in 2,400 patient FIRST Study

    New data from the large, 4-month, open-label, single-arm multi-center FIRST study demonstrate an overall low incidence of significant first dose bradycardia [i.e. 1.3% of patients experienced bradycardia < 45 bmp and no patient experienced a heart rate <30 bpm] and conduction abnormalities at treatment initiation with Gilenya. Importantly, this study provides data on continuous ECG monitoring by ambulatory Holter Electrocardiogram (ECG) for six hours following the administration of the first dose to identify any heart rate or ECG abnormalities. Results from more than 2,400 patients showed the incidence of Mobitz I second degree atrioventricular blocks (AVBs) was 1.4% at the post-dose Holter ECG for 6 hours after administration, and the incidence of Mobitz II second degree, or 2:1 AVBs was 0.5%. The short-term safety profile of Gilenya in the FIRST study was generally consistent with that observed in the phase III studies. This included the low incidence of the known cardiac effects of fingolimod at treatment initiation (typically transient decreases in heart rate and generally asymptomatic atrioventricular blocks).

    Source: Market Watch Copyright © 2012 MarketWatch, Inc (20/04/12)

    EU to rule on safety of Novartis's Gilenya MS pill

    Gilenya Europe's drug regulator will likely allow Novartis AG's Gilenya to stay on the market without asking for much stricter safety warnings as it concludes a review of the multiple sclerosis pill initiated after reports of heart problems and the death of a patient who took the drug.

    The regulator's decision could come as early as Thursday, said the London-based European Medicines Agency, the body responsible for licensing Gilenya in Europe a year ago.

    The EMA launched the in-depth study in January to assess Gilenya's benefits and risks, and recommended doctors closely monitor the hearts of patients after they have been given the first dose of the drug.

    The review was prompted by reports of heart problems in patients taking Gilenya, as well as the November death of a 59-year-old patient in the U.S. less than 24 hours after taking the first dose of the drug. The EMA had aimed to give an update on Gilenya's safety in March, but delayed its decision by about a month as it finalises its review.

    The U.S. Food and Drug Administration also announced a safety review of Gilenya in December, saying there wasn't a clear cause of the patient's death. There is no time frame for the FDA's review.

    Analysts say it is unlikely that Gilenya will be withdrawn from the market or that the EMA will request changes to the drug's label, which already warns of cardiovascular side effects.

    "This is a drug that has already been well-studied during clinical trials, and side effects have already showed up," said David Kaegi, an analyst with Bank Sarasin in Zurich. "I am optimistic that nothing will change--the drug has been on the market for a while already," said Kaegi, who has a buy rating on Novartis.

    The Swiss company said in a statement that it continues to believe that the drug provides a benefit for patients with relapsing-remitting multiple sclerosis and added that it is "engaging with the EMA, other health authorities and the MS community with the goal of ensuring that appropriate patients will have access to Gilenya."

    Gilenya is one of Novartis' most promising new drugs and has looked like becoming one of the leading treatments in the multibillion-dollar market for treating MS due to its easy use. Unlike traditional MS treatments that are given via infusions or injections, Gilenya is administered in pill form--the only one to date.

    Gilenya has been available in the European Union since March 2011 for treating relapsing-remitting MS, the most common type of the disease, in patients who have failed to respond to a beta-interferon or whose condition is severe and worsening rapidly. The drug was approved in the U.S. in 2010.

    Source: Market Watch Copyright © 2012 MarketWatch, Inc (18/04/12)

    Oral MS drug Gilenya patient develops rare brain disease

    GilenyaNovartis AG said a patient treated with its multiple-sclerosis pill Gilenya has been diagnosed with a rare and often fatal brain disease.

    The Swiss drug maker said the patient had been previously treated with another MS drug, Tysabri, co-marketed by Biogen Idec Inc. and Elan Corp. PLC, which has been already associated with progressive multifocal leukoencephalopathy.

    "The current assessment is that Tysabri is the drug most likely associated with this case of PML," Novartis said in a statement. "However, a contribution of Gilenya to the evolution of this case cannot be excluded."

    The development comes at a critical time for Novartis's Gilenya, a potential blockbuster product whose safety profile has recently come into question after the death of one person in the U.S. last autumn within 24 hours of starting treatment.

    The European Medicines Agency, the body responsible for licensing Gilenya in Europe a year ago, is expected to issue a decision on the safety of the medicine following an in-depth review next week.

    Novartis said it doesn't know of any confirmed PML cases in patients treated with Gilenya, also known as fingolimod, who hadn't previously been treated with Tysabri.

    Novartis statement: Gilenya (fingolimod) safety information update

    April 13, 2012

    Novartis has been informed of a progressive multifocal leukoencephalopathy (PML) diagnosis in a JCV antibody positive MS patient who had previously been treated with Tysabri® (natalizumab) for approximately three and a half years prior to initiating treatment with Gilenya (fingolimod).

    There is a known risk of PML associated with natalizumab treatment, especially in patients who are JCV antibody positive and have been treated with natalizumab for more than two years. The current assessment is that natalizumab is the drug most likely associated with this case of PML. However, a contribution of Gilenya to the evolution of this case cannot be excluded.

    This is the first reported PML case in approximately 36,000 fingolimod-treated patients, of whom approximately 2,400 were treated for more than two years and approximately 500 were treated for more than four years. There is currently no confirmed case of PML reported to Novartis in a fingolimod-treated patient without
    previous natalizumab treatment.

    Details on the case are being submitted to health authorities according to regulations as they become available.

    Novartis believes Gilenya is a benefit for appropriate MS patients when used in accordance with approved labeling.

    Source: 4 - Traders Copyright © 2012 Surperformance & Novartis (13/04/12)

    Watchdog group wants restrictions on Gilenya for MS

    GilenyaThe Institute for Safe Medication Practices (ISMP) is urging the US Food and Drug Administration (FDA) to put restrictions on the use of fingolimod (Gilenya, Novartis) in patients with multiple sclerosis (MS), owing to postmarketing adverse event reports.

    "Problems of widespread toxicity that were already evident in clinical testing of fingolimod are now producing strong signals in the postmarket adverse event data," the nonprofit group says in a new report.

    The ISMP sifted through adverse event reports related to fingolimod that were reported via the FDA's MedWatch program in the second quarter of 2011.

    "Notable" among them, they say, are 68 reports of serious infections, including eye, skin, urinary, and upper respiratory tract infections. Sixty eye-related side effects were also reported, including macular edema and vision disruptions.

    In 14 cases, patients taking the drug experienced more generalised symptoms, including heart-rhythm problems and liver damage, the report states. Possible complications of these vascular adverse effects include syncope (16 cases), bradycardia (27 cases), and peripheral edema (10 cases), the report notes.

    "The signals for fingolimod raise the question whether enough is known about the troubling safety profile of this drug to justify its continued unrestricted use. Its array of known adverse effects on the eyes, heart, liver, and immune response, as well as patient deaths in testing and postmarket surveillance, raise the question about its long-term use at the current approved dose," the ISMP concludes.

    The report urges the FDA and manufacturer to "consider substantial restrictions on its use and enhanced monitoring" of patients using it.

    Drug Currently Under Review

    Fingolimod is the first oral agent for the treatment of MS. It was approved by the FDA in September 2010 and by the European Medicines Agency (EMA) in March 2011. However, the occurrence of the death of a patient soon after receiving a first dose of fingolimod in December 2011 has both the FDA and the EMA looking closely again at the risks and potential benefits of fingolimod. Those reviews are still under way.

    Asked for reaction to the ISMP report, Timothy Coetzee, MD, Chief Research Officer of the National MS Society, told Medscape Medical News: "The FDA has already announced that it is reviewing the safety profile of Gilenya. We are following the matter closely and waiting to see the results of their investigation. Therefore, we feel that it would be somewhat premature to comment in advance of the release of the FDA findings, which we anticipate will be forthcoming soon."

    The ISMP report is available online.

    Source: Medscape Copyright © 1994-2012 by WebMD LLC (11/04/12)

    Relapse and disability outcomes in patients with MS treated with fingolimod

    Gilenya Subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study

    Summary

    Background
    Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics.

    Methods
    We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978.

    Findings
    Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54—1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16—0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53—1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm3 or less to 0·32 (0·14—0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21—0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18—0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29—1·62; p=0·39) and 0·73 (0·25—2·07; p=0·55), respectively, in these groups.

    Interpretation
    Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod.

    Funding
    Novartis.

    Virginia Devonshire MD, Eva Havrdova MD, Prof Ernst Wilhelm Radue MD, Paul O'Connor MD, Lixin Zhang-Auberson MD, Catherine Agoropoulou PhD, Dieter Adrian Häring PhD, Gordon Francis MD, Prof Ludwig Kappos MD

    Source: The Lancet Neurology doi:10.1016/S1474-4422(12)70056-X Copyright © 2012 Elsevier Limited (10/04/12)

    Calls for oral MS treatment, Gilenya, to be made available in Ireland

    GilenyaThe Multiple Sclerosis Society of Ireland (MS Ireland) has called on the government to make available in Ireland a controversial drug that it believes would much more effectively treat some forms of the disease.

    The call, echoed by the drug’s manufacturer, follows the decision by the National Institute for Health and Clinical Excellence (NICE) in the UK to recommend that the drug, fingolimod - known by its brand name Gilenya - , be available on the National Health Service (NHS) for some patients with a form of MS.

    It comes less than two months after a European Agency opened an investigation in to whether the medicine played a role in the deaths of at least 11 patients. The European Medicines Agency (EMA) is due to give an update on the safety of the medicine next month, the Wall Street Journal reports.

    The Department of Health said that the matter was being considered by the Health Service Executive (HSE) which said that it expects “a significant budget impact with this product” if its use in treatment could be reimbursed under the High Tech Drug Scheme as MS Ireland wants.

    The manufacturer, Novartis, claims that the drug is twice as effective as conventional treatment for the disease which affects some 8,000 people in Ireland. The drug itself was authorised by the Irish Medicines Board exactly a year ago and there has been no updated guidance in relation to it since.

    Multiple Sclerosis

    MS is an autoimmune disease which affects the brain and spinal cord. It generally affects women more than men and is more likely to affect people who have a family history of the disease.

    NICE said that the treatment was a “valuable, innovative and cost-effective therapy” for dealing with highly active relapsing-remitting MS which is characterised by periods where symptoms – which include numbness, tingling, blurred vision, balance problems and muscle weakness – worsen and then improve.

    This particular oral medication, manufactured by Novartis, will now likely be available to people in England and Wales through the NHS. Novartis said that steps are also being taken by healthcare systems in most EU countries to make it available. Much may hinge on the updated guidance of the EMA next month following its investigation.

    However, Novartis claimed that the Department of Health had decided not to make it available to Irish patients despite it being given a positive review by the National Centre for Pharmacoeconomics (NCPE) last year.

    “Novartis has submitted a proposed price as part of the high tech application process. At the price submitted the NCPE considered Gilenya ‘a cost effective therapy for the treatment of relapsing remitting multiple sclerosis patients in the Irish healthcare setting’,” a statement said.

    “The price is not out of line with other European countries already reimbursed, and is within the range of disease modifying therapies in the Irish market (including VAT).”

    ‘Significant budget impact’

    However the HSE said in a statement: “The HSE has approved – and continues to approve – all medicines for which it believes there is robust evidence that they are cost effective and budget neutral.

    The HSE expects a significant budget impact with this product and is currently considering how new medicines can be introduced into clinical care pathways as and when HSE resources become available.

    The HSE is working to ensure that all appropriate arrangements and controls are in place to support optimal use and that best value is achieved.”

    MS Ireland called on the the government to make it available for patients on long-term treatment plans in Ireland.

    “MS Ireland believes that this disease modifying therapy would be an important addition to the choice of treatments available to people with MS,” chief executive Ava Battles said.

    “It is not acceptable that people with MS in Ireland have less choice of treatments that are capable of modifying the progress of their illness than counterparts in Britain and other EU countries.

    “We have written to the Minister and the Department on this matter and anticipate it will be treated as a matter of urgency.”

    Source: The Journal.ie © Journal Media Ltd. 2012 (19/03/12)

    Scottish MS Society will challenge Gilenya decision

    GilenyaMultiple sclerosis campaigners will step up their bid to persuade Scotland’s medicines regulator to overturn its decision to reject a new treatment for the disease.

    The Multiple Sclerosis Society Scotland yesterday said it would be writing to the Scottish Medicines Consortium (SMC) to try to convince the regulator it should approve the use of fingolimod.

    Pressure mounted on the SMC after its equivalent body south of the Border, the National Institute for Health and Clinical Excellence (NICE), approved the drug in England and Wales.

    The production of draft NICE guidance recommending the use of fingolimod has raised the prospect of a north/south divide opening up when it comes to treating the disease.

    Yesterday Craig Wilkie, MSSS head of policy, said that the charity would also be lobbying MSPs on the issue.

    A SMC spokesman said: “We are always happy to hear interest groups’ points of view and we would be happy to hear from the MSSS.”

    Source: Scotsman.com © 2012 Johnston Publishing Ltd (19/03/12)

    NICE backs new oral MS drug, Gilenya

    GilenyaNovartis's multiple sclerosis pill Gilenya has been recommended for use on the U.K.'s publicly-funded National Health Service after a change of heart by the country's healthcare cost-effectiveness watchdog.

    Friday's verdict from the National Institute for Health and Clinical Excellence, whose opinions are also watched closely in other countries, is welcome news for the Swiss company's potential blockbuster product whose safety profile has come into question recently.

    NICE said it changed its mind on the medicine, also knows as fingolimod, after Novartis provided more information and analyses on the pill, allowing the British agency to compare the medicine's performance with existing injectable MS therapies.

    "The latest draft guidance from our committee recommends the NHS-use of fingolimod for a specific group of adults who have highly active relapsing-remitting multiple sclerosis," said Carole Longson director of the Health Technology Evaluation Centre at NICE.

    "Following new information provided during the consultation, the analyses show that for these people, treatment with fingolimod will be a cost effective option for the NHS in this group of people with multiple sclerosis, if Novartis provides the drug at a discounted price, as proposed in its patient access scheme."

    The Swiss drug maker applauded the move by NICE, adding: "Novartis believes that Gilenya is generally a highly efficacious and cost-effective treatment for patients with relapsing-remitting multiple-sclerosis and remains committed to engaging with reimbursement authorities with the goal of ensuring that appropriate patients will have access to the treatment."

    Gilenya was licensed in Europe a year ago and has now been approved in more than 55 countries, with more than 25,000 patients having been prescribed it so far.

    But EU regulators are conducting a review of the MS pill in light of reports of heart problems in some patients and the death of one person in the U.S. last autumn within 24 hours of starting treatment.

    Campaigners have urged Scotland's medicines regulator to reverse a decision to reject a new drug for patients with MS after the equivalent body south of the Border approved the same pill.

    The Scottish Medicines Consortium (SMC) said the makers of fingolimod, the first tablet treatment for MS, did not show it was good value for money and the body chose not to recommend it for use on the NHS.

    But now the National Institute for Health and Clinical Excellence (Nice), which rules on drugs in England and Wales, has revealed draft guidance recommending fingolimod, whose brand name is Gilenya, for prescription on the NHS for some patients with relapsing-remitting multiple sclerosis.

    It raises the prospect of a north-south divide for patients, even although Scotland suffers the highest rate of MS in the world, with 10,500 people diagnosed with the condition.

    Dr Belinda Weller, a neurologist at the Western General in Edinburgh who led the Scottish clinical trial of fingolimod, said: "It's going to be quite hard for our patients in Scotland who are aware that people over the Border are going to be having access to this.

    "But I'm also hopeful that with that decision there will be more pressure on the regulatory body in Scotland to reconsider the decision."

    Fingolimod can help reduce the number of relapses in adults with relapsing-remitting multiple sclerosis.

    A spokesman for the SMC said: "Sometimes SMC has to make very difficult decisions and we are acutely aware that our decisions have an impact on patients."

    Source: Market Watch Copyright © 2012 MarketWatch, Inc. & Herald Scotland © Copyright 2012 Herald & Times Group(16/03/12)

    Scottish Medicines Consortium (SMC) turns down oral MS drug Gilenya

    GilenyaThe Scottish Medicines Consortium (SMC) yesterday rejected recommending the prescribing of the first oral pill for sufferers of multiple sclerosis in Scotland.

    The SMC said that, while the manufacturers of Gilenya, had provided evidence about it helping to reduce relapse rates, they had not compared it with another drug commonly used in Scotland.

    It added that evidence showed that starting treatment with Fingolimod could cause a short-term decrease in heart rate and swelling of the centre of the retina inside the eye, and that about half the patients developed infections. The SMC concluded that it did not consider the drug to be “value for money” for the NHS in Scotland.

    Novartis launched Fingolimod in the UK in April 2011, but the National Institute for Health and Clinical Excellence (NICE) recommended in December that Fingolimod was not a cost effective treatment for the NHS in England and Wales to provide.

    Fingolimod works by acting on certain types of white blood cells (lymphocytes) which are involved in the immune attack that characterises MS, which results in the destruction of myelin, the substance covering and protecting nerves in the central nervous system.

    It effectively reduces the number of lymphocytes circulating in the blood, resulting in reduced immune attack on nerve cells in the brain and spinal cord.

    In addition, there is evidence that Fingolimod may have a direct effect on nerve cell damage and enhance re-myelination

    In March last year, the European Medicines Agency (EMA) approved Fingolimod as a second-line treatment to be used if people continue to have relapses or if their relapse rate has increased despite a year’s treatment with one of the first line drugs.

    It can also be used with people with rapidly evolving severe relapsing remitting MS – two or more relapses a year.

    Scotland has one of the highest rates of MS in the world, with 10,500 diagnosed cases. The debilitating disease attacks the central nervous system, with current treatment consisting of intermuscular injections or infusion therapy.

    Last night, Dr Belinda Weller, a consultant neurologist who took part in clinical trials, said: “Today’s decision is very disappointing, as we’ve waited a long time for the first pill to treat this disabling condition effectively.”

    Novartis has asked the SMC for further clarification.

    Source: The Scotsman © 2012 Johnston Publishing Ltd (13/03/12)

    Scottish decision due on oral MS drug Gilenya

    GilenyaThe Scottish Medicines Consortium (SMC) will decide on today if it will recommend the prescribing of the first oral pill for the treatment of Multiple Sclerosis in Scotland.

    Currently, suffers face painful daily injections deep into the muscle or having to travel to hospital for infusion therapy to try to control the disease, which damages the central nervous system, causing a range of disabilities such as problems with co-ordination, speech and vision.

    But this treatment could be consigned to the past for thousands of sufferers north of the Border if the SMC gives the go-ahead for the drug Gilenya, the world’s first licensed pill for the condition.

    Sufferers would instead take a daily pill estimated to halve the chances of a relapse.

    Scotland has one of the highest rates MS in the world with around 10,500 cases diagnosed. Research indicates genetic factors may play a role. The disease is mostly diagnosed in people aged between the ages of 20-40 and affects almost twice as many women than men.

    The drug is targeted at those suffering the most common form of the disease which is relapsing and remitting, characterised by exacerbations or flare-ups interspersed with remission.

    Nick Rijke, director of policy and research at the MS Society, said: “We’re expecting the Scottish Medicines Consortium to make their final decision on Fingolimod imminently. This treatment has the potential to benefit thousands of people living with MS in Scotland. We would therefore like to see it become available to all those who could benefit.”

    Fingolimod, also known as “Gilenya”, is an immunosuppressant which works by keeping lymphocytes (a type of immune cell) sequestered in the lymph nodes. This reduces the number of lymphocytes reaching the brain and spinal cord where they might attack the coating of the nerve cells.

    The annual cost of treating one patient with Fingolimod is estimated at £19,665, compared with £21,257 for Natalizumab, used in monthly infusions. Relapses requiring hospitalisation cost the NHS more than £3,000 per episode.

    The drug, already approved in 35 countries, including the US, Canada and Germany, was licensed in the UK last April meaning health officials recognised that it was “relatively safe and did something beneficial for a particular ailment”.

    However, the vital decision for sufferers in Scotland, to be announced on Monday afternoon, is whether Fingolimod can be prescribed across all health boards in Scotland making it routinely available to patients.

    Currently, clinicians can request funding on a case-by-case basis for individual patients subject to approval by their hospital trust.

    A limited number of patients in the UK, chosen to be part of pilot studies, have also had access to Fingolimod.

    A spokesman for the SMC said: “We can confirm that our decision on Fingolimod will be announced on Monday afternoon.”

    The National Institute for Health and Clinical Excellence, the medicines regulatory body for England, is due to announce its decision on the drug, the following week.

    Source: The Scotsman © 2012 Johnston Publishing Ltd (12/03/12)

    Deaths hit oral MS drug, Gilenya

    GilenyaNovartis AG's Gilenya multiple sclerosis pill lost market share for the first time in January, following the deaths of some patients soon after taking the first pill available for the disease in the United States.

    Gilenya's share of the U.S. market for so-called immunomodulatory drugs against MS fell to 6.1 percent from 6.2 percent in December, according to data from Wolters Kluwer NV, a market research company. The decline was the first after 15 months of growth, at a median of 15 percent a month, since the treatment received U.S. regulatory approval in September 2010.

    The Food and Drug Administration and the European Medicines Agency are investigating 11 deaths among Gilenya patients. In the past month, analysts have cut their forecasts for peak sales of Gilenya by 10 percent to $2.1 billion in 2016, according to the average of six estimates compiled by Bloomberg.

    The deaths have "made me a little more cautious," said Aaron Miller, chief medical officer of the U.S. National Multiple Sclerosis Society, and a medical director at Mount Sinai Hospital in New York. "I am not somebody who has recommended Gilenya as a first-line drug prior to these reports, and I'm still not recommending it as a first-line drug until we get more data."

    Source: SF Gate © 2012 Hearst Communications Inc (07/03/12)

    Safety of oral MS pill Gilenya reviewed after deaths

    GilenyaHealth Canada is reviewing a new multiple sclerosis drug that has been linked to 11 deaths.

    There have been no reports of deaths in Canada of people taking the Novartis drug, which is sold under the brand name Gilenya.

    Health Canada says that of the deaths outside the country, it's not clear whether the drug itself caused them, or whether other factors played a role.

    Both the U.S. Food and Drug Administration and the European Medicines Agency had earlier announced that they were undertaking reviews of Gilenya.

    Gilenya is used for treatment of relapsing-remitting MS to reduce the frequency of attacks and to delay physical disability; it is generally recommended when other MS treatments have not been effective or cannot be tolerated.

    At the time the drug was authorized, it was known that certain types of heart rhythm disturbances can be seen with Gilenya use and the Canadian labelling contains several warnings to this effect.

    But Health Canada says it felt the drug's benefits outweighed its risks.

    Of the 11 reported deaths, four involved serious heart-related events — three were heart attacks and another a disturbance of the heart rhythm. The seven other deaths are unexplained, including one from the United States involving a person who died within 24 hours of his or her first dose of Gilenya.

    Health Canada says people taking the drug should not discontinue it without consulting their doctor. But anyone on the drug who is feeling symptoms of heart disease — including chest pain, slow or irregular heartbeat, or dizziness — should seek medical care.

    The department says doctors should monitor patients on the drug closely. Blood pressure should be checked regularly as the drug is known to increase blood pressure.

    Source: CBC News © The Canadian Press, 2012 (28/02/12)

    A randomized, controlled trial of fingolimod (FTY720) in Japanese MS patients

    Gilenya Abstract
    Background: Fingolimod (FTY720) has previously shown clinical efficacy in phase II/III studies of predominantly Caucasian populations with multiple sclerosis (MS).

    Objectives: To report six-month efficacy and safety outcomes in Japanese patients with relapsing MS treated with fingolimod.

    Methods: In this double-blind, parallel-group, phase II study, 171 Japanese patients with relapsing MS were randomized to receive once-daily fingolimod 0.5 mg or 1.25 mg, or matching placebo for six months. The primary and secondary endpoints were the percentages of patients free from gadolinium (Gd)-enhanced lesions at months 3 and 6, and relapses over six months, respectively; safety outcomes were also assessed.

    Results: 147 patients completed the study. Higher proportions of patients were free from Gd-enhanced lesions at months 3 and 6 with fingolimod (0.5 mg: 70%, p = 0.004; 1.25 mg: 86%, p < 0.001) than with placebo (40%). Odds ratios for the proportions of relapse-free patients over six months favoured fingolimod versus placebo but were not significant. Adverse events related to fingolimod included transient bradycardia and atrioventricular block at treatment initiation, and elevated liver enzyme levels.

    Conclusions: This study demonstrated the clinical efficacy of fingolimod for the first time in Japanese patients with MS, consistent with the established effects of fingolimod in Caucasian patients.

    Full Article

    Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J.

    Dept of Neurology, Kyoto Min-Iren-Central Hospital/Institute of Neurotherapeutics/Kyoto University Hospital, Kyoto, Japan.

    Source: Pubmed PMID 22354739 & Mult Scler. 2012 Feb 21 Copyright © 2012 by SAGE Publications (27/02/12)

    EU says MS drug Gilenya needs heart monitoring

    GilenyaThe European Medicines Agency advised doctors to continuously monitor patients for six hours after giving them a first dose of Novartis AG's multiple sclerosis drug Gilenya, casting a shadow over the potential blockbuster product.

    The move came as the organisation started a review into the safety of the medicine, following reports of heart problems in patients and the death of one person in the United States within 24 hours of starting treatment.

    The Swiss drugmaker said last month it was investigating whether Gilenya, seen by analysts as a potential multibillion-dollar seller, caused the death of the 59-year-old U.S. patient.

    Gilenya can temporarily slow the heart rate. Although this usually returns to normal after a few hours, the European watchdog recommended intense cardiovascular monitoring after the first dose.

    This should include electrocardiogram (ECG) monitoring before treatment and then continuously for the first six hours afterwards, as well as measurement of blood pressure and heart rate every hour.

    Mark Schoenebaum, an analyst at ISI Group, said the call for active ECG monitoring was very different from the U.S. Food and Drug Administration (FDA) recommendation of observation and could encourage European doctors to use Biogen Idec's experimental BG-12.

    "We believe active ECG monitoring for six hours could be a material impediment to starting patients on Gilenya and could enhance BG-12's attractiveness to EU physicians once approved," he said.

    The FDA said on December 20 it was also looking into the U.S. case. Regulators on both sides of the Atlantic said the exact cause of the patient's death was still unexplained.

    Novartis was not immediately available for comment.

    SPOOKY PROSPECT

    "It's a bit early to draw too many conclusions on the basis of just one case, but if this keeps happening and serious cardiovascular problems turn out to be an issue, then this will definitely spook doctors," Vontobel analyst Andrew Weiss said.

    European authorities approved Gilenya last March for people with highly active relapsing-remitting multiple sclerosis (RRMS), the commonest form of the debilitating disease.

    More than 30,000 people have received the drug worldwide.

    Novartis is banking on the success of its newest drugs, such as Gilenya, to help it protect its top and bottom lines as established medicines lose patent protection and face competition from cheaper copies.

    Analysts, on average, forecast annual sales of $1.8 billion by 2016, according to Thomson Reuters Pharma.

    Gilenya is likely to face increased competition as other drugmakers such as Biogen and Sanofi push ahead with their latest MS medicines.

    Some experts have tipped Biogen's BG-12 to become the world's leading treatment for multiple sclerosis, while Sanofi's Genzyme unit plans to submit Lemtrada for approval in the United States and Europe in the first quarter of 2012.

    BG-12's key competitive advantage may lie in its safety profile, which looks relatively clean based on two-year data, analysts have said.

    Multiple sclerosis affects 2.5 million people worldwide and is a chronic, often disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision.

    Source: Reuters © Thomson Reuters 2012 (23/01/12)

    Oral MS drug Gilenya reviewed by EU after 11 patient deaths

    GilenyaThe European Medicines Agency started a review of Novartis AG’s Gilenya pill for multiple sclerosis after 11 deaths among patients who received treatment.

    The reports raise concern that the drug, the first oral medicine for the debilitating neurological disease, may harm the heart, the London-based agency said in an e-mailed statement today. Eric Althoff, a spokesman for Novartis in Basel, Switzerland, didn’t immediately return a call and e-mail requesting comment.

    Novartis said last month a patient died Nov. 23 after starting treatment with Gilenya. Ten other deaths have been reported among patients who began taking Gilenya, including six unexplained deaths, three heart attacks and one due to disruption of heart rhythm, the agency said today. It isn’t clear what role if any Gilenya had in the deaths, EMA said.

    “In my view this is highly unlikely to be related to the drug, but of course they have to check that,” Karl Heinz Koch, an analyst at Helvea SA in Zurich, said in a telephone interview today. “With all the experience we have with the drug, my comfort level is relatively high, but you can never be 100 percent sure. It certainly doesn’t help the share price.”

    Novartis fell 1.5 percent to 53.40 Swiss francs as of 12:21 p.m. in Zurich trading, after rising as much as 0.6 percent earlier in the session.

    First MS Pill

    Gilenya was approved in the U.S. in 2010 as the first oral treatment for multiple sclerosis, and cleared for sale in Europe in March. It’s among the products Novartis is depending on to boost sales as patents start to expire on the company’s best- selling drugs, including the hypertension pill Diovan.

    Biogen Idec Inc. plans to submit its oral MS drug, called BG-12, to regulators during the first half of this year after it was safe and effective in a late-stage trial, the Weston, Massachusetts-based company said in October.

    “Increased alertness to toxicities is not what Novartis needs,” said Andrew Weiss, an analyst at Bank Vontobel AG in Zurich, in an e-mail. “Will the tox profile become Gilenya’s Achilles heel?”

    The risk of slow heart rate, or bradycardia, after the first dose was known when the drug was approved, EMA said. The agency’s committee on human medicines expects to complete its review in March, the regulator said.

    Doctors should increase patient monitoring after the first dose is given, the EMA said. That includes electrocardiograms before treatment and for the first six hours after the first dose, and then checking blood pressure and heart rate every hour, the EMA said. After six hours, patients with a slow heart rate or problems with electricity conduction in the heart should be watched until their condition has improved.

    More than 30,000 patients worldwide have now taken the medicine, according to the EMA statement.

    Source: Bloomberg ©2012 Bloomberg L.P (20/01/12)

    Death of MS patient prompts FDA Gilenya review

    GilenyaThe death of a multiple sclerosis patient shortly after a first dose of fingolimod (Gilenya) is under review by the FDA, the agency said.

    No specific cause of death has been determined in the case, which occurred on Nov. 23, and the FDA emphasized that it had not ascertained that the drug was related to the fatal outcome.

    Fingolimod's prescribing information includes a warning about bradycardia and/or atrioventricular conduction block in the first hours after starting the drug. Clinicians are advised to monitor patients for six hours following the first dose.

    In the fatal case, the patient was also taking the beta-blocker metoprolol and the calcium channel antagonist amlodipine. These drugs are associated with increased risk for bradycardia and heart blocks, the FDA noted.

    The patient successfully completed the six-hour monitoring period but died a few hours later.

    "FDA is working with the manufacturer (Novartis) to evaluate the post-market report of death," the agency said.

    "At this time, FDA believes the benefits of Gilenya continue to exceed the potential risks when the drug is used appropriately as described in the approved drug label," it added. "FDA recommends that healthcare professionals continue to prescribe Gilenya following the recommendations in the drug label."

    Those recommendations include obtaining an electrocardiogram on patients at increased risk for cardiac side effects prior to starting the drug, and advising patients about the signs and symptoms of bradycardia.

    Of the 28,000 patients who have been started on fingolimod, this is the first death seen within 24 hours of the first dose, according to Novartis.

    Source: MedPage Today © 2011 Everyday Health, Inc (22/12/11)

    Gilenya® shows positive clinical outcomes in third phase III clinical trial

    GilenyaNovartis announced today new data from the Phase III 2309 study showing patients with relapsing-remitting multiple sclerosis (RRMS) treated with Gilenya® (fingolimod) had a statistically significant 48% reduction in annualized relapse rates (ARR) at 24 months compared to placebo. Study 2309 is the third Phase III clinical trial to demonstrate a significant reduction of relapse rates with Gilenya treatment in patients with RRMS.

    The two previous Gilenya studies involved a two-year, placebo-controlled trial and a one-year, head-to-head trial against interferon-beta-1a (IM) in which the once-daily oral medicine showed a 54% and a 52% relative reduction in ARR, respectively[1],[2].

    A reduction of brain volume loss, a pre-defined key secondary endpoint for study 2309, also achieved statistical significance for Gilenya-treated patients compared to placebo. Brain volume loss is valued as a predictor of long-term disability[3] and study 2309 is the third Phase III clinical trial where Gilenya demonstrated high efficacy in this MRI (magnetic resonance imaging) measure compared to control.

    "Study 2309 confirms the efficacy of Gilenya across several key measures, including reductions in annualized relapse rate and reductions in brain volume loss," said David Epstein, Head of the Pharmaceuticals Division at Novartis Pharma AG. "With more than 20,000 patient years of fingolimod exposure to date, Gilenya continues to demonstrate its value to patients and the MS community. We are looking forward to presenting the full data to the clinical community at a scientific congress next year."

    Gilenya-treated patients had a 17% and 28% reduction in three-month and six-month confirmed disability progression, compared to placebo as measured by EDSS (expanded disability status scale), respectively, which were not statistically significant. A post-hoc analysis of the data showed that this result is likely due to a high variability in EDSS measurements among patients with low baseline scores (i.e. 0.0 and 1.0).

    A subsequent analysis that applied a more rigorous definition of EDSS disability progression reduced the impact of this variability. Specifically, Gilenya-treated patients showed approximately a 34% reduction of six-month confirmed disability progression compared to placebo when a 1.5 point increase in EDSS was used to define progression in patients with baseline EDSS scores of zero, rather than the pre-specified 1.0 point increase. This disability reduction outcome is in range with what was seen in previous clinical trials. Further, study 2309 showed a statistically significant difference from placebo in the Multiple Sclerosis Functional Composite (MSFC), an alternative disability scale pre-defined in the clinical trial.

    "The results of this third Phase III study of Gilenya confirm data from the previous two studies that this drug is highly effective in relapsing forms of MS," said Peter Calabresi, M.D., Professor of Neurology, Johns Hopkins University. "The absence of an effect on disability in this trial is in contrast to the previous placebo comparison trial and seems to relate to inaccuracies of the EDSS scale at the low end where there is known to be quite a bit of variability. Nonetheless, there was a reduction of disability in line with previous trials if one employs a more rigorous definition of change, which is in keeping with the observed reduction in brain atrophy as well as other functional outcome measures of disease progression."

    Safety and tolerability were broadly consistent with the safety profile of fingolimod as characterized in the previous Phase III clinical trials. There were no deaths in fingolimod treated patients in the trial. Symptomatic bradycardia and associated AV-conduction blocks were rare and none required symptomatic treatment at the fingolimod 0.5 mg dose. As in previous studies, other adverse events which were observed more frequently in fingolimod-treated patients included liver transaminase elevations, hypertension and lymphopenia.

    The overall rate of infections was similar between fingolimod- and placebo-treated patients. Although herpes viral infections were reported more frequently with fingolimod in this trial, updated integrated analyses of all controlled clinical trials from the fingolimod development program show no differences in the incidence of herpes viral infections between fingolimod and placebo treatment groups. Malignancies were equally distributed across treatment groups in this study with the exception of basal cell carcinomas of the skin which, although of low incidence, were more frequently reported in fingolimod treated patients.

    Study 2309 was a two-year placebo-controlled, parallel-group, multi-center Phase III clinical trial evaluating the efficacy and safety of Gilenya (fingolimod) 0.5 mg in patients with relapsing-remitting multiple sclerosis (RRMS). Study 2309 was primarily performed to provide specific safety data for the Gilenya New Drug Application (NDA) that was submitted to the US Food and Drug Administration in December 2009.

    The study included 1083 patients across 126 sites in eight countries with most of patients enrolled in the United States, and had a central MRI review and independent EDSS raters. The study included three arms and patients with RRMS were randomized 1:1:1 to fingolimod 1.25 mg, fingolimod 0.5 mg or placebo. Patients who were randomized to the fingolimod 1.25 mg arm were switched to 0.5 mg during the course of the study in a blinded manner based on a determination of superior benefit-risk profile for the 0.5 mg dose in the Phase III studies FREEDOMS and TRANSFORMS.

    About Gilenya® (fingolimod)

    Gilenya, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of compounds called sphingosine 1-phosphate receptor (S1PR) modulators. It has demonstrated superior efficacy compared to Avonex® (interferon-beta-1a IM), a commonly prescribed treatment, showing a 52% relative reduction in annualized relapse rate (primary endpoint) and a 40% relative reduction in the rate of brain atrophy (secondary endpoint) at one year in a pivotal head-to-head trial in patients with relapsing-remitting multiple sclerosis.1 In a recent sub-analysis, Gilenya showed a 61% relative reduction in annualized relapse rate compared to interferon-beta-1a (IM) at one year in subgroups of patients with highly active relapsing-remitting MS not responding to interferon treatment.[4]

    Gilenya is generally a highly effective once-daily oral MS treatment without label restrictions specific to treatment duration. In clinical trials it was generally well tolerated with a manageable safety profile, and there is increasing experience of Gilenya's long-term effectiveness and safety profile, with more than 25,000 patients having been treated as of mid October 2011 in clinical trials and in a post-marketing setting. Currently, there is more than 20,000 patient years of exposure. In clinical trials, the most common side effects were headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects included transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction. [1],[2]

    The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups.[1],[2]


    References

    [1] Cohen J. et al. Oral Fingolimod vs. Intramuscular Interferon in Relapsing Multiple Sclerosis. N Eng J Med. Vol.362 No.5, Feb 4, 2010;362:402-415.
    [2] Kappos L, et al. Placebo-Controlled Study of Oral Fingolimod in Relapsing Multiple Sclerosis. N Eng J Med.Vol.362 No.5, Feb 4, 2010; 362:387-401.
    [3] Popescu V. et al. Brain atrophy in MS: long-term prognostic value. Poster presented at ECTRIMS, Amsterdam, October 2011.
    [4] Havrdová E. et al. Clinical outcomes in subgroups of patients with highly action relapsing-remitting multiple sclerosis treated with Fingolimod (FTY720): Results from the FREEDOMS and TRANSFORMS phase III studies. Poster presented at ECTRIMS, Amsterdam, October 2011.

    Avonex® is a registered trademark of Biogen Idec.

    Source: Reuters ©2011 Thomson Reuters (15/12/11)

    Novartis investigating death possibly linked to oral MS medication Gilenya

    GilenyaOne year after Novartis won FDA approval for a new type of drug to treat relapsing forms of multiple sclerosis and delay the progression of physical disabilities, the drugmaker is now investigating a death tied to its pill, which is called Gilenya. The disclosure, which was made by a Wall Street analyst, has the potential to cast a pall over a drug that has been expected to generate blockbuster sales.

    Specifically, this is the first death of a patient within 24 hours of taking a first dose. For now, an exact cause of death has not been disclosed, and the drugmaker suggests that it remains unclear whether its pill was the reason.

    However, in an investor note, Sanford Bernstein analyst Tim Anderson write that, “to us, it seems likely the company has a reasonable idea of the cause of death given the fact that this occurred about 20 days ago.”

    According to experts he spoke with, the patient was given the drug on November 22 and passed away the next day. And he points out that office monitoring of patients who are starting Gilenya is recommended due to a slowing heart rate associated with initiation. In any event, the case becomes the first involving sudden death among some 28,000 patients who have taken the drug. So far, the drugmaker has not issued a so-called Dear Doctor letter to alert physicians to the death.

    A Novartis spokesman tells us the patient had successfully completed six hours of post-dose observation without incident and, meanwhile, all available details are being gathered and have been submitted to the FDA and other health authorities. “At this stage, the exact cause of death has not been established, and a role for Gilenya can neither be confirmed nor excluded at this time,” he writes.

    As Anderson points out, “there is often significant safety baggage of different sorts” with MS drugs, and that efficacy “comes with a price…The question becomes whether the scale between safety and efficacy tips against a given drug, in which case its outlook becomes more clouded. With one death like the one we describe, it is not clear whether this will become a significant issue for Gilenya.”

    At the time Gilenya was approved, a survey of 43 MS specialists by Leerink Swann found the pill was forecast to grab a healthy chunk of the US market within the first two years, surpassing the competition, including Biogen’s Avonex; EMD Serono and Pfizer’s Rebif; Bayer’s Betaseron and Biogen’s Tysabri. Only Teva’s Copaxone would be a bigger seller.

    In his view, Anderson believes that Gilenya sales this year will reach $385 million, or less than one percent of total Novartis revenue of about $60 billion. By 2015, he forecasts sales of $1.4 billion, or 2 percent of companywide revenue. “If uptake of the drug were to falter – either because of new safety issues or because of intensified competition – it could dent sentiment on Novartis but it would not likely have a substantial impact on the company’s overall financial health.”

    Source: Pharmalot ©2011 UBM Canon Pharmaceutical Media Group. (13/12/11)

    Anger at NICE oral MS drug Gilenya decision

    GilenyaCampaigners have condemned a decision that could lead to a ban on the use of the first pill to treat multiple sclerosis.

    The National Institute of Health and Clinical Excellence (NICE) ruled the drug was too expensive following a second consultation on its use.

    It says it is not minded to make it available on the NHS but a final decision has not been made yet and people can still make their views known.

    It is believed the fingolimod, which is taken daily, can cut relapses in the condition, and it has been used successfully in other countries.

    Experts want it to replace injections and hospital infusions for many sufferers.

    Shana Pezaro, 32, from Hove, was diagnosed with MS more than three years ago and needs walking sticks or a motability scooter to get out and about.

    She said: “It is just devastating that there is a new effective treatment out there for people with MS, yet we're being denied it.

    “There are many people living with MS who don’t respond to the current available medications and this is their only hope for effective treatment.

    “It's just desperately unfair and really demoralising.

    “But I know this isn’t the final decision and there is still another consultation coming up.

    “I would really urge people with MS to contact Nice and tell them why it’s so important that we are allowed access to this drug.”

    The £19,000 annual cost of the pill is much higher than injections, which range from £6,000 to £8,000 a year.

    But MS specialists say the drug could make overall savings with fewer patients needing hospital treatment.

    The Multiple Sclerosis Resource Centre charity commented.. "As the first licensed oral drug therapy for MS, this has come as disheartening news to those with highly active forms of the disease that have not responded well to the other drugs currently available.

    We hope that Novartis and NICE can reach an agreement by the next meeting in February and that the public consultations are of benefit to this."

    MS Society director of policy and research, Jayne Spink, said scores of patients across Sussex would be affected.

    She said: “This is incredibly disheartening news for people with MS and it will leave some people with no effective treatment option.

    “We would like to see the drug freely available to all those that could benefit and remain hopeful that this will happen.”

    Source: The Argus © Copyright Newsquest Media Group 2001-2011 and MSRC (06/12/11)

    Oral MS drug Gilenya fails to win NICE backing in draft guidance

    GilenyaThe UK's health cost body National Institute for Health and Clinical Excellence, or NICE, in its revised draft guidance did not recommend Swiss pharmaceutical giant Novartis' multiple sclerosis pill Gilenya, as it believes the drug would not be cost effective for the National Health Service, or NHS, in comparison with other available treatments. NICE has not yet issued guidance for the NHS.

    Gilenya, or fingolimod, is a daily capsule that could reduce relapses in some people who have a particular type of multiple sclerosis.

    Even after a proposed discount from Novartis, NICE's independent appraisal committee is not convinced that offering the drug would be a cost effective option for the NHS, when compared with existing treatments such as beta interferons.

    Sir Andrew Dillon, Chief Executive of NICE said: "It is important for people with multiple sclerosis to have access to different treatment options wherever possible; however these new treatments must represent value for money so that everyone can get the most out of the NHS."

    The Multiple Sclerosis Resource Centre commented.. ‘As the first licensed oral drug therapy for MS, this will come as disheartening news to those with highly active forms of the disease that have not responded well to the other drugs currently available. We hope that Novartis and NICE can reach an agreement by the next meeting in February and that the public consultations are of benefit to this.’

    Source: NASDAQ © NASDAQ 2011 & MSRC (01/12/11)

    Oral MS drug Gilenya® shows up to 71% reduction in annualised relapse rates

    GilenyaNovartis will showcase data from 13 abstracts on fingolimod (Gilenya®), at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) taking place from 19-22 October in Amsterdam.

    The data being presented for fingolimod at ECTRIMS/ACTRIMS highlight the Novartis clinical trial program for sphingosine 1-phosphate receptor (S1PR) modulators. Fingolimod targets MS via effects on the immune system and new pre-clinical data to be presented at ECTRIMS/ACTRIMS supports an additional potential direct effect on the central nervous system (CNS)[1,2], although the clinical relevance of this remains to be determined. Additional clinical data describe efficacy in subgroups of patients with highly active disease in the pivotal Phase III studies.

    "Gilenya has already demonstrated significant efficacy in large scale clinical trials which is reinforced by these important data presented at ECTRIMS/ACTRIMS reflecting different patient populations in need of a new treatment," said David Epstein, Head of the Pharmaceuticals Division at Novartis Pharma AG. "These findings will help further solidify the role of Gilenya in the treatment of MS within its approved indication."

    Data highlights include:

    Fingolimod 0.5 mg significantly reduced annualized relapse rates (ARR) by up to 71% (from 61% to 71%) compared to interferon beta-1a IM and compared to placebo in relapsing-remitting multiple sclerosis (MS) patients with high disease activity despite previous MS disease-modifying treatment. Although the reduction in ARR in another subgroup of patients, those patients with rapidly evolving severe relapsing-remitting MS, was directionally consistent with other subgroup data, statistical significance was not achieved compared to interferon beta-1a IM due to the small number of patients in this subgroup[3]. (Abstract P473)

    In relapsing-remitting MS patients with high disease activity despite previous MS disease-modifying treatment, the relative reduction of ARR ranged from 61% compared to interferon beta-1a in TRANSFORMS to 62%-71% compared to placebo in FREEDOMS.

    In the European Union, Gilenya 0.5 mg is approved for the treatment of relapsing-remitting MS in patients with high disease activity despite treatment with interferon beta, and in patients with rapidly evolving severe relapsing-remitting MS.

    Fingolimod 0.5 mg reduced the rate of brain atrophy, or brain volume loss, compared to interferon beta 1a IM over 12 months, irrespective of disease activity prior to study start as shown in an analysis of the pivotal Phase III TRANSFORMS study[3]. (Abstract P907)

    A five year Phase II study extension showed that patients with relapsing MS treated with fingolimod maintained low disease activity with a safety profile consistent with that seen in other fingolimod clinical trials. Of the original 281 patients at the start of the Phase II study, approximately 50% (140 patients) completed five years of treatment[4]. (Abstract P978)

    In addition to the data presentations, onsite at the RAI Exhibition and Conference Centre there will be a Novartis symposium, 'Fingolimod: pioneering innovation in MS treatment', taking place on Friday 21st October, 12:45 - 13:45 CET. There will also be three interactive 'MS Innovation Exchanges,' including two October 20 and one on October 21. The 'MS Innovation Exchanges' are an opportunity for healthcare professionals to learn about innovations in patient care, neuroimaging and patient outcomes. Healthcare professionals should visit the Novartis booth for more information.

    The following key Novartis data will be presented during the ECTRIMS/ACTRIMS congress:

    Abstract P473: Clinical and magnetic resonance imaging outcomes in subgroups of patients with highly active relapsing-remitting multiple sclerosis treated with fingolimod (FTY720): results from the FREEDOMS and TRANSFORMS phase 3 studies

    Abstract P907: Fingolimod (FTY720) reduces brain volume loss over 12 months compared with intramuscular interferon beta-1a: subgroup analyses of TRANSFORMS data based on inflammatory disease activity

    Abstract P320: A controlled study on the effect of fingolimod (FTY720) on the immune response following seasonal influenza vaccination and tetanus toxoid booster injection in patients with Multiple Sclerosis

    Abstract P369: Brain distribution of BZM055, an imaging analog of fingolimod (FTY720), in non-human primate

    Abstract P978: Long-term fingolimod (FTY720) in relapsing MS: 5-year results from an extension of a phase II, multicenter study show a sustained low level of disease activity

    Abstract P239: Effect of fingolimod (FTY720) on disability progression: Application of a transition model to EDSS data collected in the FREEDOMS and TRANSFORMS trials

    Abstract P494: Fingolimod (FTY720) modulates microglial activation to augment markers of remyelination

    Abstract P930: Oral fingolimod (FTY720) in Japanese patients with relapsing multiple sclerosis: results of a 6-month, randomized, double-blind, placebo-controlled, phase 2 study

    Abstract P460: Oral fingolimod (FTY720) in Japanese patients with relapsing multiple sclerosis: Results of a 12-month, phase 2 extension study

    Abstract P961: Nervous system and immune system effects of sphingosine 1-phosphate receptor 5 deletion in mice alters experimental autoimmune encephalitis progression and the efficacy of fingolimod

    Abstract P552: Treatment experience, burden and unmet needs (TRIBUNE) in multiple sclerosis study: patient preferences for MS treatments

    Abstract P767: T-Cell response against varicella zoster virus in fingolimod treated patients with multiple sclerosis

    Abstract P823: Sphingosine 1-phosphare receptor antagonists promote axonal ensheathment by human fetal oligodendrocyte progenitors

    References

    Tamagnan G. et al. Brain distribution of BZM055, an imaging analog of fingolimod (FTY720), in non-human primate. Data Presented at ECTRIMS, Amsterdam, October 2011.
    Noguchi K. et al. Nervous system and immune system effects of sphingosine 1-phosphate receptor 5 deletion in mice alters experimental autoimmune encephalitis progression and the efficacy of fingolimod. Data Presented at ECTRIMS, Amsterdam, October 2011.
    Havrdová E et al. Clinical outcomes in subgroups of patients with highly action relapsing-remitting multiple sclerosis treated with Fingolimod (FTY720): Results from the FREEDOMS and TRANSFORMS phase III studies. Data Presented at ECTRIMS, Amsterdam, October 2011.
    Montalban X et al. Long-term fingolimod (FTY720) in relapsing MS: 5-year results from an extension of a phase II, multicenter study show a sustained low level of disease activity. Data Presented at ECTRIMS, Amsterdam, October 2011.
    Cohen J. et al. Oral Fingolimod vs. Intramuscular Interferon in Relapsing Multiple Sclerosis. N Eng J Med. 2010; 362:402-415.
    Novartis data on file.
    Kappos L, et al. Placebo-Controlled Study of Oral Fingolimod in Relapsing Multiple Sclerosis. N Eng J Med. 2010; 362:387-401.

    Source: Novartis International AG (17/10/11)

    Japan approves Novartis’ oral MS drug Gilenya

    GilenyaJapanese regulatory authorities have approved Novartis’ once-daily multiple sclerosis (MS) drug Gilenya.

    The Gilenya sanction covers use of the drug for preventing relapse and delaying progression of physical disability in adult MS patients.

    The only other drug licensed in Japan for preventing relapse of MS patients is interferon beta.

    Gilenya is already approved in over 50 countries including the U.S. and nations in the EU.

    Source: GEN © 2011 Genetic Engineering & Biotechnology News (28/09/11)

    Oral MS medication, Gilenya, may increase risk of macular edema in some patients

    GilenyaThe first U.S. Food and Drug Administration-approved oral medication for multiple sclerosis poses a potential risk of macular edema, particularly in patients with a history of uveitis, according to a neuro-ophthalmologist.

    MS patients who receive Gilenya (fingolimod, Novartis) should undergo baseline and follow-up examinations 3 to 4 months after initiation of treatment, Robert C. Sergott, MD, said at the Wills Eye Institute Alumni Conference in Philadelphia.

    “The macular edema issue is one that we as ophthalmologists are very familiar with and most neurologists are not familiar with,” he said. “It’s our obligation then to help them take care of these patients because we have an intersection of MS with a medication that can cause visual loss.”

    Fingolimod was originally approved for transplantation-related indications. The active ingredient is believed to thwart lymphocyte migration.

    “It sequesters T-cells in lymph nodes,” Dr. Sergott said. “By modulating the sphingosine-1-phosphate receptor, fingolimod keeps the lymphocytes within lymph nodes so that they cannot enter the central nervous system.”

    Fingolimod was approved in Canada in March and was recently approved in Europe, Dr. Sergott said.

    Clinical trials

    Data on ocular complications were culled from two phase 3 FDA clinical trials to assess the efficacy and safety of fingolimod. A 2-year trial compared fingolimod with placebo; a 1-year trial compared fingolimod with interferon beta-1a, Dr. Sergott said.

    Investigators were required to report patients’ medical histories, visual acuity and findings from dilated ophthalmoscopy, optical coherence tomography or fluorescein angiography. Patients underwent ophthalmic examinations at 1, 3, 6, 12 and 18 months. OCT examination was not mandatory.

    Although not currently required, spectral-domain OCT may prove to be an optimal method of following retinal changes in patients treated with fingolimod, he said.

    “It’s changing not only the way we practice in retinal disease and glaucoma but also for neuro-ophthalmology and for monitoring toxicities,” Dr. Sergott said.

    Fingolimod was administered in 0.25-mg and 1.25-mg doses. Two patients who received 1.25-mg doses of fingolimod died; one patient had herpes zoster encephalitis and one patient had herpes simplex encephalitis. No deaths or signal for increased risk of viral infections was found in the 0.5-mg trial.

    Although not required, antibody titers to varicella zoster should be measured before therapy, Dr. Sergott said. If the antibody levels are low or absent, then the patients should be vaccinated for varicella zoster. After vaccination, antibody levels should be rechecked to ensure that the patient has immune protection.

    Fingolimod reduced the MS relapse rate and increased the percentage of patients without an MS relapse in both studies. The differences were statistically significant (P < .001).

    In the 2-year trial, macular edema occurred in 0.4% of patients treated with fingolimod 0.25 mg and 0.1% of patients who received the placebo. Of four patients diagnosed with macular edema, three were symptomatic.

    Patients with a history of uveitis had a 20% rate of macular edema; patients without a history had a rate of about 0.5%, Dr. Sergott said.

    Warnings, recommendations

    The FDA requires the manufacturer to include warnings and precautions on labeling of fingolimod. Monitoring is required for cardiac patients. It has not been tested in patients with pre-existing arrhythmia.

    Warnings also address infection. Clinical trial data showed a 20% to 50% dose-dependent reduction in peripheral lymphocyte counts. Restoration of peripheral lymphocyte counts may take up to 2 months after discontinuation of fingolimod, Dr. Sergott said.

    Relapses of MS should be treated with corticosteroids only after possible viral infections have been excluded as a cause of the infections. In addition, bronchitis and, to a lesser degree, pneumonia were more common in patients treated with fingolimod during the clinical trial.

    Patients should undergo ophthalmic examination 3 or 4 months after initiation of fingolimod therapy; patients with diabetes mellitus or a history of uveitis may need more frequent examinations, he said.

    Visual acuity should be monitored at baseline and during routine exams, Dr. Sergott said.

    Physicians should use their judgment in deciding whether or not to continue fingolimod treatment in patients with macular edema, Dr. Sergott said.

    “Continuation in patients with macular edema has not been evaluated,” he said. “The decision whether or not to discontinue should be assessed from a benefit-risk profile.”

    Patients with diabetes mellitus and a history of uveitis are likely to be at elevated risk for macular edema, Dr. Sergott said.

    “They will have to be examined on a case-by-case basis,” he said. “This is new information. It will be part of your practice as comprehensive ophthalmologists in knowing the guidelines for the treatment and follow-up of these patients taking fingolimod for relapsing-remitting MS.”

    Source: OSN Supersite Copyright © 2011 SLACK Inc. (12/09/11)

    First oral MS drug, Gilenya, rejected by NICE

    GilenyaCampaigners have expressed disappointment after the National Institute for Health and Clinical Excellence (Nice) rejected the first pill to treat multiple sclerosis.

    The MS Society urged the medicines watchdog and drug firm Novartis to work together so that Gilenya – also called fingolimod – can be reappraised.

    In draft guidance which is subject to consultation, Nice rejected the drug due to "uncertainties" over its effectiveness, a lack of appropriate data and concerns over cost-effectiveness.

    It said it was unclear how much the drug would help the specific group of people for whom it was licensed – adults with relapsing-remitting multiple sclerosis (RRMS) who experienced at least one relapse a year despite being treated with beta interferon drugs. Another group of patients suitable for the drug were those with rapidly evolving severe RRMS, who experience two or more disabling relapses regardless of their treatment.

    Nice said Novartis had submitted data mainly looking at a subgroup of patients with the former type of MS. The firm also only submitted data comparing Gilenya with a placebo and a type of beta interferon not believed to be widely prescribed on the NHS, according to Nice.

    Professor Carole Longson, director of the health technology evaluation centre at Nice, said: "While it's important that people with multiple sclerosis have treatment options, Nice has to ensure that the NHS provides treatments that bring benefits that are value for money.

    "Unfortunately, our independent committee wasn't given sufficient evidence to show that fingolimod could reduce relapses considerably better than the other treatments currently being used.

    "Based on the available clinical evidence and economic analysis, our independent committee concluded that fingolimod would not be effective good use of NHS resources."

    Helen Yates, MSRC Chief Executive said, "This is not the result we were hoping to hear and for some people with MS this will reduce their treatment options when other options have been exhausted. We hope that Novartis and NICE can discuss this further to talk over why this decision has been reached."

    Simon Gillespie, chief executive of the MS Society, said: "This is disappointing news for people with MS and it will leave some people with no effective treatment option. Access to MS treatments in the UK is very poor – in fact, people with MS would be better off living almost anywhere else in Europe, and this decision will only deepen that inequality.

    "We're concerned at how this decision has been reached and strongly encourage Nice and Novartis to work together to look at how the treatment can be better reconsidered and evaluated."

    Novartis said Nice had suggested best supportive care – no active treatment at all – as the appropriate comparator for Gilenya. But it said this did not reflect current clinical practice in the UK according to neurologists.

    A statement said: "Novartis believes that comparing fingolimod to best supportive care will unfairly restrict access to fingolimod, as well as any future new treatments. It will be very difficult for any new therapy to demonstrate cost-effectiveness against best supportive care.

    "This approach is likely to restrict new treatment options in the UK to symptom management medicines only, which could result in continued relapses."

    Around 100,000 people in the UK have MS. It has traditionally been treated with injectable drugs.

    Source: guardian.co.uk © Guardian News and Media Limited 2011 & MSRC (05/08/11)

    FDA approves sNDA for Novartis’ oral MS drug Gilenya

    GilenyaNovartis Pharmaceuticals Corporation announced that the U.S. Food and Drug Administration’s approval of a supplemental New Drug Application (sNDA) for Gilenya™ (fingolimod) that includes T1 Gd-enhancing magnetic resonance imaging (MRI) data. Gilenya is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS) in adults. It can decrease the number of MS flare-ups (relapses). It does not cure MS but can help slow down the physical problems that MS causes.

    T1 Gd-enhancing lesions are areas of active inflammation in the central nervous system (CNS) and represent an important marker of disease activity in people with MS.

    “Neurologists commonly use gadolinium contrast MRI activity to assess for active inflammation in people living with MS,” said Barry Singer, MD, Director of The MS Center for Innovations in Care at Missouri Baptist Medical Center. “These data show that treatment with Gilenya helped to significantly reduce contrast MRI activity in people with relapsing-remitting MS.”

    As a result of the approved sNDA, the Clinical Studies section 14 of the Gilenya Prescribing Information has been updated to include T1 MRI findings from the 12 month TRANSFORMS and 24 month FREEDOMS studies. These phase III pivotal trials were submitted to the FDA to support the approval of Gilenya.

    At 12 months, the mean number of Gd-enhancing T1 lesions was significantly lower for patients treated with Gilenya (0.5 mg) compared to patients taking interferon beta-1a IM, 0.2 vs. 0.5 respectively (p<0.001). Gilenya (0.5 mg) demonstrated a similar effect at 24 months 0.2 vs. 1.1, when compared to placebo (p<0.001).

    The Gilenya Prescribing Information Section 5.5 was also updated in May 2011 to reflect the period of time in which liver transaminase elevations occurred, noting the majority of elevations occurred within 6-9 months after starting Gilenya treatment (original Prescribing Information indicated within 3-4 months).

    About Gilenya

    More than 11,000 people in the U.S. have been prescribed Gilenya since it became commercially available on October 4, 2010. Novartis continues to regularly submit Gilenya safety updates to the FDA and health authorities worldwide. The safety profile of Gilenya remains consistent with the current U.S. prescribing information.

    In a two-year study, Gilenya reduced MS relapses by 54% (P<0.001; primary endpoint) and showed a 30% reduction in the risk of 3-month confirmed disability (P<0.05; key secondary endpoint) compared to placebo. Data from a one-year study showed Gilenya (0.5 mg) reduced relapses by 52% (P<0.001; primary endpoint), while there was no significant difference in 3-month confirmed disability (P=0.21) compared with interferon beta-1a IM (Avonex®), one of the most commonly prescribed treatments for MS. Gilenya also reduced disease activity as measured by the number of new and newly enlarged T2 lesions on MRI scans compared to interferon beta-1a IM (1.6 vs 2.6, respectively, P=0.002; key secondary endpoint) at one year and at two years compared to placebo (2.5 vs 9.8, respectively, P<0.001).

    Licensed from Mitsubishi Tanabe Pharma Corporation, Gilenya is the first oral treatment in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. Approved in more than 40 countries including the U.S., Canada and the countries of the European Union, Gilenya has been studied in phase III clinical trials of over 2500 patients with relapsing-remitting MS.

    In MS, the immune system damages the myelin sheath that protects nerve fibers in the central nervous system (CNS). As shown in animal models, Gilenya lowers the number of white blood cells (lymphocytes) in a patient’s blood. How Gilenya works is unknown, but it is thought that Gilenya keeps more lymphocytes inside the lymph nodes, so that fewer can be released to attack the nerve fibers in the brain, spinal cord, and the eyes. These lymphocytes in the lymph nodes and in the blood continue to function with Gilenya treatment. Gilenya only keeps lymphocytes inside the lymph nodes from leaving. It doesn’t destroy them. If Gilenya treatment is stopped for any reason, the number of lymphocytes circulating in the body increases over the first few days and gradually returns to normal within 1 to 2 months.

    Source: Novartis (03/08/11)

    Oman licenses world's first oral drug for Multiple Sclerosis

    GilenyaOman has licensed the world's first oral medication for Multiple Sclerosis (MS), a move which medical experts say will improve medication tolerability and compliance for many of Oman's 200 MS sufferers.

    The Oman Ministry of Health has approved the Novartis-made drug Gilenya (fingolimod) for use in the relapsing remitting form of MS that affects around two-thirds of those diagnosed with the disease, which causes muscle weakness, problems with coordination and impaired concentration.

    Making the new oral tablets available will remove the need for patients to undergo regular injections, allowing patients to enjoy a less restricted way of life and improving medication acceptance and compliance for those who cannot tolerate injections, said a leading Oman-based doctor who specialises in MS. Improved medication acceptance and compliance will optimize patient outcomes.

    "The licensing of the first oral drug for MS will have a major impact on patients in terms of medication tolerability and compliance. Patients have been asking for an oral treatment for a long time because people generally don't like injections, which are the standard treatment for the disease," explained Dr. Jaber Al Khaboori, Senior Consultant in the Department of Neurology, The Royal Hospital, Muscat.

    "I have two MS patients who are now taking fingolimod and they are already feeling better because they no longer suffer from the side effects associated with injections, such as tiredness and redness at the administration site," he added.

    Gilenya, which has also been approved in Kuwait, UAE, Bahrain, US, Russia, Canada, Australia, Switzerland and Europe, has been shown in research papers to be more effective at delaying disease progression than some of the most commonly used current treatments.

    Two studies published in the New England Journal of Medicine last year show that fingolimod delays disability progression and is more effective at reducing relapses and brain lesions in patients with relapsing remitting MS compared with the most commonly prescribed treatment, interferon beta-1a (an intra-muscular injection) and placebo.

    "Preliminary research suggests that fingolimod has the edge over other MS medications in efficacy and effectiveness in terms of reducing the progression of the disease and relapses, which will be a major advantage for Oman's MS patients that number around 200," commented Dr. Al Khaboori.

    Research figures show MS affects around 25 to 50 people in every 100,000 in Arabic populations and about 100 per 100,000 in Northern Europeans who display the highest risk of MS across the world, with prevalence seeming to increase with further distance from the equator.

    MS is a nervous system disease with no known cause that affects the brain and spinal cord, leading to symptoms such as visual disturbances, muscle weakness, trouble with coordination and balance, sensations such as numbness, prickling or "pins and needles" and thinking and memory problems.

    Globally MS affects women more than men and often begins between the ages of 20 and 40. The disease can be mild but some people lose the ability to write, speak or walk. There is no cure for MS but medicines can slow disease progression and help control symptoms.

    Source: AME Info.com © 1996 - 2011 AME Info FZ LLC (25/07/11)

    Oral fingolimod (Gilenya) in relapsing MS: impact on health-related quality of life in a phase II study

    GilenyaSummary: This phase II, placebo controlled study in relapsing MS from Spain reports on the effects of treatment with fingolimod (Gilenya) on patient’s quality of life.

    Data from the study supports a clinically important effect of fingolimod on health-related quality of life scores and on the fatigue/thinking HAQUAMS sub-domain. Similarly, BDI-II scores indicative of clinical depression favoured fingolimod over placebo at 6 months.

    Abstract
    Background: Health-related quality of life (HRQoL) worsens with multiple sclerosis (MS) relapses and disease progression. Common symptoms including depression and fatigue may contribute to poor HRQoL.

    Objectives: To report exploratory analyses assessing the impact of fingolimod (FTY720) on HRQoL and depression in a phase II study of relapsing MS. Methods: The Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and Beck Depression Inventory second edition (BDI-II) scores were assessed during a 6-month, placebo-controlled study and optional extension.

    Results: HAQUAMS total score improved with fingolimod and worsened with placebo. Mean score change from baseline to month 6 was +0.02 with fingolimod 1.25 mg (p<0.05 versus placebo), -0.01 with fingolimod 5.0 mg andþ0.12 with placebo. Categorical data supported a clinically important effect of fingolimod on HRQoL. Fingolimod 1.25 mg was also beneficial over placebo in the fatigue/thinking HAQUAMS sub-domain (p<0.05 versus placebo). Change in mean BDI-II scores from baseline to month 6 and the proportion of patients with BDI-II scores indicative of clinical depression favored fingolimod 1.25 mg over placebo (p<0.05 for both). At month 4, mean BDI-II and HAQUAMS total scores appeared to be maintained in fingolimod-treated patients.

    Conclusion: Fingolimod 1.25 mg may improve HRQoL and depression at 6 months compared with placebo in patients with relapsing MS.

    Montalban X, Comi G, O'Connor P, Gold S, de Vera A, Eckert B, Kappos L.

    Unitat de Neuroimmunologia Clinica, Vall d'Hebron University Hospital, Barcelona, Spain.

    Sources: Mult Scler. 2011 Jul 4. and PubMed PMID: 21727148 (12/07/11)

    NICE announces timelines for appraisal of Gilenya (fingolimod)

    GilenyaFollowing last week's meeting of the Technology Appraisal Advisory Committee for the appraisal of fingolimod (Gilenya), a new disease modifying drug for relapsing remitting MS, NICE (National Institute for Health and Clinical Excellence) has announced the following timelines:

    If an Appraisal Consultation Document (ACD) is issued, it will be released during the week commencing Monday 25 July.
    If a Final Appraisal Determination (FAD) is issued, it will be released during the week commencing Monday 8 August.

    The European Medicines Agency (EMA) granted a licence for fingolimod in March 2011.

    NICE is currently appraising fingolimod to decide whether it should be funded by the NHS.

    The first meeting of the NICE appraisal committee took place last week (6 July).

    During the appraisal process, NICE will publish two consultative documents:

    The first is an Appraisal Consultation Document (ACD) that summarises the Committees initial views on the evidence and sets out the draft recommendations made by the Committee. The ACD is not NICE's final guidance on this technology. NICE will then invite feedback from the consultees and commentators for this appraisal and the public.

    The second is the Final Appraisal Determination (FAD) which takes into account feedback from the consultation on the ACD. This will allow opportunity for appeal against the document. If there are no appeals the guidance will be issued to the NHS.

    As part of its commitment to openness and transparency these documents are published on the NICE website.

    Source: MS Trust © 2004-2011 Multiple Sclerosis Trust (11/07/11)

    Appraisal of Gilenya® (fingolimod) by NICE begins

    GilenyaNICE (The National Institute for Health and Clinical Excellence) has begun its appraisal of Gilenya® (fingolimod), a new oral medication for relapsing-remitting Multiple Sclerosis.

    Fingolimod was granted a licence by the EMA (European Medicines Agency) in March 2011. The appraisal by NICE is to decide whether it should be funded by the NHS.

    Gilenya® (fingolimod) is the first in a new class of disease-modifying treatments called sphingosine 1-phosphate receptor (S1P-R) modulators and has a novel mode of action different from all currently marketed MS therapies.

    Fingolimod is licensed as a treatment for people who continue to have relapses or find the relapse rate has increased despite a year's treatment with one of the first line disease modifying drugs (Avonex, Betaferon, Copaxone, Extavia, Rebif). It can also be used with people with rapidly evolving severe relapsing-remitting MS - two or more relapses a year.

    The first meeting of NICE's appraisal committee took place yesterday (6 July). From this, a draft recommendation will be published for consultation within the next month. The final appraisal decision is expected in December.(08/07/11)

    UAE licenses world's first oral medication for Multiple Sclerosis

    GilenyaThe UAE's Ministry of Health (MoH) has licensed the world's first oral medication for Multiple Sclerosis (MS) ensuring that the country's 1,000 MS sufferers have fast access to the latest medications that will change the treatment of MS, it was announced at a press conference today.

    The MoH has approved the Novartis-made drug GilenyaTM (fingolimod) for use in the relapsing remitting form of MS that affects around two-thirds of those diagnosed with the disease, which causes muscle weakness, problems with coordination and impaired concentration.

    Making the new oral tablets available will remove the need for patients to undergo regular injections - which can cause flu-like symptoms for 24 hours and leave red marks on the skin - allowing patients to enjoy a less restricted way of life and improving medication compliance.

    "MS patients from across the UAE will now be able to access the world's first oral medication for the relapsing remitting form of the disease. The ministry fast-tracked fingolimod through the drug licensing process as part of its commitment to ensuring that those with chronic disease and disabilities receive the latest medications as soon as they are available on the world market," explained Thomas Wegmann, Head of Marketing Middle East, Novartis Pharma Services.

    "We are proud to have worked successfully with the UAE's MoH toward a shared goal of bringing a novel, efficacious treatment to those people who suffer from relapsing remitting forms of MS across the country," added Wegmann.

    The UAE MS Support Group welcomed the move, saying fingolimod will provide MS sufferers with a new and effective way of treating the disease, which mainly affects young people between the ages of 20 and 40.

    "On behalf of all members of the UAE MS Support Group, I thank Novartis for providing the drug fingolimod that will provide another opportunity to treat MS patients. Many thanks to the Ministry of Health for approving this drug and making it available in hospitals, which will lighten the weight on the shoulders of MS patients in the UAE," said Maha Raisy, Head of Patients Affairs Committee, UAE MS Support Group.

    "The main threat of MS lies in the consequences that accompany the disease, more than the illness itself, especially given the fact that most patients are young people, and if we neglect them then we would be neglecting an important segment of our society," Raisy concluded.

    Fingolimod, which has also been approved by the US, Russia, Canada, Australia, Argentina, Switzerland and Europe, has been shown in studies to be more effective at delaying disease progression than some of the most commonly used current treatments.

    Two studies published in the New England Journal of Medicine last year show that fingolimod delays disability progression and is more effective at reducing relapses and brain lesions in patients with relapsing remitting MS compared with the most commonly prescribed treatment, interferon beta-1a (an intra-muscular injection) and placebo.

    Research figures show MS affects around 25 to 50 people in every 100,000 in Arabic populations and about 100 per 100,000 in Northern Europeans who display the highest risk of MS across the world, with prevalence seeming to increase with further distance from the equator.

    MS is a nervous system disease with no known cause that affects the brain and spinal cord, leading to symptoms such as visual disturbances, muscle weakness, trouble with coordination and balance, sensations such as numbness, prickling or "pins and needles" and thinking and memory problems.

    Globally MS affects women more than men and often begins between the ages of 20 and 40. The disease can be mild but some people lose the ability to write, speak or walk. There is no cure for MS but medicines can slow disease progression and help control symptoms.

    Source: AMEinfo.com © 1996 - 2011 AME Info FZ LLC (27/06/11)

    Gilenya can only gain as Merck scraps rival oral MS drug

    GilenyaNovartis AG's chances of eventually dominating the multibillion dollar multiple-sclerosis market with its new Gilenya pill got a boost Wednesday when Merck KGaA of Germany abandoned attempts to market a rival treatment.

    Merck's decision to stop market applications for its MS medicine cladribine and pull the product from Russia and Australia—which comes after the U.S. Food and Drug Administration required more testing to allay safety concerns—means Novartis has the only oral multiple-sclerosis treatment in the market at the moment.

    While Merck's plight is expected to add more revenue to Gilenya, it also helps ease the Swiss drugs giant's pain after a U.S. regulatory panel this week questioned the safety of its gout treatment Ilaris, asking for more testing.

    The adverse regulatory stance could delay or block the launch of Ilaris in the U.S. if the FDA backs the panel.

    That setback doesn't cloud Novartis's prospects, however. The Swiss group has one of the industry's healthiest pipelines, a fact that should help the group manage the expected sales drop from patent expiries of key drugs that will soon face generic competition.

    "We see Novartis bucking the trend of generic dilution given its ability to replace ... blockbusters such as heart drug Diovan and cancer medicine Gleevec with innovative products such as Gilenya, [blood-pressure drug] Tekturna and [cancer medicine] Tasigna," Nomura analyst Amit Roy said. "These drugs address genuine unmet medical needs that should enable the company to withstand pricing pressure and so support margins."

    Nomura expects that because of Gilenya's pill form—most multiple-sclerosis drugs are administered via infusion or injection—Gilenya could net "at least $3.5 billion in peak sales" by 2014. The bank said the estimate was conservative as more people suffering from multiple sclerosis could use Gilenya, given that 40% of MS sufferers currently don't take any medicine to treat their disease.

    When Gilenya was approved in the U.S. last year, analysts and industry experts expected the pill to be a game-changer, together with Merck's cladribine, and take a substantial portion of the market in MS drugs which had a size of about $12.6 billion in 2010, according to research firm Espicom. Merck's failure to market its own pill now gives Novartis a cutting edge.

    Multiple sclerosis, a chronic autoimmune neurological disease, affects around 2.5 million people world-wide. The market—currently led by Biogen Idec Inc., Teva Pharmaceutical Industries Ltd., Sanofi SA and Merck—is expected to grow rapidly and reach sales of about $15.3 billion by 2016, according to data provided by consultancy Piribo Ltd. It noted that new players such as Novartis but also generic companies could generate some $4 billion in sales by that time.

    Source: Wall Street Journal Copyright ©2011 Dow Jones & Company, Inc. (22/06/11)

    Comparison of Gilenya with Avonex in relapsing-remitting MS

    GilenyaSummary

    Background

    In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod.

    Methods

    Patients randomly assigned to receive 0·5 mg or 1·25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0·5 mg or 1·25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834.

    Findings

    1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0·5 mg fingolimod [n=356], 0·12 [95% CI 0·08—0·17] in months 0—12 vs 0·11 [0·08—0·16] in months 13—24; 1·25 mg fingolimod [n=330], 0·15 [0·10—0·21] vs 0·11 [0·08—0·16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0·5 mg fingolimod [n=167], 0·31 [95% CI 0·22—0·43] in months 0—12 vs 0·22 [0·15—0·31], in months 13—24 p=0·049; interferon beta-1a to 1·25 mg fingolimod [n=174], 0·29 [0·20—0·40] vs 0·18 [0·12—0·27], p=0·024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p<0·0001 for T2 lesions at both doses; p=0·002 for T1 at 0·5 mg; p=0·011 for T1 at 1·25 mg), and the pattern of adverse events shifted towards that typical for fingolimod. Over 24 months, in continuous fingolimod groups compared with the group that switched from interferon beta-1a to fingolimod, we recorded lower ARRs (0·18 [95% CI 0·14—0·22] for 0·5 mg; 0·20 [0·16—0·25] for 1·25 mg; 0·33 [0·27—0·39] for the switch group; p<0·0001 for both comparisons), fewer new or newly enlarged T2 lesions (p=0·035 for 0·5 mg, p=0·068 for 1·25 mg), and fewer patients with Gd-enhancing T1 lesions (p=0·001 for 0·5 mg fingolimod vs switch group; p=0·002 for 1·25 mg fingolimod vs switch group). There was no benefit on disability progression.

    Interpretation

    Switching from interferon beta-1a to fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to fingolimod, continuous treatment with fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes.

    Funding

    Novartis Pharma AG.

    Source: The Lancet Neurology Copyright © 2011 Elsevier Limited (19/05/11)

    Cardiovascular effects of oral MS drug Gilenya mostly transient

    GilenyaThe first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

    The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

    The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

    Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

    In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

    A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

    The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

    Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

    Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

    "Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

    Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

    Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

    One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

    "Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

    The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

    "The significance of these findings is uncertain," he said.

    Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

    Patients who were treated responded to standard antihypertensive therapy.

    Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

    Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

    The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

    Source: Internal Medical News Copyright © 2011 International Medical News Group, LLC(19/05/11)

    Reducing the side effects of MS drug, Gilenya

    GilenyaThe drug Gilenya (FTY720) is approved for the treatment of multiple sclerosis. Although highly effective it can have serious side effects, including reduced lung function and fluid accumulation in the eye.

    Understanding the multiple molecular mechanisms by which the drug affects its target (the S1P receptor) could lead to the development of a drug with the same therapeutic efficacy but reduced side effects.

    In this context, a team of researchers, led by Timothy Hla, at Weill Cornell Medical College, New York, has now detailed the molecular mechanism by which FTY270 causes adverse effects in the lungs of mice.

    Specifically, Hla and colleagues outlined a mechanism by which FTY270 causes S1P receptor degradation on the cells lining the blood vessels of the lungs and found that this reduction in S1P receptor levels causes leakage of the blood vessel contents into the lungs, impairing lung function. In contrast, S1P receptor degradation appears not to be required for the effects of FTY720 on immune cells, which are the effects that mediate its therapeutic efficacy.

    Hla and colleagues therefore suggest that developing a drug that does not act on S1P receptor on the cells lining the blood vessels of the lungs but does target S1P receptor on immune cells may provide a therapeutic with decreased side effects.

    Full Article: Engagement of S1P1-degradative mechanisms leads to vascular leak in mice

    Source: EurekaAlert! (10/05/11)

    Oral MS drug Gilenya has yet to show ‘full potential'

    GilenyaNovartis's multiple sclerosis pill Gilenya, which faces a threat from a rival product under development by Biogen Idec Inc, has yet to show its full potential, the Swiss drugmaker’s head of development said.

    Gilenya, approved by U.S. regulators last year as the first pill against relapsing forms of multiple sclerosis, may also work in patients with a more severe form of the disease called primary progressive, Novartis’s Trevor Mundel said yesterday in a telephone interview. “We haven’t seen the full potential with Gilenya,” according to Mundel.

    Biogen last week reported advanced clinical test results on its own experimental pill, called BG-12, that suggested it may become patients’ best treatment option and prompted some analysts to slash their sales forecasts for Gilenya. Seamus Fernandez of Leerink Swann & Co. cut his Gilenya estimate to $1.5 billion from $3.1 billion for 2017 after what he described as Biogen’s “impressive” study results.

    The data on BG-12 was “pretty good,” though it’s also “somewhat partial” because Weston, Massachusetts-based Biogen did not disclose absolute numbers when it said that a twice- daily dose of the pill reduced the proportion of patients whose disease flared up by 49 percent over two years, Mundel said.

    Multiple sclerosis affects about 2.5 million people in the world, including 400,000 patients in the U.S., according to the National Multiple Sclerosis Society.

    The chronic disease attacks the central nervous system and can cause numbness in limbs, paralysis and vision loss. Gilenya, developed by Basel, Switzerland-based Novartis, blunts the attack by targeting white blood cells that harm the protective coating of nerve cells.

    Source: Bloomberg ©2011 BLOOMBERG L.P. (28/04/11)

    Colchester charity welcomes new drug for multiple sclerosis

    GilenyaA Colchester charity has described a new pill as a major breakthrough in the treatment of multiple sclerosis.

    Helen Yates, chief executive of the Multiple Sclerosis Resource Centre, believes the drug, fingolimod, would make a huge difference to the quality of life of many of the 100,000 people nationwide with MS.

    In trials, fingolimod reduced relapses by more than half and slowed progression of the disease by 30 per cent.

    The pills can be given to patients who do not have to give themselves injections of other drugs.

    But campaigners are waiting to see if the National Institute for Clinical Excellence recommends that health bosses should distribute it widely.

    Mrs Yates said: “As a capsule rather than injection it is great news for the many people who find that the existing injections don’t work for them or who find the actual injecting very difficult.

    “We hope that NICE will offer a positive recommendation for fingolimod to ensure funding on the NHS, as the basic price is very high.”

    Things to note:

    Gilenya prescribing cannot be via a GP, it will be via a Neurologist in secondary care.

    It is worth noting the total cost of treatment calculation of Gilenya versus natalizumab, the other second line therapy, is outlined below.

    The total cost of treatment calculation, per patient, per year based on DH list price and average infusion rates (this can be much higher) is as follows:
    • Gilenya:  £1470/28 days = £19,162.50 plus cost of six hour first dose observation tariff code AA30Z £502 = £19,665
    • Tysabri:  £1130/28 days = £14,731.40 plus average infusion cost using tariff code AA30Z ( as it can't be taken any other way) of £502 x 13 (every 28 days) = £21,257.

    Based on an average infusion price, Gilenya costs less per patient per year than the other second line treatment, the infusion.

    Source: Daily Gazette  © Copyright 2001-2011 Newsquest Media Group & MSRC (19/04/11)

    First oral MS drug, Gilenya, now available in UK

    GilenyaA new drug for multiple sclerosis that is twice as effective as the current standard treatment is now available in the UK.

    Fingolimod - also known by its brand name Gilenya - is the first pill available to treat MS.

    It has been licensed by the European medicines watchdog to treat patients with relapsing-remitting MS who have failed to respond to injections of beta interferon.

    Studies show it reduces the relapse rate by 54% compared to untreated patients, and the progression of disability by 30%.

    It is twice as effective as beta interferon.

    Dr Eli Silber, consultant neurologist at King's College Hospital in London, said: "This has the potential to be one of the most significant advances since the first-line therapies arrived over a decade ago.

    "Fingolimod is not just the first oral treatment, which is an innovation in itself, but provides a new option for people with more active disease."

    Helen Yates, Chief Executive of the Multiple Sclerosis Resource Centre (MSRC) said, "Of course MSRC is pleased  that European regulators have approved fingolimod (Gilenya) as a second line disease modifying treatment for relapsing remitting MS.
     
    As a capsule rather than injection it is great news for the many people who find that the existing DMDs dont work for them or who find the actual injecting very difficult.
     
    We hope that NICE will offer a positive recommendation for fingolimod to ensure funding on the NHS as the basic price is very high."

    MS is the most common neurological condition affecting young adults.

    An estimated 100,000 people in the UK have MS, which causes progressive disability.

    Around 80% have the relapsing-remitting form of the disease.

    Amanda Cook used to suffer one relapse a year. But since starting the new treatment she has been well.

    And she no longer has the flu-like symptoms she suffered while taking beta interferon.

    She told Sky News: "I can do whatever I like. Before it was difficult to plan anything because I never knew how I would feel for 48 hours after the injection.

    "I could not go out or go to work. My life was planned around my injections, which I do not have to do now."

    The medicines watchdog Nice (National Institute for Health and Clinical Excellence) will not give its verdict on the cost effectiveness of the treatment until later this year.

    For the time being neurologists will have to make a special case for funding to treat individual patients.

    Things to note:

    Gilenya prescribing cannot be via a GP, it will be via a Neurologist in secondary care.

    It is worth noting the total cost of treatment calculation of Gilenya versus natalizumab, the other second line therapy, is outlined below.

    The total cost of treatment calculation, per patient, per year based on DH list price and average infusion rates (this can be much higher) is as follows:
    • Gilenya:  £1470/28 days = £19,162.50 plus cost of six hour first dose observation tariff code AA30Z £502 = £19,665
    • Tysabri:  £1130/28 days = £14,731.40 plus average infusion cost using tariff code AA30Z ( as it can't be taken any other way) of £502 x 13 (every 28 days) = £21,257.

    Based on an average infusion price, Gilenya costs less per patient per year than the other second line treatment, the infusion.

    Source: SkyNews.com Copyright (c) 2011 BskyB & MSRC (19/04/11)

    Gilenya reduced the risk of MS disability progression regardless of treatment history or disease severity

    GilenyaA new analysis demonstrated that Gilenya(TM) (fingolimod) reduced the risk of disability progression in patients with relapsing-remitting multiple sclerosis (RRMS), regardless of treatment history.

    This analysis of the phase III two-year FREEDOMS study is one of 11 abstracts on Gilenya being presented at the 63rd annual meeting of the American Academy of Neurology (AAN).

    "In developing Gilenya, Novartis initiated a large clinical trial program that would provide the MS community with robust data to define the efficacy and safety profile of this oral treatment for relapsing forms of MS," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "Our scientific presence at AAN is evidence of our commitment to continued research and ongoing reporting of clinical information to physicians and patients."

    The primary endpoint for the two-year FREEDOMS study was relapse rate, in which Gilenya reduced relapses by 54% compared to placebo (p<0.001). In a key secondary endpoint, Gilenya showed a 30% reduction (p<0.05) in the risk of 3-month confirmed disability progression as compared to placebo over two years.

    The FREEDOMS analysis presented this week at AAN showed that 0.5 mg Gilenya-treated patients who were new to therapy (n = 493) had a 37% reduction in the risk of 3-month confirmed disability progression compared to placebo (HR: 0.63; 95% CI: 0.41-0.95) while those previously treated with alternate therapies (n = 350) Gilenya 0.5 mg led to a 30% reduction in risk (HR: 0.70; 95% CI: 0.43-1.14). Consistent favorable effects on disability progression were observed for Gilenya-treated patients compared to placebo for subgroups defined by age, gender, and disease severity as defined by EDSS score, relapse activity prior to study, magnetic resonance imaging (MRI) lesion burden or lesion activity at the time of the start of the study.

    "These data provide deeper insights into the effect of Gilenya in significantly reducing MS disability progression across the broad range of patient subpopulations that this analysis evaluated," said Virginia Devonshire, MD Director of the University of British Columbia MS Clinic and a FREEDOMS trial investigator.

    Gilenya, licensed from Mitsubishi Tanabe Pharma Corporation, is the first oral treatment in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. Approved in more than 35 countries including US, Canada and Germany, Gilenya has been studied in phase III clinical trials of over 2500 patients with relapsing-remitting MS. In MS, the immune system damages the myelin sheath that protects nerve fibers in the central nervous system (CNS), which includes the brain and spinal cord. As shown in animal models, Gilenya stops many of the white blood cells (lymphocytes) from leaving the lymph nodes. Exactly how Gilenya works in MS is unknown, but it is thought that it results in fewer white blood cells entering the CNS to attack and damage the myelin sheath. If Gilenya treatment is stopped for any reason, the number of white blood cells circulating in the body increases over the first few days and gradually returns to normal within 1 to 2 months.

    The most common side effects are headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects include transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction.

    The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups.

    Source: Novartis (11/04/11)

    Dubai health authority backs new oral medication for MS

    GilenyaThe UAE's Multiple Sclerosis (MS) community is set to become the first in the region to benefit from a new oral medication designed to reduce debilitating symptoms and prevent disability, it was announced today by Dr. Ali Al Sayed, Director of Pharmaceutical Services, Dubai Health Authority (DHA).

    Dr. Al Sayed said the new therapy called Gilenya (fingolimod) is now available in the UAE after being approved as a first-line treatment in a number of countries for relapsing forms of MS, which affect two-thirds of those diagnosed with the disease that causes muscle weakness, problems with coordination, and impaired concentration. Up until now MS patients have had to inject their medications.

    The medication received full licensing by regulators in the US and Russia last year in response to research that shows the Novartis-made drug is more effective at delaying disease progression than currently prescribed therapies (1), (2).

    "Treatment adherence tends to be a major problem in MS. Many patients are reluctant to continue injections long-term," said Dr. Al Sayed. "The treatments which are currently available have to be given by frequent injections or intravenous infusions, and the benefits have to be weighed up against a number of side effects. Therefore optimizing adherence and sustaining injection therapies has been most challenging."

    "Novartis has prioritized the patients of this region and this is indicated by the fact that UAE is the first country in the region to receive Gilenya," he added.

    Treatment with pills is expected to improve the quality of life of many MS patients as it will remove the need for self-administered injections that can leave red marks on the skin and can cause flu-like symptoms for 24 hours.

    Two studies detailing the efficacy of Gilenya were published in the New England Journal of Medicine in 2010. Results show that fingolimod delays disability progression and is more effective at reducing relapses and brain lesions in patients with relapsing and remitting MS compared with the most commonly prescribed treatment, interferon beta-1a (an intra-muscular injection), and placebo (1),(2).

    Gilenya is a sphingosine 1-phosphate receptor modulator, which reduces the frequency of clinical exacerbations and delays the accumulation of physical disability. The aims of treatment are to return function after an attack, to prevent new attacks and to prevent disability. It is therefore the first of its kind once-daily oral pill solution for MS patients, bringing great relief and enhanced patient compliance.

    Global figures show MS affects around 25 to 50 people in 100,000 in Arabic populations and about 100 per 100,000 in Northern Europeans, who display the highest risk of across the world, with prevalence seeming to increase the further you move away from the equator [3].

    MS is a nervous system disease with no known cause that affects the brain and spinal cord. It damages the myelin sheath that surrounds and protects the nerve cells which slows down or blocks messages between the brain and the body, leading to the symptoms of MS: these include visual disturbances, muscle weakness, trouble with coordination and balance, sensations such as numbness, prickling, or "pins and needles" and thinking and memory problems.

    Worldwide MS affects women more than men. The disease often begins between the ages of 20 and 40 and can be mild but causes some people lose the ability to write, speak and walk. There is no cure for MS but medicines can slow disease progression and help control symptoms.

    Research:

    [1] Cohen J. et al. Oral Fingolimod vs. Intramuscular Interferon in Relapsing Multiple Sclerosis. N Eng J Med 2010; 362:402-415.

    [2] Kappos L. et al. A Placebo-Controlled trial of Oral Fingolimod in Relapsing Multiple Sclerosis. N Eng J Med 2010; 352:5.

    [3] Kurtzke JF. Multiple sclerosis in time and space - geographic clues to cause. J Neurovirol 2000; 6 (suppl 2): S134-40.

    Source: Zawya Copyright © 2011 Zawya (23/03/11)

    Gilenya, the first oral MS treatment, approved by European commission

    GiThe European Commission has granted Novartis approval for Gilenya® (fingolimod) 0.5 mg daily as a disease modifying therapy in patients with highly active relapsing-remitting multiple sclerosis (RRMS) despite treatment with beta interferon, or in patients with rapidly evolving severe RRMS.

    “Today marks an important step forward in the way we manage this chronic, debilitating disease in Europe,” said Professor Hans-Peter Hartung, Professor and Chairman, Dept. of Neurology, Heinrich-Heine University, Germany. Gilenya is the first approved therapy for MS that offers significant efficacy in a capsule, which for many patients will come as a welcome additional option.”

    The approval was based on the largest clinical trial program submitted to date for a new MS drug, and included data from clinical studies showing significant efficacy in reducing relapses, the risk of disability progression, and the number of brain lesions detected by magnetic resonance imaging (MRI), a measure of disease activity1,2

    “Today’s announcement marks another major regulatory approval and we are pleased that Gilenya will become available to more eligible MS patients,” said David Epstein, Division Head of Novartis Pharmaceuticals. “Novartis is dedicated to bringing innovative new treatments to patients where there is significant unmet need. Gilenya has been in clinical development for MS since 2003 and we are grateful for the commitment of those involved, especially the trial participants, who have contributed significantly to the development of this novel medicine.”

    Gilenya, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. In MS, the immune system damages the covering that protects nerve fibers in the central nervous system (CNS), which includes the brain and spinal cord. The novel mechanism of Gilenya is thought to work by reducing the immune system’s attack on the CNS by retaining certain white blood cells (lymphocytes) in the lymph nodes. This prevents the white blood cells from reaching the CNS, where they could potentially attack the protective covering around the nerve fibers, resulting in less inflammatory damage to the nerve cells. The white blood cell retention is reversible if Gilenya treatment is stopped.

    The EU application included data showing Gilenya 0.5 mg reduced relapses by 52% (P<0.001) at one year compared with interferon beta-1a IM (Avonex®), one of the most commonly prescribed treatments for MS. Data from a two-year placebo-controlled study showed a reduction in the risk of disability progression among Gilenya patients (30% reduction confirmed at three-month follow-up visit P=0.02, compared with placebo) 2. In clinical studies, treatment with Gilenya also resulted in statistically significant reductions in brain lesion activity as measured by MRI.

    Gilenya has been studied in more than 4000 MS patients. The most common side effects are headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects include transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction1,2

    The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups1,2

    Avonex® is a registered trademark of Biogen Idec.

    References

    1Cohen et al. Oral Fingolimod vs. Intramuscular Interferon in Relapsing Multiple Sclerosis. N Engl J Med. Vol.362 No.5, Feb 4, 2010 (printed version)
    2Kappos L, et al. Placebo-Controlled Study of Oral Fingolimod in Relapsing Multiple Sclerosis. N Eng J Med. Vol.362 No.5, Feb 4, 2010 (printed version).

    Source: European Pharamaceutical Reveiw © Russell Publishing Limited, 2010, 2011. (21/03/11)

    Oral Gilenya for multiple sclerosis approved in Canada

    GilenyaNovartis Pharmaceuticals Canada Inc. announced today that its new MS treatment, Gilenya™ (fingolimod), has received Notice of Compliance in Canada. Gilenya™ (fingolimod) is the first disease modifying oral therapy developed for the relapsing-remitting form of multiple sclerosis (MS) which is the most common type of the disease in adults.

    Unlike current therapies which all require daily or regular injections or infusions, Gilenya offers simple once daily oral dosing (0.5 mg) in a capsule, providing an efficacious and convenient treatment method for a complex and lifelong illness. Gilenya is approved for use in patients who have tried one or more MS therapies, but are unresponsive or intolerant to them.

    "The approval of Gilenya is a significant milestone for the Canadian MS community," says Dr. Daniel Selchen, a neurologist from Toronto, Ontario. "Oral therapies have been greatly anticipated by both patients and physicians who are eager for alternatives to injection and infusion therapies.  With its excellent clinical trial efficacy data, along with convenience, Gilenya is welcome news for those seeking a new option to manage their disease." 

    "I feel like I have my life back again," says Ms. Himani Ediriweera, a 39 year old from Toronto, who was diagnosed with MS over six years ago and has been on Gilenya for the last four years since participating in a clinical trial. "I have a fear of needles and hate the limitations my disease places on my lifestyle. I have gone from having five to six relapses per year to one or two since I started Gilenya - MS no longer has control over my life."

    Data demonstrates efficacy
    The approval of Gilenya was based on the largest clinical trial program ever submitted to Health Canada for a new MS drug, and included studies demonstrating significant efficacy in reducing relapses. Compared to a current standard of treatment (Avonex®, interferon beta-1a IM 30µg), Gilenya showed superior efficacy over one year by reducing relapses by 52%. The submission also included a two-year placebo controlled study, which demonstrated the significant efficacy of Gilenya in delaying disability progression. In both submitted studies, treatment with the medication also resulted in a statistically significant reduction in the number and volume of active brain lesions (a measure of disease activity) in people with the relapsing-remitting form of MS.

    Gilenya has a well-studied safety and tolerability profile. It has been studied in over 4,000 MS patients around the world. Some of these patients are in their seventh year of treatment with Gilenya. To date, there are over 8,000 years of patient exposure data on Gilenya.

    How Gilenya works
    Gilenya is the first in a new class of medications called sphingosine 1-phosphate receptor (S1PR) modulators. It is thought to reduce the frequency of MS relapses (when new symptoms appear, or existing ones get worse) by retaining certain white blood cells (lymphocytes) in the lymph nodes. This prevents the white blood cells from reaching the central nervous system (CNS) and potentially attacking myelin, the fatty substance that insulates nerves and helps them transmit impulses between the brain and the body. Gilenya does not cure MS, but it can help delay the progression of the disease.

    Gilenya will be available in pharmacies as of April 1, 2011.

    About MS
    Canada has one of the world's highest rates of MS with an estimated 55,000 - 75,000 Canadians living with the disease. Typically, MS strikes in early adulthood between the ages of 20 and 50 and women are more than three times more likely to develop MS than men.

    MS is an unpredictable, often disabling disease of the CNS. It occurs because the body attacks the myelin, a protective covering wrapped around the nerves of the CNS, causing lesions or scars in the CNS as demyelination occurs.

    The cause of MS is still unknown, though current research increasingly points to a complex interplay of environmental and possibly genetic risk factors. The most common form of the disease, relapsing-remitting MS (RRMS) describes a type of MS characterized by unpredictable, but clearly defined episodes during which new symptoms appear, or existing ones get worse. These 'episodes' are also known as attacks, relapses, exacerbations, or flare-ups. The hallmark of RRMS is the recovery, or 'remission', that occurs between attacks.

    Safety information
    The most common side effects are headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects include reversible, generally asymptomatic, heart rate reduction upon treatment initiation, mild blood pressure increase, macular edema, and mild effect on lung function. Gilenya also lowers the number of white blood cells and may therefore increase the risk of infections. Patients should contact their doctor if they experience any changes in their vision, if they have trouble breathing, if they have symptoms of infection, or if they have abnormal dark urine.

    Gilenya can cause a patient's heart rate to slow down, especially after the first dose. The patients will be under medical supervision for the first six hours after the first dose to see if they have any serious side effects, including irregular heart beat. Slow heart rate usually returns to normal within one month. Patients should call their doctor if at any time they experience dizziness, tiredness or a slow or irregular heart rate.

    Gilenya may cause harm to an unborn child. Women should talk to their doctor if they are pregnant or planning to become pregnant. Women who become pregnant while on Gilenya should inform their doctor right away.

    Patients should tell their doctor about all their medical conditions, including if they have heart problems, are unable to fight infections, have eye problems, diabetes, breathing difficulties,  liver or kidney problems. Patients should also inform their doctor about all the medicines they take.

    Gilenya Patient Support Program
    Novartis provides patients and their families with a Gilenya Patient Support Program, which is designed to help optimize outcomes among those with MS. It provides patients with a wealth of up-to-date resources, including patient education, access to the personalized services of a trained nurse and access to reimbursement support services for all patients requiring Gilenya. For more information, patients and their loved ones should contact their treating physician.

    Source: ovartis Pharmaceuticals Canada Inc.(10/03/11)

    Himalayan fungus boosts Mitsubishi Tanabe sales with MS drug Gilenya

    GilenyaTetsuro Fujita’s eureka moment about a Himalayan fungus in 1985 may mean part of a $5 billion payout for Mitsubishi Tanabe Pharma Corp. a quarter-century later.

    While the scientist drove over a bridge between Japan’s Shikoku and Honshu islands on his way to take up a research post for traditional herbal remedies, Fujita realized the fungus, used in a Chinese medicinal soup, must be suppressing the immune system of the insects on which it grew.

    His research at Kyoto University not only helped yield Gilenya, a new treatment for multiple sclerosis -- the debilitating condition afflicting more than 2 million people worldwide -- it also promises to bring Mitsubishi Tanabe its biggest money earner. Annual sales of the pill, the first for the autoimmune disease, may exceed $5 billion, UBS AG said.

    “Little did I think that it would be a treatment for multiple sclerosis,” Fujita, 80, said in an in interview Kyoto. “I was more interested in immune suppression for organ transplants. I knew nothing about the disease back then.”

    Novartis AG, based in Basel, Switzerland, began selling Gilenya in the U.S. in October. Projected sales of the medicine would rank it among the 10 best-selling drugs worldwide, based on data from IMS Health Inc., a Norwalk, Connecticut-based research company.

    Mitsubishi Tanabe will probably book royalties equivalent to 10 percent of sales, based on the median of four analyst estimates in a Bloomberg News survey.

    Better Than Expected

    Kazuko Hamada, a spokeswoman for Mitsubishi Tanabe, declined to comment on the royalty payments that the Osaka, Japan-based drugmaker will receive. Novartis spokesman Eric Althoff also declined to comment on the royalties.

    Gilenya’s fourth-quarter sales of $13 million were above expectations, Dhavalkumar Patel, who heads Novartis’s autoimmune research, said last week.

    “Novartis says 2,000 people are already using the drug in three months,” Kenji Masuzoe, an analyst at Deutsche Bank AG in Tokyo, said by telephone on Jan. 28. “That’s great progress as I’ve been expecting 10,000 people by the end of this year, which will mean sales of about $350 million.”

    Multiple sclerosis causes the immune system to attack the myelin sheath, which surrounds and protects nerve cells, leading to symptoms including numbness, difficulty in coordination and memory loss, according to Medline Plus, a website of the U.S. National Institutes of Health. In its severest form, multiple sclerosis can shorten life and, in rare cases, lead to death, the U.S. National Multiple Sclerosis Society said on its website.

    Worst Performance

    Mitsubishi Tanabe rose 1.2 percent to 1,357 yen as of 10 a.m. in Tokyo trading. The stock gained 18 percent last year, outperforming Japan’s benchmark Topix index, which fell 1 percent.

    Sales at the Japanese company declined 2.4 percent in the 12 months ended March 2010, the worst performance in five years, to 404.7 billion yen ($5 billion), according to data compiled by Bloomberg.

    Annual sales of Gilenya may peak at $5.3 billion in 2018, Fabian Wenner, an analyst at UBS in Zurich, said Feb. 1.

    Gilenya is approved for the relapsing-remitting form of multiple sclerosis, the most common type, and competes with injected drugs on the market including Biogen Idec Inc.’s Avonex and Teva Pharmaceutical Industries Ltd.’s Copaxone.

    Superior Drug

    The Novartis drug cut relapses by more than half compared with Avonex, an injected therapy from U.S. drugmaker Biogen Idec Inc., according to a patient study published in the New England Journal of Medicine last year.

    Gilenya gained the support of a European medical committee in January, and a European Commission decision on approval may come in about three months. It’s also being reviewed by regulators in Japan.

    In the U.S., the drug is priced at $4,000 for a monthly prescription. That’s 66 percent more than the $2,414.99 for a pre-filled syringe of 30 micrograms per milliliter of Avonex, a month’s supply, according to PharmacyChecker.com. Analysts including UBS’s Wenner expect Gilenya to be cheaper in Europe.

    Current medicines require patients to inject themselves every other day or once a week, Kyoko Nakata, the Tokyo-based chairman of Japan’s MS Cabin, a support group for the condition, said in an e-mail.

    “They are shots, so during the course of treatment, they are a constant reminder to patients of their condition,” said Nakata, who was diagnosed with multiple sclerosis in 1993 and has been taking Bayer AG’s Betaferon since 2000. “Gilenya would make it easier to treat the disease as it saves time and brings patients closer to having a normal life.”

    Larva Invader

    With the help of another researcher, Fujita partnered with Yoshitomi Pharmaceutical Industries Ltd. and Taito Co., now respectively part of Mitsubishi Tanabe and Mitsui Sugar Co. The scientists began studying in 1986 the Cordyceps fungus known in Chinese and Japanese as “winter insect, summer plant,” so called because it invades insect larva during winter and grows out of the host by summer.

    Fujita said he was inspired by the discovery of ciclosporin, also derived from a fungus, which spurred research into how the immune system may be subdued in transplant patients. Fujita, now a professor emeritus at Kyoto University, said he was unaware the immune-modulating properties of Cordyceps could eventually help multiple sclerosis patients.

    “I knew from reading the Chinese medicinal encyclopedia that the fungus feeds off the larva, lives in a symbiotic relationship for a year, and comes out of the ground in summer by growing out of the carcass,” he said. “That made me think the fungus must be suppressing the larva’s immune response.”

    Centuries-Old Remedy

    Used as an herbal remedy for centuries, the fungus contains an insoluble, toxic compound called myriocin, said Kenji Chiba, who worked on the project at Yoshitomi. It took scientists at least three more years before they could modify the compound into a usable form, creating fingolimod, or Gilenya.

    Novartis licensed the overseas rights to fingolimod from Mitsubishi Tanabe in 1997.

    “Although it took a quarter of a century, I’m happy it’s become a drug while I’m still alive,” Fujita said. “It makes me happy that something I did is making others happy.”

    Source: Bloomberg ©2011 BLOOMBERG L.P (03/02/11)

    Oral MS drug Gilenya® approved in Australia and Switzerland

    GilenyaNovartis International AG said that Swissmedic, the Swiss Agency for Therapeutic Products, and the Australian Therapeutic Goods Administration or TGA have granted approval for Gilenya 0.5 mg as a first-line, oral disease-modifying therapy for the treatment of relapsing-remitting multiple sclerosis.

    The company stated that the data from a two-year placebo- controlled study showed a reduction in relapse rate of 54% compared with placebo.

    The studies also demonstrated that treatment with Gilenya resulted in statistically significant reductions in brain lesion activity as measured by magnetic resonance imaging.

    Ludwig Kappos,Neurology and Department of Research, University Hospital, Basel, Switzerland said "The significant efficacy and manageable safety profile of Gilenya make it a valuable new option for patients with relapsing-remitting MS and the physicians who treat them."

    Source: RTT News Copyright © 2011 RTTNews.(31/01/11)

    EU agency recommends new oral MS medication, Gilenya®

    GilenyaEuropean regulators recommended approval of Novartis's multiple sclerosis pill Gilenya on Friday, consolidating its lead as the first pill to treat the disease.

    The green light from the European Medicines Agency in London follows approval in the United States last month, where it has gone on sale at an average cost of $48,000 per patient a year.

    Recommendations for marketing approval by the agency's Committee for Medicinal Products for Human Use (CHMP) are normally endorsed by the European Commission within a couple of months.

    Gilenya is designed to treat patients with relapsing multiple sclerosis (MS), the commonest form of the debilitating disease, and its convenient dosing and efficacy is expected to make it a popular alternative to current injections.

    The European endorsement of the Novartis product comes after the EU's drug watchdog stuck to its recommendation against Merck KGaA's rival MS pill cladribine, dealing another blow to what was once the German group's biggest pipeline hope.

    Several other companies are also developing oral MS drugs, including Sanofi-Aventis, Teva Pharmaceutical Industries and Biogen Idec.

    Gilenya's first-mover advantage, however, may allow it to dominate the market and some analysts believe it could become a $3 billion-a-year-plus seller. Leading injectable drugs currently offered to treat MS are made by Biogen, Bayer and Teva.

    Offering a pill for MS could win over some of the estimated 40 percent of MS patients who do not currently receive therapy and who may be put off by painful injections and the flu-like symptoms associated with some existing drugs.

    The agency also gave a positive opinion for informed consent application for Novartis's Riprazo HCT.

    Source: Reuters © Copyright 2011 Thomson Reuters (21/01/11)

    Biogen still gauging impact of rival MS drug, Gilenya

    GilenyaBiogen Idec expects a new rival drug from Novartis AG to affect its flagship multiple sclerosis franchise, but the company's chief executive officer believes it is too early to gauge the extent of any sales erosion.

    Biogen, which makes the multiple sclerosis drugs Avonex and Tysabri, said it added 1,700 new Tysabri patients in the fourth quarter and a total of 8,200 in 2010.

    The injected drug, which Biogen sells along with Irish drugmaker Elan Corp Plc, is widely considered to be the most important growth driver for both companies.

    Swiss drugmaker Novartis won U.S. approval in September for multiple sclerosis pill Gilenya, making it the first oral treatment for the ailment in the United States.

    "Gilenya will take some market share for sure ... it is way too soon to tell how much," Biogen CEO George Scangos told Reuters during an interview at the JP Morgan Healthcare conference on Tuesday.

    In the first nine months of last year, Biogen's sales of Avonex totaled $1.86 billion, while Tysabri sales were $659 million.

    Scangos said sales of Avonex continue to do well and called Tysabri an "amazingly efficacious drug," for which Biogen is taking steps to control the risk of progressive multifocal leukoencephalopathy, or PML, a potentially fatal brain infection that has been associated with long-term use of the drug.

    The company is working with regulators to set up guidelines so that patients who use the drug are first tested for a virus associated with PML.

    "We believe there is substantial upside to Tysabri," Scangos said.

    As of the end of December, the company estimated that about 56,000 multiple sclerosis (MS) patients were on the drug worldwide, including about 600 in clinical trials.

    As of early December, Biogen reported a total of 79 PML cases, including 16 deaths.

    Source: Reuters (c) Copyright 2011 Thomson Reuters (12/01/11)

    Study reveals unexpected mechanism of new Multiple Sclerosis treatment

    GilenyaIn September, patients with multiple sclerosis (MS) received the welcome news that the U.S. Food and Drug Administration (FDA) had approved a promising new drug for their condition called Gilenya.

    Now, a team from The Scripps Research Institute has discovered that this drug’s success may involve an unexpected biological mechanism acting within the central nervous system (CNS). This difference may mean that Gilenya offers even more benefits than previously realized and would represent the first MS therapy with direct CNS activities.

    “This drug could make a big difference to MS patients,” says Jerold Chun, M.D., Ph.D., a professor in the Department of Molecular Biology and member of the Dorris Neuroscience Center at Scripps Research. “And these results are going to make doctors and scientists consider CNS mechanisms in MS therapies, as they follow patients being treated with Gilenya.”

    Beyond the Immune System?

    Gilenya is the first oral MS drug available and it was approved to treat relapsing forms of MS, the most common initial presentation of the debilitating and potentially deadly disease. The understanding among biomedical researchers has been that, like all other primary MS therapies, Gilenya acts on a patient’s malfunctioning immune system to prevent the attack on the brain that causes the disease.

    This was a logical conclusion. Among other important effects in the immune system, researchers have well documented that after Gilenya goes through a transformation in the body called phosphorylation, it binds with molecular receptors known as S1Preceptors (S1PRs) found on the surfaces of certain cells. “Then it does something weird,” says Chun.

    This binding causes the cell to internalize the receptor and ultimately destroy it. In the case of immune system cells, one subtype of receptors, called “S1P1“ are critical in the release of white blood cells (lymphocytes), from lymphoid organs, which in MS patients can damage nervous system cells. So the hypothesis was that this receptor destruction pathway gives the drug its positive MS results.

    But the Scripps Research team suspected the drug might also have important effects within the CNS. Fifteen years ago, Chun’s group was the first to discover the family of receptors that includes the S1P receptors (S1PRs). Many receptors from this family are expressed in the brain, suggesting that a drug tied to the receptors might well have important activity in the brain.

    Intriguing Brain Activity

    To test this hypothesis, the researchers genetically altered mice so that they lacked S1P1 only within the CNS. S1P1 in immune system cells remained intact.

    “If there was purely an immunologic effect, if the CNS was just a bystander, then there should be no effect from removing those CNS receptors,” says Chun.

    But that’s not what the researchers found.

    Knocking out the nervous system S1PRs decreased the severity of a mouse disease analogous to MS (experimental autoimmune encephalomyelitis). And when the team administered Gilenya to these mice, it had no effect, while it continued to affect the immune system.

    All told, these results strongly suggested that Gilenya’s main disease-fighting properties must be centered within the CNS.

    “It’s a surprising result especially considering the purely immunological focus of current MS therapies as well as many under development. That you can alter the course of this disease through S1PR signaling in the CNS points to new ways to treat MS,” says Chun.

    Precisely how Gilenya acts in the brain isn’t yet clear. The researchers have narrowed the drug’s key activity to a specific S1P receptor subtype (S1P1) and a kind of nerve cell known as an astrocyte. Other cell types expressing S1P1 or different S1P receptor subtypes may also be involved, however a dominant influence appears to involve S1P1 and the astrocyte. The researchers also found that the knockout mice had lower levels of inflammatory proteins called cytokines that are known to play a role in MS and EAE. “Exactly how all that happens still needs to be understood,” says Chun.

    Multiple Benefits

    Regardless of the specifics, which the team is now exploring, the results offer some good news for MS patients. One initially promising MS treatment that acts on the immune system (Tysabri) was taken off the market because it caused a deadly side effect in some patients—a disease called progressive multifocal leukoencephalopathy (PML), also associated with AIDS immunosuppression. Tysabri has reentered the market with a “black box” warning of PML risk.

    If Gilenya is chiefly an immunosuppressant, the fear is that it might eventually cause PML. But if the Chun team’s results apply to humans as expected, then such a problem would be less likely

    Another benefit of the work is that now that the team has shown that nervous system S1PRs play an important role in MS, researchers have a possible new target on which to focus when developing new treatments.

    The researchers will also be exploring the possibility that Gilenya’s brain locus of activity could offer neuroprotective benefits, meaning that it could shield nerve cells against MS-associated deterioration. If the drug does have such properties, it would open the possibility of actually preserving the nervous system, rather than simply reducing the number of MS attacks as is the case with other current MS drug treatments.

    Reference:
    FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte S1P1 modulation
    Ji Woong Choi, Shannon Gardell, Deron Herr, Richard Rivera, Chang-Wook Lee, Kyoko Noguchi, Siew Teng Teo, Yun C. Yung, Melissa Lu, Grace Kennedy, and Jerold Chun, Proceedings of the National Academy of Sciences, December, 2010.

    Source: BioScholar News © 2010 BioScholar News. (22/12/10)

    Novartis explores the potential of Gilenya® against primary progressive MS

    GilenyaFive years ago, Jason DaSilva, a film maker with multiple sclerosis, was able to roam his New York neighborhood, bar hopping or visiting coffee shops. Today, he needs a walker to manage 10 feet because the degenerative nerve disorder has worsened and there’s nothing to treat his severe form of the disease.

    Novartis AG is working on a pill to change that. The drugmaker won approval in September to sell the first oral medicine in the U.S. to treat the commonest form of MS, Relapsing - Remitting MS and the European Union’s drug regulator may follow suit as soon as next month. The company is beginning to test the pill, Gilenya, against the steadily worsening form of the disease that afflicts DaSilva.

    “There is still a big need, an urgent need,” said Alan Thompson, a neurologist at University College London. “An oral agent would be a big deal.”

    Gilenya already may be on its way to becoming Basel, Switzerland-based Novartis’s biggest product, with analysts on average predicting $1.8 billion of annual revenue by 2014. Sales may surge to $5.4 billion a year by 2016 as the drug’s use is expanded to advanced MS, UBS AG says. Gilenya is the most expensive MS drug, costing about $48,000 annually.

    Success would help Chief Executive Officer Joseph Jimenez overcome the loss of Novartis’s current top seller, Diovan, which had sales of $6 billion last year. The hypertension drug starts to lose U.S. patent protection in 2012.

    Immune System

    Multiple sclerosis causes the immune system to attack the insulating tissue around nerve fibers, called myelin, leading to scars and inflammation. This stops nerve cells from sending signals, leading to symptoms such as blurred vision and muscle weakness. Injected drugs including Teva Pharmaceutical Industries Ltd.’s Copaxone and Biogen Idec Inc.’s Avonex treat a common form of MS in which symptoms come and go. The more debilitating form that can rob sufferers of the ability to walk has defied therapy.

    Experiments with rats and brain scans of humans taking Gilenya led Novartis to believe the drug that may be effective against the more severe form of the disease, known as primary- progressive multiple sclerosis, said Trevor Mundel, Novartis’s head of development. The company is looking for volunteers to test the drug in 86 centres in North America and Europe, according to the Web site clinicaltrials.gov.

    ‘Holy Grail’

    “If they can show that it works, then this is a home run,” Karl-Heinz Koch, an analyst at Helvea SA in Zurich, said in an interview. “This is the holy grail.” He recommends buying the shares and predicts they may gain 28 percent in the next year.

    Gilenya blocks white blood cells called lymphocytes from circulating in the body, preventing them from reaching and doing damage to the brain, spinal cord and optical nerves. Not only did the drug protect a certain type of nerve cell in rat and test tube experiments, scans of patients taking the drug showed a slowing of brain shrinkage, a sign that the treatment may lessen the destruction of nerves.

    This may mean that in addition to calming the immune system, Gilenya may also curb inflammation, offering two possible ways to take on the disease, Mundel said.

    Inflammation

    Primary-progressive MS seems to be marked by a lower level of inflammation that is more damaging to nerve cells, said Thompson, who also is editor in chief of the journal Multiple Sclerosis. Patients may not benefit from available therapies, so-called immunomodulators, because they primarily target inflammation, Thompson, the UCL researcher, said.

    The trial of the drug in primary-progressive multiple sclerosis also may encourage doctors to prescribe Gilenya for patients with the milder form as well, because it would show that the drug both repairs nerves and calms the immune system, Thompson said. “If you had a treatment that combined the two, using it early could have profound effect on the long-term outcome,” Thompson said.

    Multiple sclerosis affects about 2.5 million people worldwide, many of whom have trouble sticking with current therapies because they’re difficult to use or have side effects, according to the National Multiple Sclerosis Society, a New York-based patient group. About 10 percent have primary- progressive multiple sclerosis.

    ‘Challenging Form’

    “The medicines on the market have been evaluated in clinical trials based on their ability to slow relapses, while people with PPMS don’t have relapses,” Nicholas LaRocca, the society’s vice president of health-care delivery and policy research. “This is a very challenging form of MS.”

    Roche Holding AG’s Rituxan, approved for rheumatoid arthritis, non-Hodgkin’s lymphoma and leukemia, failed to slow PPMS in a two-year study, according to results published in 2008. Analysts at Deutsche Bank AG had expected it to earn more than 500 million Swiss francs ($518 million) annually for Roche. Biogen Idec’s Avonex also didn’t make it beyond clinical testing for the advanced form of the disease.

    The lack of alternatives has led DaSilva to try Rituxan anyway. “There’s nothing else out there, so I chose something better than nothing,” DaSilva, 32, who lives in New York’s East Village, said in an interview.

    History of Disappointment

    Merck KGaA also has developed an oral treatment for the more mild form of MS. European regulators in September rejected the drug, cladribine, as being too risky, and the FDA delayed a decision until February. The drug, which is approved for use in Russia, isn’t being tested in the more severe form of the disease, said Gangolf Schrimpf, a spokesman for the Darmstadt, Germany-based company.

    “The history of PPMS has been one of disappointment,” Novartis’s Mundel said. “Everything has been thrown at this disease and nothing has worked.”

    Still, using Gilenya as a treatment may be a long way off. Because of the slow-moving nature of the disease, the last patients may not finish the trial until 2013, according to clinicaltrials.gov. Even then, there’s no guarantee the drug will prove successful, said Thompson, of University College.

    “It’s impossible to say, but I am an optimist,” said Aaron Miller, a neurologist at the Mount Sinai School of Medicine in New York. “The trial is designed in a way to have optimal chances of success.” Miller is an investigator in the PPMS study.

    Even for people with the milder form, Novartis expects Gilenya sales to build slowly, as it takes some time for doctors to shepherd patients through the safety tests the U.S. Food and Drug Administration required for the drug.

    DaSilva, who is making a film called “When I Walk” about living with the disease and searching for treatment, says he would be willing to try any new drug.

    “It would be wonderful to have something we can try,” he said.

    Source: Bloomberg ©2010 BLOOMBERG L.P (21/12/10)

    Oral Gilenya & Cladribine expected to secure initial European approval

    CladribineThe majority of surveyed neurologists in France, Germany, Italy, Spain and the United Kingdom expect that both Novartis/Mitsubishi Tanabe's oral agent Gilenya (FTY-720/fingolimod) and Merck Serono's oral cladribine will most likely secure initial European approval for use in relapsing forms of multiple sclerosis (MS), which includes relapsing-remitting MS (RR-MS) and relapsing forms of secondary progressive MS (SP-MS).

    The new European Physician & Payer Forum report entitled Multiple Sclerosis in Europe: How Will Clinician Attitudes and Payer Hurdles Determine How Late-Stage Oral Therapies Will Compete with Current Disease-Modifying Drugs? finds that the greatest proportion of surveyed neurologists expect that the first approved use of either disease-modifying drug will be for the treatment of patients with relapsing forms of MS who have failed first line therapy. However, very few neurologists in any market under study anticipate that either agent will not attain European regulatory approval an important finding given the previous rejection of oral cladribine by European regulators in September 2010.

    "Despite the convenient oral formulations and robust efficacy offered by Gilenya and oral cladribine, surveyed neurologists anticipate that regulatory authorities will stipulate that both drugs be used in the later line, a restriction that currently only applies to Biogen Idec/Elan's Tysabri," said Decision Resources Director Bethany Kiernan, Ph.D. "This finding likely reflects neurologists' conservative attitude towards these drugs, owing to safety concerns."

    Surveyed neurologists expect that, one year after its launch, a greater percentage of RR-MS patients will receive Gilenya than any other subtype of the disease. When asked to assign a patient share for oral cladribine one year after its launch, surveyed neurologists in the EU5 anticipate that they will likewise prescribe the drug to more RR-MS patients than patients within other disease subtypes.

    The report also finds that the anticipated high cost of Gilenya and oral cladribine will not be a significant hurdle to their reimbursement.

    "Even as most European markets are instituting more stringent cost-containment measures to reign in overall healthcare costs, interviewed reimbursement experts in each of the EU5 countries expect that assuming each agent attains approval Gilenya and oral cladribine will be fully reimbursed according to their labeled indications," Dr. Kiernan said. "These experts likewise anticipate that emerging disease-modifying therapies will not have a sizeable impact on the reimbursement status of currently available therapies, reinforcing the perception of new agents as an addition to not as a replacement for the current MS armamentarium."

    Source: Medical News Today © 2010 MediLexicon International Ltd (20/12/10)

    Novartis MS program guides patients to new oral drug, covers out-of-pocket costs

    GilenyaNovartis AG will pay out-of-pocket costs for non-Medicare patients who use the company’s multiple sclerosis pill Gilenya when the drug, to be priced at $4,000 a month, goes on sale in the U.S. this week.

    The Swiss drugmaker will pay as much as $800 monthly in co- payments for Gilenya, the first oral medicine for the condition, the company said in an e-mail. Novartis will also help patients navigate testing and monitoring recommended by U.S. regulators who approved Gilyena on Sept. 22, paying as much as $600 per patient for that expense.

    While many drugmakers provide medicine for the poor and help people with insurance, Novartis’s plan isn’t contingent on income or medical history, said Darlene Jody, head of Novartis’s MS medical unit. Andrew Weiss, an analyst at Bank Vontobel AG in Zurich, predicts peak sales of $3 billion a year for Gilenya, which will compete with Biogen Idec Inc.’s Avonex, an injectable drug that generated $2.3 billion in sales last year.

    “It’s a pretty aggressive approach,” said Ira Loss, an analyst with Washington Analysis. “It seems like an enhancement of what was required. Maybe Novartis decided to build on that and make it a patient-friendly program. My hat’s off to them.”

    The FDA, in approving the drug, recommended that patients treated with Gilyena be monitored for six hours after their first dose, and that an array of baseline tests be done to check their liver, eyes, blood and heart.

    Disabling Disease

    Loss, who regularly monitors actions of the Food and Drug Administration, said he hasn’t heard of such an extensive payout program by a drugmaker in the 30 years he’s covered the industry.

    Multiple sclerosis is a chronic, often disabling disease that attacks the central nervous system, which is made up of the brain, spinal cord, and optic nerves. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision, according to the National Multiple Sclerosis Society website.

    The Novartis program assigns “nurse navigators” to patients enrolled independently or through their doctors, Jody said. The nurses provide logistical support, educational materials, and a hotline. The program also will offer money for co-payments and related tests and, for those without insurance who earn less than 500 percent of federal poverty levels, full coverage of treatment costs.

    ‘Best Support’

    “We are providing what we believe is the best support to the MS community,” Novartis’s Jody said. “This group and their caregivers have a certain degree of expectation. We think it’s important that every appropriate patient has access to Gilenya.”

    The Novartis program will cover costs for patients with commercial health insurance, she said. Patients enrolled in government insurance programs, such as Part D for Medicare, the U.S. health plan for the elderly and disabled, aren’t eligible to participate because of legal restrictions. That’s also true of patients who live in Massachusetts, with some restrictions for patients in Michigan, Rhode Island and Minnesota.

    Less than half of the estimated 400,000 people in the U.S. with the illness are now getting therapy, said Trevor Mundel, global head of drug development for Novartis, in a telephone interview.

    Side Effects

    The drug may help patients who can’t use existing medications because of side effects or continued relapses, he said. New patients and those who fear the use of needles may also consider Gilenya, Mundel said.

    Eric Althoff, a spokesman for Basel-based Novartis, said in a Sept. 30 e-mail that the pill will be priced wholesale at about $48,000 annually. Injectable treatments such as Avonex, Merck KGaA’s Rebif and Teva Pharmaceutical Industries Ltd.’s Copaxone cost between $2,800 and $3,200, for a standard month’s supply, according to the Web site destinationrx.com.

    WellPoint Inc., an Indianapolis-based health insurer that provides pharmacy benefits for about 25 million Americans, will make the drug immediately available for its members, said Jeff White, director of drug evaluation and clinical analytics.

    WellPoint, along with rivals like UnitedHealth Group Inc., of Minnetonka, Minnesota, will place Gilenya in a top price tier that typically carries the highest out-of-pocket expense until a data review determines its value for patients, officials said.

    At Wellpoint, the least favorable tier of service carries a $45 a month co-pay and potentially a 20 percent co-insurance fee, with an upper limit of $250 a month, White said. A 30-day supply of a standard injected drug for multiple sclerosis is currently about $266, White said.

    ‘Other Than a Needle’

    The drug is a welcome relief to Seth Morgan, a 56-year-old neurologist in Chevy Chase, Maryland, who practiced until symptoms from multiple sclerosis and the medicine he took to treat it led him to retire. While he suffered relapses of the disease every six months to 12 months since he was diagnosed six years ago, he hasn’t had one since starting Gilenya in one of the clinical trials, Morgan said.

    “This isn’t a godsend for everyone,” Morgan said in a telephone interview. “But this drug has arrested my exacerbations, and I’m pretty much where I was three years ago,” before starting Gilenya, he said. “And I wanted something other than a needle, quite frankly.”

    Patients are already calling Jeffrey Cohen, a physician at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, about the drug, he said.

    Cohen, who has led studies of Gilyena, said he is counseling patients who are doing well with the shots to stick with them for the moment.

    “For patients on one of the available treatments, we’re advising them, even though they are tempted to change to a pill, to hold off until we get a little more information,” Cohen said. “But they are still tempted.”

    Source: Bloomberg ©2010 BLOOMBERG L.P. (05/10/10)

    FDA approval for oral MS drug Gilenya(TM)

    GilenyaNovartis announced that the US Food and Drug Administration (FDA) approved the oral multiple sclerosis (MS) treatment Gilenya(TM) (fingolimod) 0.5 mg daily, a first-line treatment for relapsing forms of multiple sclerosis - the most common forms of the disease.

    The FDA approval makes Gilenya the first oral treatment indicated for relapsing forms of MS available in the US.

    "Today is a significant and encouraging day for people with relapsing forms of MS in the US," said Nicholas LaRocca, Vice President of Healthcare Delivery and Policy Research at the National Multiple Sclerosis Society. "A new treatment option that offers significant efficacy in the convenience of a capsule is a welcome alternative to frequent injections for individuals living with this chronic disease."

    Gilenya reduces the frequency of MS relapses (flare-ups) and helps slow the build-up of some of the physical problems caused by MS. In clinical trials, Gilenya has a well-studied safety and tolerability profile, which has been characterized in over 2,600 clinical trial patients, some of whom are in their seventh year of treatment, with more than 4,500 patient years of experience.

    "Through a novel mechanism of action, Gilenya can significantly improve clinical outcomes among patients with relapsing forms of MS," said Fred Lublin, MD, Saunders Family Professor of Neurology, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine. "Gilenya provides significant efficacy and manageable safety when used in accordance with approved labeling, making it a valuable advancement for relapsing MS patients and the physicians who treat them."

    The Gilenya approval was based on the largest clinical trial program ever submitted to date to the FDA for a new MS drug and included combined data from clinical studies showing significant efficacy in reducing relapses, the risk of disability progression, and the number of brain lesions detected by magnetic resonance imaging (MRI), a measure of disease activity, in people with relapsing forms of MS.

    "We are proud to have worked successfully with the MS community toward a shared goal of bringing a novel efficacious treatment to people with relapsing forms of MS," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "We are actively pursuing regulatory approval in Europe and the rest of the world."

    Gilenya is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. In MS, the immune system damages the covering that protects nerve fibers in the central nervous system (CNS), which includes the brain and spinal cord. Gilenya's novel mechanism is unknown, but it is thought to work by reducing the immune system's attack on the CNS by retaining certain white blood cells (lymphocytes) in the lymph nodes. This prevents the white blood cells from reaching the CNS, where they could potentially attack the protective covering around the nerve fibres, resulting in less inflammatory damage to the nerve cells. The white blood cell retention is reversible if Gilenya treatment is stopped.

    About Gilenya
    Gilenya is a prescription medicine used to treat relapsing forms of MS in adults. Gilenya can decrease the number of MS flare-ups (relapses). Gilenya does not cure MS, but it can help slow the build up of physical problems that MS causes.

    The FDA regulatory application included data showing Gilenya 0.5 mg reduced relapses by 52% (P<0.001) at one year compared with interferon beta-1a IM (Avonex®), one of the most commonly prescribed treatments for MS Gilenya also reduced disease activity as measured by the number of new and newly enlarged T2 lesions on MRI scans compared to interferon beta-1a IM (1.6 vs 2.6, respectively, P=0.002) at one year.

    Data from a two-year placebo-controlled study showed a reduction in relapse rate (54% reduction P<0.001, compared with placebo) and risk of disability progression among Gilenya patients (30% reduction confirmed at three-month follow-up visit P=0.02, compared with placebo).

    In both studies, treatment with Gilenya also resulted in statistically significant reductions in brain lesion activity as measured by MRI.

    Gilenya was submitted to the European Medicines Agency (EMA) and to the US Food and Drug Administration for review in December 2009. The EMA regulatory review and other filings worldwide are ongoing.

    Gilenya Important Safety Information
    Gilenya may cause serious side effects such as slow heart rate (bradycardia or bradyarrhythmia), infections, macular edema, breathing and liver problems.

    Gilenya can cause a patient's heart rate to slow down, especially after the first dose. The heart rate will usually slow down the most about six hours after a patient takes their first dose of Gilenya. Patients might feel dizzy or tired or be aware of a slow or irregular heartbeat if their heart rate slows down. A doctor will watch patients for the first six hours after they take the first dose to see if they have any serious side effects. A patient's slow heart rate will usually return to normal within about one month after they start taking Gilenya. Patients should call their doctor if at any time they have dizziness, tiredness or a slow or irregular heartbeat.

    Gilenya can increase a patient's risk of serious infections. Gilenya lowers the number of white blood cells (lymphocytes) in the blood. This will usually go back to normal within two months of stopping treatment. A patient's doctor may perform a blood test before they start taking Gilenya. Patients should call their doctor right away if they have fever, tiredness, body aches, chills, nausea or vomiting.

    Macular edema can cause some of the same vision symptoms as an MS attack (optic neuritis). Patients may not notice any symptoms with macular edema. Macular edema usually starts in the first three to four months after taking Gilenya. A doctor should test a patient's vision before they start taking Gilenya and three to four months after they start taking Gilenya, or any time they notice vision changes during treatment. Risk of macular edema may be higher if a patient has diabetes or has had an inflammation of the eye called uveitis. Patients should call their doctor right away if they have blurriness, shadows or a blind spot in the center of their vision, sensitivity to light or unusually coloured vision.

    Some patients who take Gilenya have shortness of breath. Patients should call their doctor right away if they have trouble breathing.

    Gilenya may cause liver problems. A doctor should do blood tests to check a patient's liver before they start taking Gilenya. Patients should call their doctor right away if they have nausea, vomiting, stomach pain, loss of appetite, tiredness, dark urine, or their skin or the whites of their eyes turn yellow.

    Gilenya may harm an unborn baby. Women should talk to their doctor if they are pregnant or planning to become pregnant. Women who can become pregnant should use effective birth control while on Gilenya and for at least two months after stopping. If a patient becomes pregnant while taking Gilenya or if they become pregnant within two months after stopping Gilenya, they should tell their doctor right away. Women who take Gilenya should not breastfeed, as it is not known if Gilenya passes into breast milk.

    Patients should tell their doctor about all their medical conditions, including if they have had or now have an irregular or abnormal heartbeat, a heart rate of less than 55 beats a minute, a fever, infection or if they are unable to fight infections, eye problems, diabetes, breathing or liver problems, or high blood pressure. Patients should especially tell their doctor if they have had chicken pox or have recently received the vaccine for chicken pox. A doctor may do a test for chicken pox virus and patients may need to get the vaccine for chicken pox and wait one month before starting Gilenya.

    Patients should tell their doctor about all the medicines they take, including medicines for heart problems or high blood pressure, vaccines, other medicines to control their immune system or treat cancer, or ketoconazole (an antifungal) by mouth.

    The most common side effects with Gilenya were headache, flu, diarrhea, back pain, abnormal liver tests and cough.

    Gilenya Risk Evaluation and Mitigation Strategy (REMS)
    Gilenya has been approved in the US with a Risk Evaluation and Mitigation Strategy (REMS) to inform patients and healthcare providers on the safe use and serious risks of Gilenya in treating relapsing forms of MS. The approved REMS includes a medication guide for patients, and a letter and safety information guide for healthcare providers. Additionally, Novartis will initiate a five-year, worldwide post-authorization safety study to monitor selected safety-related outcomes and a voluntary pregnancy registry, the findings from which will be used to give healthcare providers important information for treating and counseling patients with MS that are pregnant or may become pregnant.

    Source: Novartis Pharma AG.(22/09/10)

    Russian regulatory approval for Gilenya(R) oral multiple sclerosis therapy

    GilenyaNovartis International AG announced Russian regulatory approval for Gilenya(R), a once-daily oral multiple sclerosis therapy and first in a new class processed and transmitted by Hugin AS. The issuer is solely responsible for the content of this announcement.

    - Russia is first country to approve Gilenya for the treatment of relapsing remitting MS, the most common form of the disease

    - Gilenya is the first disease-modifying treatment in a new drug class and offers significant efficacy with a well-characterized safety tolerability profile

    - Action from the US Food and Drug Administration (FDA) on Gilenya is expected in September 2010; other submissions under review worldwide

    Basel, September 10, 2010 - The Russian health authority, the Federal Service on Surveillance in Healthcare and Social Development, has granted approval for Gilenya(R) (fingolimod) 0.5 mg once-daily oral therapy for the treatment of relapsing remitting multiple sclerosis (MS).

    Approximately 85% of patients with MS are estimated to have the relapsing remitting form at the onset of disease. Russia is the first country to approve Gilenya, providing a new treatment option offering significant efficacy for patients in the convenience of an oral capsule. Novartis expects to launch Gilenya in Russia in early 2011.

    In June, an advisory committee of the US Food and Drug Administration (FDA) unanimously recommended approval of Gilenya and action from the FDA is expected in September 2010. Gilenya is also under review by the European Medicines Agency (EMA) as well as other health authorities worldwide.

    Data from one of the largest-ever Phase III clinical trial programs conducted in MS were submitted to support the regulatory submissions. These studies provided evidence of the efficacy of Gilenya in reducing relapses, disability progression and brain lesions in patients with relapsing remitting MS as well as safety data.

    Gilenya is the first in a new class of compounds called sphingosine 1-phosphate receptor (S1PR) modulators. Gilenya provides selective and reversible retention of lymphocytes in lymph nodes, preserving key immune functions and flexibility in patient management.

    Source: Marketwatch © 2010 MarketWatch, Inc (10/09/10)

    Most neurologists plan to prescribe new oral Multiple Sclerosis drugs

    Oral MS DrugsStudy indicates that neurologists’ apprehension regarding side effects will not stop them from prescribing new oral MS drugs, but concerns will likely relegate their use to second- or third-line therapy.

    In a study published this week by Majestic Research, almost 60% of neurologists expressed unaided concern about the side effects/safety of oral MS therapies in development, including NVS’s Gilenia and MRK/EMD Serono’s cladribine.

    Despite their concerns, the vast majority of neurologists expect to prescribe these drugs if they are approved, as the new oral MS therapies are expected to be highly efficacious and more convenient for patients than available injectable therapies. Data from the study suggests that new orals will steal share primarily from multiple sclerosis market leaders, including BIIB’s Avonex and TEVA’s Copaxone.

    The study titled Event Pulse Preview: Multiple Sclerosis shows that 84% of neurologists expect to prescribe Gilenia for some MS patients if approved, but prescribing will likely be limited to second- or third-line therapy until concerns about safety and monitoring requirements are resolved. Jemma Lampkin, Director of Market Research, said, “Neurologists are clearly worried about the side effects that have come up in the clinical trials for these drugs in development, and the negative press regarding Tysabri’s PML cases over the past few years also seems to be a factor. Still, almost all of the neurologists in this study expect to prescribe Gilenia, so there is optimism regarding its potential.” The study suggests that Gilenia, which is expected to be approved in September 2010, could have a more significant impact than some have predicted.

    Event Pulse Preview: Multiple Sclerosis includes analysis of a targeted Internet survey of 75 neurologists, 10 in-depth telephone interviews with pharmacy directors at major managed care organizations, and proprietary longitudinal treatment data from a panel of 200 neurologists spanning 2005-2010. Conducted in August 2010, the report takes an in-depth look at how new MS therapies will affect the multiple sclerosis market. In addition, Event Pulse Preview: Multiple Sclerosis evaluates uptake and use of recently approved Ampyra and Botox for MS. The qualitative portion also examines the current reimbursement climate for multiple sclerosis drugs as well as the anticipated response to new oral MS drugs among major managed care organizations.

    About Event Pulse

    Event Pulse is a syndicated report series that evaluates the impact of market events on physician treatment practices. This report series provides information on how changes such as new products, data, or guidelines fit into the treatment algorithm, impact current therapies, and change market dynamics.

    Source: BusinessWire © 2010 BusinessWire (02/09/10)

    Oral MS drug FTY720 recommended for approval by FDA committee

    FTY720An advisory committee of the US Food and Drug Administration (FDA) recommended approval of FTY720 (fingolimod) for the treatment of patients with relapsing multiple sclerosis, the most common form of the disease.

    The FDA has the option of seeking the advice of one of its advisory committees as it reviews and decides whether to approve a new treatment. The committee voted unanimously that FTY720 demonstrated substantial efficacy in treating relapsing-remitting MS and that safety of the proposed 0.5 mg dose justified approval.

    "This is an encouraging and important milestone for the MS community," said Dr. Patricia O'Looney, Vice President, Biomedical Research at the National Multiple Sclerosis Society. "We believe that a treatment that reduces relapses and slows disability progression in a convenient oral formulation could encourage more people with MS to initiate treatment in the course of this life-long disease."

    The committee evaluated data from the largest clinical trial program ever submitted to the FDA as part of an MS new drug application. This study data provided evidence of superior efficacy of FTY720 over one of the most commonly prescribed treatments, interferon beta-1a IM (Avonex®), and to placebo, in reducing relapses and brain lesions (a measure of disease activity) (1,2). In addition, the two-year placebo-controlled study showed FTY720 significantly delayed disability progression(2). The advisory committee discussed monitoring parameters for the therapeutic use of FTY720 and also recommended post-marketing collection of additional safety data and evaluation of a lower dose.

    "Novartis is pleased by the committee's vote to recommend FDA approval of FTY720 as a treatment that has demonstrated substantial efficacy for relapsing remitting multiple sclerosis. The committee's positive vote affirms the favourable benefit/risk profile of FTY720 and we will work closely with the FDA as it finalizes its review of our new drug application," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "If approved, FTY720 will offer patients an effective treatment in the convenience of a pill and we look forward to making this innovative therapy available for people with MS."

    If approved, FTY720 would potentially be the first oral therapy for treating relapsing MS. FTY720 would be the first in a new class of therapies developed for relapsing MS called sphingosine1-phosphate receptor (S1PR) modulators, which work by retaining certain immune cells (lymphocytes) in the lymph nodes, preventing them from reaching the central nervous system and causing damage. This lymphocyte retention is reversible, allowing circulating lymphocytes to regain normal levels if treatment is stopped.

    Source: Medical News Today © 2010 MediLexicon International Ltd (08/08/10)

    Neurologists twice as aware of oral MS drug Cladribine than oral FTY-720

    CladribineDecision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that surveyed neurologists have low awareness of Novartis/Mitsubishi Tanabe's FTY-720 (Gilenia) among the surveyed oral emerging therapies for the treatment of multiple sclerosis (MS).

    According to the new report, Brand Perception Series: Physician Segmentation in Multiple Sclerosis, just over one-third of surveyed physicians have heard of FTY-720 (Gilenia) compared with three-quarters of surveyed physicians who are aware of Merck Serono/EMD Serono's oral cladribine and half of surveyed physicians who are aware of Teva/Active Biotech's laquinimod.

    The majority of surveyed physicians indicate that they will use the surveyed emerging oral agents in relapsing/remitting MS patients who have failed therapy with interferon betas and Teva's Copaxone.

    Only a small percentage (10 percent or less) will use the surveyed emerging oral agents in treatment-naive patients. Surveyed physicians report they will most likely prescribe these emerging oral agents for patients who cannot tolerate the side effects of their current therapy or who are unwilling to risk the side effects of Biogen Idec/Elan's Tysabri.

    Thirty percent of physicians surveyed fall into the high-volume, cost-conscious prescriber segment, and value out-of-pocket cost to the patient and reimbursement restrictions more than the other segments in this analysis.

    "Among the three physician segments identified in this analysis, the high-volume, cost-conscious prescribers are the most-likely to prescribe FTY-720 (Gilenia) if approved. Survey results indicate the majority of these physicians will reserve prescribing the agent to patients who have failed both interferon-betas and Copaxone, or to those who have failed Tysabri," said Decision Resources Analyst Cindy Fung, Ph.D. "While FTY-720 may be reserved as a later-line therapy, high-volume, cost-conscious physicians are not as concerned about familiarity with an agent, so they may be more willing to adopt a novel emerging agent, provided it is priced competitively."

    About Brand Perception Series: Physician Segmentation

    Brand Perception Series: Physician Segmentation identifies key physician segments to uncover targeted opportunities for current and emerging drug brands. This series offers a fresh look at a competitive drug market by analyzing physician perception of current and emerging drugs using unique physician profiles that will help biopharmaceutical companies understand and size market opportunities.

    Source: Medical News Today © 2010 MediLexicon International Ltd (19/07/10)

    Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients

    FTY720Abstract
    FTY720 (Fingolimod) reduces multiple sclerosis disease activity by inducing lymphopenia and inhibiting lymphocyte re-entry from lymph nodes.

    Peripheral lymphocyte reconstitution following drug discontinuation has been considered relatively rapid (2-4weeks), based on short-term studies.

    We investigated the kinetics of lymphocyte reconstitution in MS patients in open label extension phases of FTY720 clinical trials who discontinued therapy after prolonged use (>1-5years), and examined histological features of a mediastinal lymph node obtained from a lymphopenic FTY720 patient.

    Although three patients showed reconstitution of peripheral lymphocytes within the predicted timeline, two patients continued to be lymphopenic 9 and 34months after therapy cessation. Lymph nodes from the latter patient showed preserved architecture.

    Notwithstanding preserved lymph node integrity, time for lymphocyte reconstitution after prolonged FTY720 therapy can be significantly greater than predicted by shorter-term studies.

    This is relevant for clinical decisions regarding management of patients using this therapy and for introducing alternate therapies.

    Johnson TA, Shames I, Keezer M, Lapierre Y, Haegert DG, Bar-Or A, Antel J.

    Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

    Source: Clin Immunol. 2010 Jul 2 - Copyright © 2010 Elsevier Inc. & Pubmed PMID: 20599429. (14/07/10)

    FTY720 oral MS treatment gets unanimous FDA approval

    FTY720Novartis investigational treatment FTY720 (fingolimod) has received unanimous FDA approval for the treatment of patients with relapsing multiple sclerosis (MS).

    The advisory committee of FDA, that reviews and decides whether to approve a new treatment, has voted that FTY720 demonstrated substantial efficacy in treating relapsing remitting MS and that safety of the proposed 0.5mg dose justified approval.

    Novartis said that the committee has assessed data from the clinical trial program which provided evidence of superior efficacy of FTY720 over interferon beta-1a IM (Avonex), and to placebo, in reducing relapses and brain lesions (a measure of disease activity).

    Reportedly, the two-year placebo-controlled study showed FTY720 delayed disability progression. The advisory committee discussed monitoring parameters for the therapeutic use of FTY720 and also recommended post-marketing collection of additional safety data and evaluation of a lower dose.

    Novartis stated that the FDA granted FTY720 priority review status in February 2010, reducing the standard 10-month review to six months. In May, the FDA extended the priority review period by three months to September 2010.

    Novartis claimed that if approved, FTY720 would be the first oral therapy for treating relapsing MS. FTY720 would be the first in a new class of therapies developed for relapsing MS called sphingosine1-phosphate receptor (S1PR) modulators.

    Patricia O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society, said: "We believe that a treatment that reduces relapses and slows disability progression in a convenient oral formulation could encourage more people with MS to initiate treatment in the course of this disease."

    Trevor Mundel, global head of development at Novartis, said: "Novartis is pleased by the committee's vote to recommend FDA approval of FTY720.

    "The committee's positive vote affirms the favorable benefit/risk profile of FTY720 and we will work closely with the FDA as it finalises its review of our new drug application.

    "If approved, FTY720 is expected to offer patients treatment in the convenience of a pill and we look forward to making this therapy available for people with MS."

    Source: PBR © Business Review, Progressive Media Group (11/06/10)

    FDA says Novartis’ oral multiple sclerosis drug, FTY720, works, but has side effects

    FTY720Federal health regulators said Tuesday a highly anticipated Novartis drug for multiple sclerosis appears effective but carries a number of side effects, including lung and eye problems.

    Swiss drugmaker Novartis has asked the Food and Drug Administration to approve its drug Gilenia to treat patients with relapsed multiple sclerosis, which causes tremors and movement problems. The drug is a daily pill and would offer an alternative to older injectable drugs.

    FDA reviewers said two studies of the drug “provide substantial evidence for an effect.”

    However, FDA staff also noted a number of side effects with the drug, including eye disorders, heart problems and weakened lung function.

    Serious side effects occurred in at least 8.5 percent of patients taking Novartis’ drug, compared with 5.8 percent of patients taking older multiple sclerosis drugs.

    FDA reviewers complained that there was little data on the long-term effects of using Gilenia.

    On Thursday the FDA will ask a panel of experts whether additional safety studies should be required to assess the drug’s risks. The panel will also vote on whether the drug should be approved. The FDA is not required to follow the group’s advice, though it usually does.

    In its own briefing documents posted online, Novartis said it would distribute educational materials on using the drug safely to doctors and patients.

    About 2.5 million people around the world have multiple sclerosis, a neurological disease that can cause muscle tremors, paralysis and problems with speech, memory and concentration. In the most common form of the disease, patients experience periods of well-being followed by periodic relapses.

    Current treatments can reduce the duration and severity of symptoms but require daily or regular shots or infusions.

    Physicians who treat multiple sclerosis are mindful of safety problems with other recent treatment for the disease. Biogen Idec’s drug Tysabri was approved for the condition in November 2004 and pulled from the market the next year after cases of a rare but lethal brain inflammation in some patients. It was reintroduced in 2006 under an FDA-approved distribution program.

    Source: Business News © 2010 Taragana (09/06/10)

    Fingolimod (FTY720) supports ADLs in Multiple Sclerosis

    FTY720Multiple sclerosis patients who took the oral investigational agent fingolimod were better able to maintain activities of daily living over a year than those treated with injected interferon beta-1A, according to a study presented here at CMSC-ACTRIMS.

    Patients taking the standard injected therapy interferon beta-1A (Avonex) had more pronounced decline in their ability to perform ADLs based on a patient reported activity scale -- dropping by 0.43 points over 12 months, compared with those on either of two doses of fingolimod, whose scores dropped by just 0.08 and 0.12 points (P<0.05 for both comparisons), Jeffrey Cohen, MD, of the Neurologic Institute of the Cleveland Clinic in Cleveland, Ohio, reported.

    Fingolimod has previously been shown to reduce multiple objective measures of disease activity in patients with relapsing-remitting MS, as part of the TRANSFORMS study, which compared fingolimod to interferon beta-1A, Cohen said here at the meeting of the Joint Consortium of Multiple Sclerosis Centers and America's Committee on Treatment and Research in Multiple Sclerosis.

    The current study is a tertiary analysis from that study.

    Fingolimod modulates sphingosine-1-phosphate receptors on lymphocytes, blocking their exit from the lymph node, and thus reducing self-reactive lymphocytes in the central nervous system, Cohen explained.

    Patients in the study were randomized to receive daily oral fingolimod at either 0.125 mg or 0.5 mg, or 30 μ of intramuscular interferon beta-1A, for 12 months.

    All patients concurrently received a placebo treatment matching the other treatment arm. The three treatment groups were matched for mean age (36 years), disease duration (mean seven years), recent relapses, and disability.

    The effect of treatment on activities of daily living was measured with the PRIMUS scale, a patient self-reported measure developed with patient input.

    The scale comprises 15 items covering numerous domains, such as ability to do light jobs around the house, climb a flight of stairs, or prepare food, and has been validated for use in clinical trials. Each question is scored either 0 (no limitations), 1 (activity performed with difficulty), or 2 (cannot perform the activity), for a minimum score of 0 and a maximum of 30.

    The scale was administered at baseline, six months, and 12 months. Because the scale was not available in the language of all participating countries, only 909 of the 1,292 patients in the TRANSFORMS study participated, and 832 completed the 12-month evaluation.

    Baseline PRIMUS scores were "overall quite low," Cohen said, with mean scores of 3.2, 3.2, and 3.0, in the low-dose fingolimod, high-dose fingolimod, and in the interferon groups, respectively.

    Low-and high-dose fingolimod were superior to interferon beta-1A not only in total change from baseline, but also in the percentage of patients who improved on the PRIMUS scale during the 12 months (17.5%, 19.5%, and 14.1% respectively), and the percent who worsened (17.9%, 19.6%, and 24.1%, respectively).

    But, Cohen noted, the baseline disability of the patients was "quite mild," and "the overall magnitude of mean change was quite small in all three groups."

    "The trial was of relatively short duration, and a longer follow-up will be needed to obtain more clinically meaningful results," he said.

    Rock Heyman, MD, of the Department of Neurology at the University of Pittsburgh School of Medicine, commented that a quality-of-life scale is valuable in MS.

    The standard measures of MS progression, including even relapse rates, "may mean a lot to neurologists," he said, "but may not mean as much to patients," who are likely more interested in those aspects directly measured by quality-of-life scales.

    The results on the PRIMUS scale in this trial indicate the medicine "is helping to preserve day-to-day function," he continued. "Patients want to see everything else as well, but they want to know, 'how am I going to feel after a year?'"

    Heyman did not recommend that quality-of-life measures be the major outcome of trials, since they do not directly measure disease modification, "but they are very important and should be taken into account."

    An FDA advisory panel is meeting on Thursday to decide whether to recommend fingolimod for approval.

    Sources: Primary: International Journal of MS Care
    Source reference:
    Cohen J, et al "Oral fingolimod (FTY720) improves performance of daily activities compared with intramuscular interferon beta-1a: Patient-reported indices for multiple sclerosis (PRIMUS activities) results from the TRANSFORMS phase 3 trial" International J MS Care 2010; 12(suppl1): 16.

    Souce: Medpage Today © 2004-2010 MedPage Today, LLC. (08/06/10)

    Safety fears hang over pioneering Novartis MS pill

    FTY720* Gilenia leads U.S. race as first multiple sclerosis pill

    * FDA panel to vote on drug June 10, staff documents June 8

    * Cancer and heart safety concerns expected to loom large

    * Rival drugs in works from Merck KGaA, Teva, Sanofi, Biogen

    Swiss drugmaker Novartis AG's race to get the first multiple sclerosis pill to market reaches a pivotal point next week when U.S. experts vote on whether Gilenia should be recommended for approval.

    A green light is far from assured. Although the new drug has outperformed current injectable medicines in trials, it is associated with a range of potentially serious side effects that could limit its use or block it from the market altogether.

    Industry analysts at Citigroup think the safety issues on Gilenia are a "50/50 call" and the market generally is cautious, suggesting scope for significant share price moves depending on the outcome of the June 10 advisory meeting.

    Novartis officials, however, are hopeful the experts will see a positive risk-reward balance for the medicine, especially now that a lower dose is being used, which has reduced the frequency of side effects.

    If it is successful, Gilenia -- which Novartis licensed from Mitsubishi Tanabe Pharma Corp (4508.T) -- could win a sizable chunk of existing multiple sclerosis (MS) drug sales, totalling some $10 billion a year, and expand the overall market.

    With its potential to help Novartis overcome patent losses on older drugs, the decision on Gilenia is seen by analysts as a key news event for the group this year.

    The drug has a clear advantage in being easier to take than injectables from Biogen Idec Inc, Bayer AG, Merck KGaA and Teva Pharmaceutical Industries Ltd, as well as not causing the flu-like symptoms seen with some of these products.

    But in clinical trials Gilenia has been linked to a range of worrying side effects, including skin cancer, heart problems and infections. These are expected to dominate when Food and Drug Administration (FDA) staff publish briefing documents on the medicine ahead of the panel meeting on June 8.

    BILLIONS OF DOLLARS

    Jeffrey Holford and colleagues at brokerage Jefferies think these issues are manageable -- especially given the lower dose of the drug now being used -- and predict Gilenia will generate peak annual sales of $3.5 billion, with $1.6 billion by 2014.

    Nomura forecasts an even faster ramp-up, to $2.1 billion by 2014. But the overall view is more cautious, with consensus forecasts pointing to sales of $987 million by 2014, according to Thomson Reuters data.

    Hovering in many investors' minds is the recent history of Biogen and Elan Corp's Tysabri, an antibody drug for MS whose sales potential has been severely cut by side effects and a restrictive surveillance programme.

    Gilenia's fate will be watched closely by rivals with competing MS pills a year or two behind in development.

    They include laquinimod from Teva, teriflunomide from Sanofi-Aventis SA  and BG-12 from Biogen -- as well as Mylinax from Germany's Merck, which initially looked ahead of Gilenia in the race until a rebuff from the FDA last November. [ID:nGEE5AT1KS]

    The FDA, which doesn't always follow the advice of its advisory committees, is due to give its verdict on Gilenia by September.

    In Europe, a decision is expected from regulators around the end of the year or early in 2011.

    Developing new drugs for MS is an innately tricky business because treatment centres on dampening the body's immune system, which increases the risk of other health problems.

    MS disrupts the way in which nerve impulses are carried to and from the brain and can cause permanent disability. Symptoms may include numbness or weakness in one or more limbs, partial or complete loss of vision, tingling or pain and tremors.

    Source: Reuters © Thomson Reuters 2010 (05/06/10)

    Federal advisory panel to consider oral Multiple Sclerosis drug FTY720

    FTY720Next week, a federal advisory panel will consider whether the Food and Drug Administration should approve fingolimod, making it the first pill on the market for the treatment of multiple sclerosis.

    Fingolimod is one of two MS drugs in pill form that have been submitted for FDA approval, with three more fairly far along in patient studies. Current drugs have to be injected or infused by patients. And many have been looking forward to an option that doesn't involve needles.

    “I think there's not a single person taking injectables who doesn't wish they had a pill instead. Because they hurt,” said Bob Major, 68, of Lakehills, west of San Antonio. “Every time I inject, I get another welt. My back looks like a pincushion.”

    “Patients right now fall into two groups,” said Dr. Fred Lublin, director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York. “There's one group that says, ‘Get me a pill. I'm tired of injecting myself.' And another group says, ‘I've been doing really well now for all these years with these injections, I don't know about this new one. Maybe I'll let it get some exposure first before I try it.'”

    Lublin, who attended a national meeting of the Consortium of Multiple Sclerosis Centers held in San Antonio this week, said that while fingolimod and cladribine, the other drug submitted for approval, worked well in research studies, both carry the risk of serious side effects.

    Then there's the cautionary tale of the last promising MS drug to hit the market, natalizumab, or Tysabri— an infused targeted therapy that was found in rare cases to cause a viral brain infection called progressive multifocal leukoencephalopathy, or PML.

    That risk led to the drug being temporarily pulled from the market. It now carries a black-box warning.

    “We as a medical community were blindsided by the appearance of PML,” Dr. Joseph Berger, professor of neurology at the University of Kentucky in Lexington, said at a symposium on the risks and benefits of the new treatments.

    The problem is that the newer drugs work — although in different ways — by suppressing parts of the immune system. That leaves patients vulnerable to infections and even cancers.

    PML is caused by a virus that a large percentage of the population carries, normally without causing illness.

    Source: SA News © 2010 San Antonio Express-News (04/06/10)

    FDA review of oral MS drug FTY720 extended
    FTY720Novartis International AG / Novartis announces extension of US regulatory priority review period for FTY720, an investigational once-daily oral multiple sclerosis therapy.

    * US Food and Drug Administration (FDA) extends priority review period by three months to September 2010, in line with previously announced expectations

    * FDA Advisory Committee meeting scheduled for June 10 to review data from FTY720 clinical trial program in MS

    * FTY720 clinical trial program is largest ever submitted to FDA to support approval of a new medicine in this therapeutic area

    Novartis announced today that the US Food and Drug Administration (FDA) has extended by three months, to September 2010, its review period for the regulatory approval of FTY720 (fingolimod). FTY720 once-daily 0.5 mg has the potential to be the first oral therapy for relapsing multiple sclerosis (MS).

    A meeting of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee remains scheduled for June 10, 2010, to discuss the benefit/risk profile of this new active ingredient (New Molecular Entity).

    The FDA granted priority review status for FTY720 in February 2010, reducing the standard 10-month review period to six months, which was set to end on June 21, 2010. The extension was based on the FDA's request for further analysis of available data, which Novartis responded to and which triggered the three-month extension. The agency did not ask for additional clinical trials. Priority reviews are granted by the FDA for investigational medicines that could offer significant advances beyond current treatments or where no adequate therapy exists.

    "The announcement of this revised timeline is in line with our expectations, and reflects the comprehensive clinical program and resulting large amount of data to be reviewed in the NDA," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "MS is a leading cause of neurological disability in young adults and we are very committed to bringing new therapies to patients with this disabling condition."

    Data from the FTY720 MS clinical trial program, the largest ever submitted to the FDA to support approval of a new medicine in this therapeutic area, have demonstrated the significant benefits of FTY720 in reducing relapses in people with MS.

    Source: Novartis International AG (25/05/10)

    Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices

    Gilenia (FTY720)Abstract
    Remyelination, which occurs subsequent to demyelination, contributes to functional recovery and is mediated by oligodendrocyte progenitor cells (OPCs) that have differentiated into myelinating cells.

    Therapeutics that impact remyelination in the CNS could be critical determinants of long-term functional outcome in multiple sclerosis (MS).

    Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier.

    Previous studies using isolated dissociated cultures indicate that neural cells express S1P receptors and respond to receptor engagement.

    Our objective was to assess the effects of fingolimod on myelin-related processes within a multicellular environment that maintains physiological cell-cell interactions, using organotypic cerebellar slice cultures.

    Fingolimod treatment had no impact on myelin under basal conditions. Fingolimod treatment subsequent to lysolecithin-induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes, while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein. The number of phagocytosing microglia was not increased by fingolimod.

    Using S1P receptor specific agonists and antagonists, we determined that fingolimod-induced effects on remyelination and astrogliosis were mediated primarily through S1P3 and S1P5, whereas enhanced microgliosis was mediated through S1P1 and S1P5.

    Taken together, these data demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain.

    Source: Pubmed PMID: 20413685 (05/05/10)

    Multiple sclerosis therapy Gilenia® (FTY720) shown to reduce relapse rates regardless of treatment history

    Gilenia (FTY720)Data presented at the American Academy of Neurology (AAN) annual meeting add to the accumulating evidence of the positive benefit/risk profile of Gilenia, a potential first-in-class, once-daily oral therapy for relapsing forms of multiple sclerosis (MS).

    Data from the two-year FREEDOMS study showed that Gilenia 0.5 mg reduced annual relapse rates (ARR) by 62% for treatment naïve patients compared to placebo. For patients previously receiving other treatments, the annual relapse rates were reduced by 44%. In addition, at two years Gilenia delayed the progression of disability by 30% for patients on 0.5 mg compared to placebo[1].

    "These findings reinforce the potential for Gilenia to be a breakthrough therapy option for physicians and people with relapsing forms of MS," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "The data demonstrate the effectiveness of Gilenia irrespective of treatment history, and further support both the sustained efficacy of Gilenia over two years and the potential benefits of switching from interferon beta-1a, a currently approved MS therapy, to Gilenia."

    Of the 1153 patients who participated in the one-year TRANSFORMS study, 1027 (89%) elected to enter the one-year extension study. Patients in the extension study who also received Gilenia in the core study remained on their original dose (0.5 mg or 1.25 mg), while patients who had received intramuscular interferon beta-1a (Avonex®) were randomized to receive Gilenia 0.5 mg or 1.25 mg[2].

    Patients who received Gilenia 0.5 mg for two years experienced a consistently low ARR at year one (0.16) and at year two (0.18). These patients also retained a significant reduction in relapses and MRI brain lesions over two years compared to the group originally randomized to intramuscular interferon beta-1a and later switched to Gilenia[2].

    In the subset of patients who received intramuscular interferon beta-1a during year one and Gilenia 0.5 mg during year two, the annual relapse rate in year two was reduced by 31% and  the number of new or newly enlarged T2 lesions in the brain, a marker of disease activity, was reduced by 67% in the second year[2].

    These findings on efficacy are consistent with those of the one-year core TRANSFORMS study demonstrating Gilenia significantly reduced annualized relapse rates by 52% (0.5 mg dose) vs. intramuscular interferon beta-1a[3].

    Additional data presented at AAN showed that patients in the core TRANSFORMS study taking Gilenia 0.5 mg had a 71% reduction in relapses resulting in hospitalization, and a 52% reduction in relapses requiring steroid treatment compared with patients taking intramuscular interferon beta-1a[4].

    The safety profile of Gilenia has been well studied in one of the largest-ever Phase III clinical trial programs conducted in MS. The full program, including completed as well as on-going studies in MS, now has more than 6600 patient years of experience, with some patients now in their sixth year of treatment.

    In the TRANSFORMS and FREEDOMS studies the most commonly reported adverse events for both Gilenia and control groups were nasopharyngitis, headache and fatigue. Gilenia-related adverse events included transient, dose-related, generally asymptomatic heart rate reduction and infrequent transient AV conduction block at treatment initiation, mild (1-3 mm Hg) blood pressure increase, macular edema (more common with 1.25 mg than the 0.5 mg target dose), and asymptomatic, reversible elevation of liver enzymes.

    The rates of infections overall, including serious infections, were comparable between treatment groups, although a slight increase in lung infections (primarily bronchitis) was seen in patients treated with Gilenia. The number of malignancies reported across the two studies was small with comparable rates between the Gilenia and control groups.

    Novartis has submitted the 0.5 mg dose for regulatory approval in the US and EU as results from the studies indicate that this dose has the most favourable benefit/risk profile. Applications for regulatory approval for Gilenia 0.5 mg were submitted to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in December 2009. In February 2010, the FDA granted Gilenia priority review status. Since Gilenia involves a new active ingredient (New Molecular Entity), the FDA has required an Advisory Committee meeting on June 10 and will evaluate the risk management program, which

    References

    [1]Kappos L. et al. Oral Fingolimod (FTY720) vs Placebo in Relapsing-Remitting Multiple Sclerosis: 24-month Clinical Efficacy Results from a Randomized, Double-Blind, Multicenter Phase III Study (FREEDOMS). Slide deck associated with Oral Presentation at the American Academy of Neurology (AAN) Annual Meeting 2010 in Toronto.
    [2]Khatri B. et al. 24-Month Efficacy and Safety Outcomes from the TRANSFORMS Extension Study of Oral Fingolimod (FTY720) in Patients with Relapsing-Remitting Multiple Sclerosis. Poster presented at AAN, Toronto, April 2010.
    [3]Cohen J. et al. Oral Fingolimod vs. Intramuscular Interferon in Relapsing Multiple Sclerosis. N Eng J Med 2010; 362:402-415.
    [4]Khatri B et al. Oral Fingolimod (FTY720) Reduces the Rate of Relapses that Require Steroid Intervention or Hospitalization Compared with Intramuscular Interferon β-1a: Results from a Phase III study (TRANSFORMS) in Multiple Sclerosis. Poster presented at AAN, Toronto, April 2010.

    Source: Novartis Media Relations (13/04/10)

    Novartis' Gilenia (FTY720) gets FDA priority review status

    Gilenia
     Novartis AG pulled further ahead of rival Merck in the bid to get the first oral multiple sclerosis treatment to market after the Swiss drugmaker's Gilenia was given U.S. priority review status.

    Novartis's Gilenia, FTY720, is competing with Merck MGaA's pill cladribine against the debilitating nervous disease. U.S. regulators held up Merck's application to bring its cladribine drug to market in November.

    The German drugmaker met with U.S. regulators in January about the approval process but it does not yet have a clear resubmission timetable.

    The priority review for Gilenia, which cuts the standard review time to six months from 10, comes after the U.S. Food and Drug Administration accepted the regulatory submission made in December for the drug.

    Novartis said, however, the FDA could still extend its review at the end of the six month period in June as Gilenia involves a new active ingredient, meaning the FDA is likely to require an advisory committee meeting.

    The two treatments from Novartis and Merck are expected to take a sizable chunk of the $8.6 billion market for MS since they are easier to take than the injectables from Teva, Biogen Idec, Bayer and Merck KGaA itself that currently dominate.

    However both experimental drugs have serious side effects because they interfere with the body's immune system and the companies have to convince physicians and investors the balance of risk and benefit stacks up.

    MS can cause mild symptoms in some people and permanent disability in others. Symptoms may include numbness or weakness in one or more limbs, partial or complete loss of vision, tingling or pain, an electric-shock sensation with certain head movements, tremors and an unsteady gait.

    Source: Yahoo! News © 2010 Reuters Limited. (22/02/10)

    Oral MS therapy FTY720 shows reduced risk of confirmed disability progression

    FTY720Results of the TRANSFORMS1 and FREEDOMS2 studies, the two pivotal Phase III clinical trials with oral FTY720 (fingolimod), have been published in The New England Journal of Medicine, providing comprehensive evidence to support the efficacy and safety profile of this first-in-class therapy for multiple sclerosis (MS).

    The data, from one of the largest Phase III programs conducted in MS, were included in
    the applications for regulatory approval submitted to the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) in December 2009.
    In both studies, two doses of FTY720 were examined (0.5 mg and 1.25 mg). Approval is
    sought for the lower 0.5 mg dose as the results from the studies indicate that this dose
    has the most positive benefit-risk profile.

    “Innovative science leading to new medicines for MS patients is greatly needed,” said
    John Richert, MD, Executive Vi ce President for Research and Clinical Programs at the
    US National Multiple Sclerosis Society. “The positive results published in The New
    England Journal of Medicine showing benefit of fingolimod on the clinical and MRI
    outcomes assessed is very encouraging for MS patients, their families and their
    physicians .”

    The one-year TRANSFORMS study involving 1,292 patients showed that oral FTY720
    0.5 mg reduced relapses by 52% compared to interferon beta -1a (Avonex®)† given by
    intramuscular injection, while the reduction with FTY720 1.25 mg was 38% (both
    p<0.001).

    The two-year FREEDOMS study, involving 1,272 patients, showed that FTY720 reduced the relapse rate by 54% for the 0.5 mg dose and 60% for the 1.25 mg dose compared to placebo (both p<0.001). Patients on FTY720 0.5 mg also had a 30% lower risk of disability  progression, three-month confirmed (p=0.02) and a 37% lower risk of disability progression, six-month confirmed (p=0.01) over two years compared to 2/4 placebo. Similarly, the FTY720 1.25 mg dose reduced the risk of three-month and six month confirmed disability progression by 32% (p=0.02) and 40% (p=0.006) respectively.
    In both studies, treatment with FTY720 also resulted in statistically significant reductions
    in brain lesion activity and reduced loss of brain volume as measured by magnetic
    resonance imaging (MRI).

    “The TRANSFORMS data demonstrate the efficacy of fingolimod compared to a current
    standard of care. These findings may represent a real step forward in the fight against
    MS,”
    said Jeffrey Cohen, MD, TRANSFORMS study lead investigator and staff physician
    at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research in
    Cleveland, Ohio, USA. “Current disease-modifying therapies for relapsing-remitting MS
    are administered by injection or infusion, which may negatively affect tolerability,
    convenience, and compliance for patients on these therapies.”

    Professor Ludwig Kappos, MD, principal investigator for the FREEDOMS clinical trial and
    Chair of Neurology and Research Group Leader in the Department of Biomedicine at the
    University Hospital in Basel, Switzerland, said: “FTY720 demonstrated clear clinical
    superiority over placebo in terms of reducing relapse rates and disability progression.
    The positive findings of TRANSFORMS and FREEDOMS give an increasingly complete
    understanding of the efficacy and safety of FTY720.”

    Up to 2.5 million people worldwide are affected by MS, an inflammatory and
    neurodegenerative condition that often begins when patients are in the prime of their
    lives 3.

    FTY720 has the potential to be the first approved therapy in a new class of drugs called
    sphingosine 1-phosphate (S1P) receptor modulators. These medicines reduce
    inflammation and may also have a direct beneficial effect on cells in the central nervous
    system (CNS). FTY720 acts selective ly by retaining certain lymphocytes (a sub-group of
    white blood cells) in the lymph nodes , reducing the number of lymphocytes that reach the
    brain where they can cause inflammatory destruction. This lymphocyte retention is
    reversible, allowing circulating lymphocytes to regain normal levels if treatment is
    stopped.

    “These data demonstrate that oral FTY720 has the potential to offer an important new
    treatment option for patients with MS,”
    said Trevor Mundel, MD, Global Head of
    Development at Novartis Pharma AG. “We have a long-term commitment to the MS
    community, and trust that FTY720, once approved, will prove to be a valuable treatment
    option for many people who live with this disease.”

    In both TRANSFORMS and FREEDOMS, adherence to therapy was best for the FTY720
    0.5 mg and control groups compared to the 1.25 mg group. The most commonly reported
    adverse events for both FTY720 and control groups were nasopharyngitis, headache and
    fatigue. FTY720-related adverse events included dose-related, transient, generally
    asymptomatic heart rate reduction, infrequent transient AV conduction block, mild (1-3
    mm Hg) blood pressure increase, macular edema (more common with 1.25 mg than the
    0.5 mg target dose), and asymptomatic, reversible elevation of liver enzymes.

    The rates of infections overall, including serious infections, were comparable between
    treatment groups, although a slight increase in lung infections (primarily bronchitis) was
    seen in patients treated with FTY720. The number of malignancies reported in the two
    studies was small with comparable rates between the FTY720 and control groups;
    malignancies were reported more frequently with FTY720 than the control group in the
    one-year TRANSFORMS study but the opposite pattern was seen in the two-year
    FREEDOMS study.3/4

    Serious adverse events were comparable between treatment groups, though generally
    slightly higher with the 1.25 mg than 0.5 mg dose. Overall rates of drug-related adverse
    events, particularly those related to the mechanism of action, as well as discontinuations
    due to adverse events , were more common with 1.25 mg than 0.5 mg.

    The completed MS FTY720 studies and their extensions include more than 2,300
    patients with approximately 4,000 patient-years of exposure, including some patients
    now in their sixth year of treatment. Safety is also being monitored in approximately
    1,000 additional patients in ongoing MS studies.
    The publication in The New England Journal of Medicine marks the first presentation of
    full results from the two studies. Top line results of FREEDOMS and TRANSFORMS
    have been disclosed in Novartis press releases, and the TRANSFORMS study has also
    been presented at scientific congresses 4.

    †Avonex® is a registered trademark of Biogen Idec.

    Dr. Jeffrey Cohen conducts research and is a paid consultant for Novartis.

    References
    1 Cohen J. et al. Oral Fingolimod vs. Intramuscular Interferon in Relapsing Multiple Sclerosis. N Eng J Med. Vol.362
    No.5, Feb 4, 2010 (printed version).
    2 Kappos L, et al. Placebo-Controlled Study of Oral Fingolimod in Relapsing Multiple Sclerosis. N Eng J Med. Vol.362
    No.5, Feb 4, 2010 (printed version).
    3 National Multiple Sclerosis Society website. Last accessed Jan 15, 2010.
    4 Cohen J. et al. Oral Fingolimod (FTY720) Versus Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis:
    Results from a Phase III Study (TRANSFORMS). Slide deck associated with Oral Presentation at the American
    Academy of Neurology Annual Meeting 2009. [S21.004].

    Source: Novartis International AG (21/01/10)

    Oral Therapy for Multiple Sclerosis — Sea Change or Incremental Step?

    CladribineOral Therapy for Multiple Sclerosis — Sea Change or Incremental Step? William M. Carroll, M.B., B.S., M.D., F.R.A.C.P.

    The long-awaited arrival of oral formulations for the treatment of relapsing-remitting multiple sclerosis is welcome news for the estimated 2.5 million people worldwide who have this chronic, disabling disease. Since the publication of the first pivotal trial of interferon beta-1b in 1993,1 practitioners and patients alike have been anticipating the approval of oral therapies because of the relative ease of administration, which should improve adherence and reduce restrictions on lifestyle.

    In this issue of the Journal, researchers report the results of three well-conducted trials of the first two oral agents, cladribine and fingolimod, in the treatment of multiple sclerosis. The researchers studied cladribine in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial2 and fingolimod in the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trial3 and the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS).4 Although these two drugs differ in their mechanisms of action, both reduce the number of potentially autoaggressive lymphocytes that are available to enter the central nervous system. The articles, which report that the agents are effective and have manageable adverse-effect profiles, raise three questions: How do these therapies measure up against the existing treatments? Are all the longer-term adverse effects known? What do these drug trials tell us about multiple sclerosis and our treatment goals?

    Both cladribine (in the CLARITY trial) and fingolimod (in the FREEDOMS trial) were highly effective against placebo over a 2-year period, and fingolimod was more effective than intramuscular interferon beta-1a over a 12-month period (in the TRANSFORMS trial). Each of the three studies involved more than 130 centers in up to 32 countries, and the enrollments of 1272 to 1326 patients ensured that the trials were sufficiently powered to detect an effect of two doses of the active oral agent. Patients had active relapsing disease with durations of 7 to 9 years. On the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), patients had a median score of 2.0 in the fingolimod trials and mean scores ranging from 2.9 to 3.0 in the cladribine trial.

    All three studies used the annualized rate of relapse as the primary end point, and high and low doses of cladribine and fingolimod were shown to be superior to both placebo and interferon beta-1a. For cladribine versus placebo, the relative risk reduction in the annualized relapse rate was 57.6% for the group receiving 3.5 mg per kilogram of body weight and 54.5% for those receiving 5.25 mg per kilogram. For fingolimod versus placebo, the relative risk reduction was 54% for the 0.5-mg dose and 60% for the 1.25-mg dose. For fingolimod versus interferon beta-1a, the relative risk reduction was 52% for the 0.5-mg dose and 39% for the 1.25-mg dose. Both agents were superior to the comparators with respect to secondary end points, including measures on magnetic resonance imaging and a number of clinical end points, including the time to the progression of sustained disability at 3 months.

    Furthermore, although only fingolimod was tested against the widely used interferon beta-1a, it is likely that the two oral therapies will be at least as effective as other currently available disease-modifying therapies. In this regard, head-to-head trials of subcutaneous interferon beta-1b5 and interferon beta-1a6 versus intramuscular interferon beta-1a showed advantages of both subcutaneous regimens over the latter. More recent trials were unable to separate the clinical efficacy of the two subcutaneously administered forms of interferon beta from that of glatiramer acetate.7

    Adverse effects were similar in all three trials of cladribine and fingolimod, and rates of events leading to discontinuation of a study drug were low but still at least twice as frequent with high-dose cladribine (7.9% for the 5.25-mg dose) and fingolimod (10% and 14% for the 1.25-mg dose). Herpetic infections occurred among patients receiving both cladribine and fingolimod. The rate of herpes infections among patients receiving the 1.25-mg dose of fingolimod was 5.5%; such infections were serious in three of these patients, two of whom died. Twenty cases of cutaneous herpes zoster were recorded among patients receiving cladribine, three of which were serious. Three solid tissue cancers (pancreatic, ovarian, and melanoma) occurred among patients receiving low-dose cladribine (3.5 mg per kilogram). Basal-cell carcinoma, melanoma, and breast cancer were all more common among patients receiving fingolimod than among those receiving interferon beta-1a. Macular edema was confirmed in 13 patients, 11 of whom received high-dose fingolimod (7 in the FREEDOMS trial and 4 in the TRANSFORMS trial). Of these 13 patients, 11 recovered within 1 to 6 months after discontinuation of therapy, and the condition of the other 2 patients stabilized. Transient bradycardia and first- and second-degree heart block occurred more frequently among patients receiving high-dose fingolimod than in the comparator groups. Lymphocytopenia was frequent in patients receiving both agents, more so with higher doses. Clinicians and patients will need to evaluate the risks and benefits of each of these drugs. Given the recent studies documenting the development of progressive multifocal leukoencephalopathy among patients receiving natalizumab, a monoclonal antibody against 4-integrin,8 close postmarketing surveillance will be important to detect any increase in these or other unexpected adverse effects.

    The mechanism of action of both oral agents represents a major change from those of currently available drugs for multiple sclerosis. Among a number of actions that are claimed for current therapies is that they change the emphasis of the immune response from activation of proinflammatory type 1 helper T cells to activation of antiinflammatory type 2 helper T cells. Even though cladribine is administered in two or four short courses annually, whereas fingolimod is given daily, both drugs were associated with persistent lymphocytopenia. Cladribine is resistant to the enzyme adenosine deaminase, which causes an accumulation of toxic deoxyribonucleotides in lymphocytes, resulting in relatively selective long-term depletion of CD4+ and CD8+ T cells.9 Fingolimod is a synthetic analogue of myriocin that is derived from a fungus (Isaria sinclairii). Once phosphorylated, the drug acts to down-regulate the sphingosine-1-phosphate receptor required for antigen-activated lymphocytes to egress, effectively locking them in the nodes.10 Thus, both cladribine and fingolimod are targeting inflammation, the key driver of immune injury in multiple sclerosis. Similarly, both natalizumab, which blocks lymphocyte access to endothelium in the central nervous system, and the anti-CD52 monoclonal antibody alemtuzumab, which destroys T and B cells, have shown impressive reductions in disease activity.11 Insights from these trials and others treating the initial stages of disease12 suggest that early direct targeting of the immune system offers the best hope for the prevention of later disability.

    The studies in this issue of the Journal provide a new horizon for patients with relapsing–remitting multiple sclerosis and a welcome increase in the range of treatment options. Although current therapies remain very effective, particularly when they are administered early, and have well-defined side-effect profiles, oral therapies further support a change in treatment approach to directly prevent immune-mediated injury. This approach will probably be followed until the next step in the therapeutic advance occurs, but such a change in strategy highlights the final question: What are the long-term goals of this new phase of therapy? The question will not be fully answered until the underlying cause of multiple sclerosis is better understood, but the lack of a definable end point remains a contentious issue for clinicians and health care funders alike. Time will determine the long-term effectiveness of these treatments in delaying the development of irreversible disability, and as ongoing, real-life experiments, they will contribute to our understanding of this enigmatic disease.

    References

    The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661.
    Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0902533.
    Kappos L, Radue E-W, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0909494.
    Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0907839.
    Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453-1460.
    Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the Evidence Trial. Neurology 2002;59:1496-1506. 
    Achiron A, Fredrikson S. Lessons from randomised direct comparative trials. J Neurol Sci 2009;277:Suppl 1:S19-S24. 
    Iaffaldano P, D'Onghia M, Trojano M. Safety profile of Tysabri: international risk management plan. Neurol Sci 2009;30:Suppl 2:S159-S162.
    Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005;5:721-727.
    Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate -- modifiers of lymphocyte migration. N Engl J Med 2006;355:1088-1091. 
    The CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786-1801. 
    Goodin DS, Bates D. Treatment of early multiple sclerosis: value of treatment initiation after a first clinical episode. Mult Scler 2009;15:1175-1182.

    Source: The New England Journal Of Medicine (10.1056/NEJMe0912019) © 2010 Massachusetts Medical Society. (21/01/10)

    Phase II study of oral Fingolimod (FTY720) in multiple sclerosis: 3-year results

    FTY720In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS).

    The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study.

    In the extension (months 7-36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose.

    During months 15-24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36.

    Most patients were free from gadolinium-enhanced lesions (88-89%) or new T2 lesions (70-78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20-0.21, and 68-73% remained relapse-free at month 36.

    Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3-5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer.

    The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients.

    The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

    Source: PubMed PMID: 20028707 (06/01/10)

    Could Novartis be first to launch Multiple Sclerosis oral therapy?

    FTY720Novartis AG is jockeying with German drug maker Merck KgaA to deliver the first disease modifying treatment for relapsing forms of multiple sclerosis that can be taken orally, rather than by infusion or injection.

    Fingolimod could finally move ahead in the race to market, as the FDA rejected Merck's new drug application for its Cladribine tablet.

    On November 30, US regulators issued a "refusal to file letter" to Merck Serono, the US subsidiary. Company spokesman Gangolf Schrimpf told me the FDA preliminary action of the cladribine submission was not an assessment of the efficacy and safety of the compound. Nonetheless, the agency obviously felt the deficiencies in the filing were material enough - scientific or legal - to delay its formal review of the tablet.

    Initial results from Novartis' two-year FREEDOMS FTY-720 study show that once-daily oral fingolimod reduced the relapse rate by 54 percent for the 0.5 mg dose in patients with relapsed MS. Novartis looks to file its new drug application with the FDA within next few months, followed fast track approval and launch in summer 2010.

    Though efficacy over standard-of-care beta interferon treatments is similar for the two oral agents, I suspect that neurologists' prescribing behaviours might be more favourably disposed towards cladribine, which offers a more convenient - a short-course regimen - five-day dosing, twice a year. Merck's setback is thus Novartis' gain, as it affords a window of time for providers - and patients - to gain clinical experience with fingolimod therapy.

    In my opinion, the FDA being circumspect about cladribine did have more to do with safety than efficacy. Abnormal low blood levels of white blood cells (called lymphopenia) and four cases of malignant tumors were reported in cladribine-treated patients in the pivotal CLARITY trial. No surprise, as the drug reduces circulating levels of white blood cells (lymphocytes, which are involved in the pathogenesis of MS) and inhibits DNA synthesis and repair (parenteral cladribine was approved as a chemotherapeutic for Hairy Cell Leukemia back in the 1990s).

    Concerns exist, too, that cladribine can affect the immune system many years after cessation of treatment. Merck Serono would not answer my question on whether or not the rejection had to do with the company's post-marketing safety protocol, its Risk Management and Mitigation Strategy (RiskMap). "We will work closely with the FDA to fully understand FDA's concerns and define a path forward for a successful resubmission of this application at the earliest point in time," is all spokesman Schrimpf would diplomatically say.

    No disease-modifying agent is without risk. Fingolimod, first in a new class of immunomodulatory drugs called S1P-receptor modulators, also reduces circulating levels of white blood cells (by bottling them up in lymph nodes). Skin cancer is a risk associated with fingolimod treatment. The FDA will likely weigh the drugs promising efficacy, however, against this adverse event by requiring Novartis to develop a RiskMap protocol.

    With the expected loss of its blockbuster blood pressure drug Diovan in 2012 (more than $4 billion in expected 2009 sales), Novartis is looking to fingolimod to launch a successful new franchise in MS. Although injection-based interferon therapies are likely to remain the preferred choice (due to patient years of experience), discomfort with having to take injections daily or weekly will ensure a step on the treatment paradigm for oral drugs. And, in a market that had global sales of more than $6 billion last year - expected to exceed $9 billion by 2015 - there is room for two blockbuster oral formulations.

    If approved, Novartis should have two years to cement fingolimod's position as a preferred oral treatment. Come 2012, the oral MS market could get more crowded, as Teva Pharmaceuticals (laquinimod), Sanofi-Aventis (teriflunomide) and Biogen-Idec (BG-12) all have oral formulations in late stage clinical development.

    Source: BNET UK © 2009 CBS Interactive Inc. (07/12/09)

    Multiple Sclerosis therapy FTY720 reduces relapses and disability progression

    FTY720Initial results from the two-year Phase III FREEDOMS study show that oral FTY720 (fingolimod) was significantly superior to placebo in reducing both relapses and disability progression in patients with relapsing-remitting multiple sclerosis (MS)[1] - one of the leading causes of neurological disability in young adults[3].

    The FREEDOMS study met its primary and secondary endpoints for both the 0.5 mg and 1.25 mg doses, with no significant difference in efficacy between doses. This result builds on previous data showing superior efficacy to interferon beta-1a[2] in TRANSFORMS, the largest head-to-head Phase III study against a standard of care treatment in MS.

    In FREEDOMS, FTY720 was generally well tolerated with a lower incidence of adverse events at the 0.5 mg dose than 1.25 mg [1]. Regulatory submissions for FTY720, planned in the US and EU at the end of 2009, will seek approval for the lower 0.5 mg dose based on comprehensive Phase III results establishing its positive benefit-risk profile. Future development of FTY720 in relapsing forms of MS will focus on the 0.5 mg dose.

    "We are proud to have reached this critical milestone in the development of FTY720, a novel oral therapy that has the potential to transform the treatment of this ultimately disabling disease," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "FTY720 0.5 mg therapy offers compelling efficacy on all relevant endpoints compared to both placebo and a standard of care, complemented by extensive safety data."

    Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, "MSRC welcomes this latest data set on FTY720 also known as Fingolimod.  The advancement of oral therapies for people affected by MS is a very welcome progression and will ultimately mean that very many people with the disease will not have to look to therapies that require injection on a regular basis"

    Results from the placebo-controlled FREEDOMS study show that FTY720 reduced the relapse rate by 54% for the 0.5 mg dose and 60% for the 1.25 mg dose compared to placebo (both p<0.001)[1]. In addition, FTY720 reduced the progression of disability by 30% for patients on 0.5 mg (p=0.024) and 32% for those on 1.25 mg (p=0.017) compared to placebo over two years[1]. These findings were supported by positive effects on brain lesions as measured by magnetic resonance imaging (MRI) scans.

    FREEDOMS is the second of three Phase III studies to report results in the largest development program ever conducted in MS, involving more than 4,000 patients worldwide. Previously reported results from the one-year TRANSFORMS study showed a reduction in relapse rates of 52% and 38% for FTY720 0.5 mg and 1.25 mg respectively compared to interferon beta-1a (both p<0.001)[2]. FREEDOMS II, currently under way, is a two-year placebo-controlled Phase III study, similar in design to FREEDOMS.

    "The positive results from the FREEDOMS study confirm the efficacy and safety of fingolimod, and provide important evidence of its effect on disability," said Professor Ludwig Kappos, Chair of Neurology and Research Group Leader in the Department of Biomedicine at the University Hospital in Basel, Switzerland, and the principal investigator of the FREEDOMS study. "As an oral therapy, it is clear that fingolimod potentially represents a significant advance in the treatment of MS."

    FTY720 has a well-studied safety profile with more than 5,300 patient-years of exposure, including patients now in their sixth year of treatment. Previous data from the development program raised questions about potential side effects including macular edema, melanoma, liver injury, infections, and increased blood pressure. In the FREEDOMS study, at the 0.5 mg dose there were no cases of macular edema or melanoma[1]. Reversible and generally asymptomatic liver enzyme elevations were observed more frequently with FTY720 than placebo, and lung infections were also slightly more common[1]. Mild elevation in blood pressure was observed with FTY720. No new safety signals were seen in FREEDOMS compared to previous clinical trials. Three patients died during the FREEDOMS study, one on FTY720 1.25 mg and two on placebo. None of the deaths was assessed as being related to the study drug[1] .

    FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) was a double-blind, placebo-controlled study involving 1,272 patients in 22 countries to assess the efficacy, safety and tolerability of FTY720. The primary endpoint was reduction in annual relapse rate and the key secondary endpoint was reduction in disability progression, defined as an increase from baseline in Expanded Disability Status Scale (EDSS) scores confirmed at three months[1].

    FTY720 has the potential to be the first in a new class of MS therapies called sphingosine 1-phosphate (S1-P) receptor modulators. Comprehensive analyses of the FREEDOMS data are ongoing, and detailed results are planned to be presented at a leading scientific congress in 2010.

    References
    [1] Novartis. Data on file.
    [2] Cohen J. et al. Oral Fingolimod (FTY720) Versus Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis: Results from a Phase III Study (TRANSFORMS). Slide deck associated with Oral Presentation at the American Academy of Neurology Annual Meeting 2009. [S21.004].
    [3] Cochrane Database of Systematic Reviews 2001, Issue 4. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD002002/frame.html (Accessed 29 September 2009).

    Source: Novartis AG & MSRC (30/09/09)

    Nearly 90% of surveyed US neurologists indicate they will prescribe oral Cladribine for the treatment of Multiple Sclerosis

    Oral CladribineOwing to its infrequent dosing and positive efficacy, nearly 90 percent of surveyed neurologists indicate they will prescribe Merck Serono/EMD Serono's oral cladribine for the treatment of multiple sclerosis.

    The new Physician & Payer Forum report entitled Multiple Sclerosis: How Will Clinician Attitudes and Reimbursement Issues Determine How Orals Will Compete with Current Disease-Modifying Drugs in this Dynamic Landscape? finds that the percentage of surveyed neurologists willing to prescribe oral cladribine is higher than the percentage willing to prescribe the emerging oral therapies Biogen Idec's BG-12 and Novartis/Mitsubishi Tanabe's FTY-720 (fingolimod).

    The report also finds that emerging oral therapies will likely be prescribed most often to patients with relapsing-remitting multiple sclerosis and as second-line therapies.

    "Neurologists we surveyed indicate that oral cladribine, FTY-720, and BG-12 will each be prescribed to patients with any disease subtype but that these therapies will be preferentially prescribed to approximately one-quarter of patients with relapsing-remitting disease," said Decision Resources Analyst Bethany Kiernan, Ph.D. "This is likely due to these agents' ongoing clinical trials involving relapsing-remitting multiple sclerosis patients. Additionally, surveyed neurologists will prescribe emerging oral therapies to about one-fifth of secondary progressive multiple sclerosis patients. Yet despite the similarities in projected prescribing patterns among these therapies, our findings indicate that oral cladribine will be favoured over FTY-720 as well as BG-12, suggesting that clinicians have begun to differentiate these oral agents from one another."

    The report also finds that the majority of surveyed MCO pharmacy directors will give emerging oral therapies non-preferred tier status on their commercial plans. More than half of surveyed MCOs expect to place oral cladribine, FTY-720 and BG-12 on tier 3 of their commercial plans' formularies. Surveyed pharmacy directors cite the high cost of these agents as the main reason for their non-preferred status. However, about one-quarter of surveyed pharmacy directors expect to place these therapies on tier 2 of their formularies, which is likely due to their perceived advantages in efficacy, safety, and/or convenience compared with current drugs.

    Multiple Sclerosis: How Will Clinician Attitudes and Reimbursement Issues Determine How Orals Will Compete with Current Disease-Modifying Drugs in this Dynamic Landscape? is based on a U.S. survey of 102 neurologists and 20 MCO pharmacy directors. Their responses were compared to assess similarities and differences of opinion regarding clinical, economic and scientific factors.

    Source: Decision Resources (10/09/09)

    80-83 percent of patients taking multiple sclerosis drug FTY720 are relapse-free

    FTY720

    Novartis AG said a study shows that 80-83 percent of patients taking its multiple sclerosis drug FTY720 are relapse-free compared to 69 percent of those on the leading current treatment.

    Novartis, which is presenting new Phase III results to the American Academy of Neurology, said the data reinforces results announced in December that showed the annual relapse rate was 52 percent lower compared with patients taking Biogen's injectable multiple sclerosis drug Avonex.

    It said full results from the so-called TRANSFORMS study would be submitted to a peer-reviewed journal in the next few months, adding regulatory filings were on track for the United States and European Union at the end of 2009.

    Lead investigator Jeffrey Cohen said the trial showed that FTY720 "may provide patients with an alternative choice to currently available medications for treating relapsing-remitting multiple sclerosis".

    Novartis AG and Germany's Merck KGaA are leading the charge to develop MS drugs that can be taken orally, rather than by infusion or injection, but the firms must persuade physicians and investors that the treatments are safe.

    Novartis said serious adverse effects were reported in fewer than 2 percent of patients treated with FTY720 and said a role for the drug in the death of a patient in February could neither be confirmed nor ruled out.

    It added that the safety profile of a 0.5 mg dose appeared to be better than the 1.25 mg dose.

    "The results are statistically significant," said Vontobel analyst Andrew Weiss. "Somewhat comforting is the fact that no new safety concerns in the TRANSFORMS trial have emerged."

    Novartis also presented longer-term results from a Phase II study that showed continued low relapse rates after four years of treatment, with no change in the safety profile.

    FTY720 has been associated with potentially fatal infections, skin cancer and, recently, a case of haemorrhaging focal encephalitis, an inflammation of the brain with bleeding. It is unclear whether the drug was responsible for the events.

    Merck's drug, Cladribine, has been linked to a reduction in white blood cells, which can lead to infection, and in January the company said four patients in a late-stage trial were diagnosed with cancer. It is also due to present study results at the neurology meeting in Seattle.

    Earlier this year Merck said results of a late-stage trial showed Cladribine reduced the number of relapses per year by as much as 58 percent, compared with those taking a placebo.

    Biogen is developing an oral MS drug, known as BG-12, but it is not as far advanced as the Merck or Novartis drugs.

    Source: Reuters.com © Thomson Reuters 2009 (29/04/09)

    Multiple Sclerosis drug FTY720 reduces relapses

    FTY720

    Novartis has announced late-stage results from a clinical study that showed its experimental daily pill for multiple sclerosis, FTY720,  was more effective than a currently approved injectable drug sold by Biogen Idec.

    The Swiss-based drug maker said it intends to seek regulatory approval for the drug, FTY720, in the U.S. and Europe by the end of the year. If approved, FTY720 would offer patients with relapsing-remitting multiple sclerosis, the most common form of the disease, the convenience of an oral treatment for the first time.

    However, serious safety concerns have dogged FTY720, including reports of fatal infections and increased risks for heart and liver problems. While all existing multiple sclerosis drugs carry side-effect risks, FTY720's safety profile is likely to be scrutinized very closely by regulators.

    The global market for MS drugs is expected to reach $5.8 billion in 2008, according to a recent report from JPMorgan.

    Biogen Idec's Avonex is the market leader with 2007 sales $1.9 billion, followed closely by Sanofi-Aventis' Copaxone, Merck Serono's Rebif and Betaseron from Bayer. The most recently approved MS drug was Tysabri, marketed by Biogen Idec and Elan.

    All these drugs are administered by injections, which leaves them commercially vulnerable to an oral MS drug, if one can be approved that is equally or more effective with an acceptable safety profile.

    The "Transforms" study reported by Novartis Friday was the first head-to-head comparison of FTY720, taken as a daily pill, against Biogen Idec's leading multiple sclerosis drug Avonex, which is administered via a weekly injection.

    The results showed that MS patients treated with FTY720 experienced significantly fewer disease relapses than patients taking Avonex. The annualized relapse rate after one year of treatment with FTY720 was reduced by 52% at the low dose and 38% at the high dose compared with Avonex patients, according to Novartis. The results from both doses of FTY720 compared with Avonex were statistically significant.

    "We are encouraged by the early results from Transforms, which represent a major step towards delivering an effective oral treatment for people with relapsing-remitting MS," said Trevor Mundel, Novartis' global head of development, in a statement. "These positive results reinforce the potential for FTY720 to provide a significant advance in the future treatment of this devastating disease."

    Last June, Novartis disclosed that two patients taking FTY720 in the study suffered fatal herpes infections. At that time, Novartis said there were confounding medical factors that contributed to the deaths, although FTY720 could not be ruled out as a cause because the drug works by suppressing a patient's immune system. An independent safety monitoring board allowed the FTY720 study to continue.

    Novartis said Friday that adverse safety events related to FTY720 reported in the Transforms study included lowered heart rate, increases in blood pressure and elevations of liver enzymes, a potential signal of liver damage. Seven cases of localized skin cancer were diagnosed in FTY720-treated patients compared with one case reported in Avonex patients. All the cancers were successfully removed with surgery.

    Overall, Novartis said that 87% of FTY720 patients completed the one-year study. The discontinuation rate for FTY720 was 10% for the low-dose patients and 15% for the high-dose patients compared with 12% for Avonex patients.

    Novartis is conducting two additional phase III studies of FTY720 in MS patients, both comparing the drug to placebo after two years of treatment. Data from these studies, which will be required for the drug's approval, are expected to be released in 2009.

    Source: The Street.com © 1996-2008 TheStreet.com, Inc. (12/12/08)

    FTY720 Multiple Sclerosis therapy exerts differential effects on T cell subsets

    FTY720

    In this study the authors found changes in the T cells in the blood, a type of cell involved in the immune response, in people who received a new tablet medication called FTY720 which is under investigation in MS.

    BACKGROUND: The oral immunomodulator FTY720 has shown efficacy in patients with relapsing multiple sclerosis (MS). FTY720 functionally antagonizes sphingosine 1-phosphate receptor-1 (S1P1) on T cells and consequently inhibits S1P/S1P1-dependent lymphocyte egress from secondary lymphoid organs. Little is known about the phenotype and function of T cells remaining in peripheral blood during long-term FTY720 treatment.

    METHODS: T cells from FTY720-treated, interferon-beta (IFNbeta)-treated and untreated patients with MS, and healthy donors (HD) were analyzed with respect to T cell subpopulation composition, proliferation, and cytokine production.

    RESULTS: In FTY720-treated patients (n = 16), peripheral blood CD4+ and CD8+ T cell counts were reduced by approximately 80% and 60% when compared to the other groups (IFN beta: n = 7; untreated: n = 5; HD: n = 10). This related to selective reduction of naive (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) T cells (TCM), and resulted in a relative increase of peripheral effector memory (CCR7-CD45RA- [TEM] and CCR7-CD45RA+ [TEMRA]) T cells. The remaining blood T cell populations displayed a reduced potential to secrete IL-2 and to proliferate in vitro, but rapidly produced interferon-gamma upon reactivation, confirming a functional TEM/TEMRA phenotype.
    Neither FTY720 nor FTY720-P directly suppressed proliferation or cytokine production by T cells.

    CONCLUSION: Therapeutic dosing of FTY720 reduces naïve T cells and TCM, but not TEM, in blood, without affecting T cell function. This is presumably because naive T cells and TCM express the homing receptor CCR7, allowing recirculation to secondary lymphoid tissues on a regular basis and, thus, trapping of the cells by FTY720 in lymph nodes.

    Authors: Mehling M, Brinkmann V, Antel J, Bar-Or A, Goebels N, Vedrine C, Kristofic C, Kuhle J, Lindberg RL, Kappos L.

    Department of Biomedicine and Neurology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.

    Source:PubMed 2008 Oct 14;71(16):1261-7 (22/10/08)

    Multiple Sclerosis drug may work against viral infection

    FTY720

    A drug that Novartis AG is currently testing, in people with Multiple Sclerosis; also has the potential to treat certain viral infections, perhaps including the AIDS virus, U.S. researchers said.

    Low doses of the drug FTY720, also called Fingolimod, given to mice once a day for three days eliminated an infection by a virus that can cause meningitis, an inflammation of the membranes surrounding the brain and spinal cord.

    The findings suggest the drug, which boosted anti-viral immune responses in the mice, may be useful against viruses that cause high-level, long-lasting infections in people such as hepatitis C and HIV, the researchers said.

    Microbiologist and immunologist; John Altman of Emory University in Atlanta, Georgia, USA, who led the study, said the researchers plan to assess the effects of the drug on other viruses including the monkey version of the AIDS virus.

    Altman, whose findings were published in the journal Nature, expressed cautious optimism that the drug might work against certain chronic viral infections in people.

    "We think it's crucial that we do experiments to check it out," Altman said in a telephone interview.

    The drug is generally considered to be an immunosuppressant that works to restrain the body's natural defences. That could be helpful in multiple sclerosis, an autoimmune disease in which the immune system attacks body parts as if they were foreign invaders.

    But one effect of the drug seems to facilitate the immune response, the researchers said. FTY720, among other things, traps white blood cells -- key soldiers in the immune system's fight against infections -- in the lymph nodes, Altman said.

    With viral infections, the lymph nodes are where the immune response can get primed and started, Altman said. Some viruses replicate themselves at high levels in lymph nodes, including the human immunodeficiency virus that causes AIDS.

    They tested the drug against a mouse virus called lymphocytic choriomeningitis, which causes chronic infections by escaping immune responses. "In the absence of treatment (with FTY720) we have an exhausted immune response. In the presence of treatment, we regain a robust cellular immune response," Altman said.

    June 2008, Swiss drug maker, Novartis, said two multiple sclerosis patients taking FTY720 in clinical trials had problems with infections and one died, but the role of the drug in the cases was unclear. Novartis plans to seek approval by the European Union for FTY720 to treat MS, at the end of 2009, spokeswoman Valerie Tate said by e-mail. The drug is currently in late-stage trials.

    Altman said his study was backed by the U.S. government's National Institutes of Health and was not funded by Novartis. (15/08/08)

    FTY720 trial continues despite death
    Novartis AG said two patients taking its multiple sclerosis drug FTY720 in clinical trials had problems with infections and one died, but the role of the medicine in the cases was unclear.

    Independent experts recommended that clinical trials with the drug — which unusually for an MS medicine is taken orally — should continue as planned, the Swiss drugmaker said.

    “Novartis was recently notified of two infection-related incidents among FTY720 patients, including one fatality,” the company said in a statement.

    “The efficacy data looks good and comparable to existing agents,” said Sanford C Bernstein analyst Tim Anderson, who sees a launch of the drug in 2010 and sales of $1.2 billion by 2015.

    “Existing MS drugs also have safety issues. Investors very much appreciate the tenuous balance of efficacy-risk with FTY720, but clearly a termination of this programme would be likely to hurt Novartis’s share price performance nonetheless,” said Anderson.

    Shares of U.S.-based biotechnology company Biogen Idec, which sells MS drugs Avonex and Tysabri, were up 4 percent.

    “The read-through is it would be good for Tysabri, it would be good for all the other MS drugs,” said Leerink Swann analyst William Tanner.

    “FTY720 I think historically has been looked at as being kind of a category killer for some of the injectable agents. If there are some issues that are compromising the study then that’s going to be a problem,” Tanner said.

    Novartis said it was in talks with health authorities and experts to try and improve awareness of the risks of infections and how these may be reduced.

    “Both cases involved confounding factors, including the use of very high doses of steroids in the first patient and the delayed use of antiviral therapy in the second patient,” it said.

    The company said FTY720’s role in the cases was unclear but could not be excluded, since its mechanism of action leads to suppression of the immune system, which can increase the risk of infection.

    Novartis had previously said it expected to submit the once-daily therapy, currently in late-stage trials, for approval before the end of 2009.

    Source: Reuters © Reuters 2008 (09/06/08)

    Oral drug, FTY720, reduces disease activity in Multiple Sclerosis
    A drug that can be taken orally reduces the number of attacks people with multiple sclerosis (MS) have, according to research that will be presented at the American Academy of Neurology 60th Anniversary Annual Meeting in Chicago, April 12–19, 2008.

    “All of the current treatments for MS must be injected, so having a pill you can swallow with a glass of water would be a welcome improvement for many people,” said study author Giancarlo Comi, MD, of Vita-Salute San Raffaele University in Milan, Italy.

    The results reported are from an extension of a six-month study with 281 people with relapsing MS, two-thirds of whom took the drug FTY720 (fingolimod) and one-third of whom took a placebo. After six months, those taking FTY720 had more than 50 percent fewer relapses, or attacks, than those who took the placebo. At that point, all of the participants could enter an ongoing extension of the study where all would receive the drug.

    A total of 173 people have finished three-years of the study. Continuous use of the drug led to sustained low relapses, with more than 67 percent of the participants remaining free of relapses after three years. In addition, the inflammatory activity associated with MS, as assessed by MRI scans, remained low, with 89 percent of patients free of disease activity and 75 percent of patients free of new or newly enlarged lesions.

    “The first line treatments for MS, beta interferon and glatiramer acetate, reduce the relapse rate by only about 30 percent, so this is a significant development for people with MS,” Comi said.

    The most frequently reported side effects of the drug were headache, fatigue, flu, and cold symptoms.

    FTY720 is an immune-modulating drug that binds to a receptor site on immune cells, sequestering them in the lymph nodes. As a result, FTY720 reduces their ability to cause damage associated with the symptoms experienced by people with MS.

    Source: American Academy of Neurology (16/04/08)

    New Preclinical Data Suggests FTY720 May Repair or Reduce Damage Caused by Multiple Sclerosis Through a Direct Effect in the Brain
    • Potential beneficial impact on central nervous system in addition to well established action on immune cells.
    • Recruitment complete for two of three pivotal Phase III trials; recruitment for third study is ongoing and on track.
    • MS most common neurological disorder in young adults, affecting more than an estimated 2.5 million people worldwide.

    New preclinical data presented at European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS) in Prague suggests that FTY720 (fingolimod) directly reduces neurodegeneration and enhances repair of the central nervous system (CNS) damage caused by multiple sclerosis (MS) by interacting with sphingosine-1-phosphate receptors (S1P-R) expressed on brain cells. This mechanism of action may be in addition to the established anti-inflammatory role of FTY720 that is mediated by the reduction of inflammatory immune cells, called lymphocytes, from reaching the brain.

    FTY720 is a novel, once-daily, oral treatment currently in worldwide Phase III clinical development to test its safety and efficacy as a disease modifying therapy for relapsing-remitting MS, which affects approximately 85% of people with multiple sclerosis.

    The potential direct beneficial effect of FTY720 in the CNS is supported by the results of several preclinical experiments being presented at ECTRIMS, including research in animal models of MS and in vitro studies on CNS cells called oligodendrocytes.

    In an animal model of MS (experimental autoimmune encephalomyelitis in rats), the administration of FTY720 directly into the CNS resulted in a statistically significant reduction in disease severity. This decrease in disease activity was seen in the absence of a reduction of lymphocytes in the bloodstream, suggesting that the favorable effect of FTY720 seen in this model is due to a direct effect in the CNS that is independent of the effects on peripheral lymphocytes.

    In two experiments presented at ECTRIMS, the modulation of S1P-R by the addition of FTY720 resulted in an increase in the number, growth and survival of oligodendrocytes in cell culture. This effect of FTY720 on oligodendrocytes may help limit destruction of myelin and promote its repair and, thus, may contribute to the effectiveness of FTY720 in MS. Oligodendrocytes are cells in the CNS that make a fatty tissue, called myelin, which is necessary for normal signal transfer along nerve fibers in the CNS. Myelin and oligodendrocytes are typically damaged in MS.

    "FTY720 crosses the blood-brain barrier and the drug's target - S1P receptors - are present on brain cells, including oligodendrocytes as shown in animal cell studies," said Jack Antel, Professor, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. "We are able to confirm that FTY720 directly modulates the S1P receptors on human oligodendrocyte progenitor cells."

    FTY720 is currently being investigated in the largest worldwide Phase III clinical trial program to be conducted in MS to evaluate further its efficacy and safety as a disease modifying therapy for relapsing-remitting MS. This comprehensive program includes trials referred to as FREEDOMS, FREEDOMS II and TRANSFORMS. Recruitment is complete for FREEDOMS and TRANSFORMS. Recruitment is ongoing and on track for FREEDOMS II and FTY720 regulatory filing is planned for the second half of 2009.

    "Novartis has a significant long-term investment and commitment to multiple sclerosis and neuroscience through its extensive research and development program," said Ludwig Hantson, PhD, Senior VP for Commercial Development & Specialty Businesses at Novartis Pharmaceuticals Corporation. "We believe oral FTY720 is an exciting and promising experimental therapy for MS as shown by the compelling Phase II data. As an oral therapy with a novel mechanism of action and promising efficacy, FTY720 has the potential to be a significant and innovative therapeutic advance."

    Phase II Study Results

    The six-month, placebo-controlled Phase II study conducted in 281 patients with relapsing MS in 11 countries (Europe and Canada) showed that oral FTY720, taken once-daily, reduced relapse rates by more than 50% compared to placebo and reduced MRI (magnetic resonance imaging) measures of inflammation with approximately 80% of patients free of active brain lesions.

    In patients continuously treated with FTY720 for up to two years (placebo-controlled study plus the extension trial), up to 77% of patients were relapse-free and more than 80% of patients were free of active brain lesions at two years.

    In the six-month placebo-controlled phase of the Phase II study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis) and dyspnea, plus diarrhea and nausea. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory air flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and an increase in blood pressure were also observed. No unexpected adverse events emerged in patients treated for up to 24 months compared with the six-month placebo-controlled phase. There was no further elevation of blood pressure with continued treatment beyond the effect seen at six months.

    The ongoing Phase III study program includes comprehensive monitoring, which will provide further characterization of the safety profile of FTY720.

    Source: Novartis (15/10/07)

    Preclinical Studies Suggest FTY720 Mechanisms In Multiple Sclerosis May Include Direct Activity In The Brain
    New preclinical data, presented at the American Academy of Neurology (AAN) annual meeting in Boston, reflect the expanding understanding of FTY720's (fingolimod) mechanism of action in multiple sclerosis (MS), suggesting direct beneficial effects in the brain. The data suggest that FTY720 may have the potential to reduce neurodegeneration and enhance repair of the central nervous system (CNS) by modulating S1P receptors expressed on brain cells. Separately, new clinical data presented from the six-month Phase II study found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups compared to placebo.

    These new preclinical data add to a growing body of evidence that FTY720 has multiple, specific mechanisms of action. The ongoing Phase III clinical development program includes comprehensive monitoring to further understand the clinical and safety implications of these mechanisms of action.

    Preclinical studies

    FTY720's previously known activity is based on its ability to bind to the sphingosine 1-phosphate receptor-1 (S1P-R1) on circulating lymphocytes (white blood cells). This activity reversibly traps a proportion of lymphocytes in the lymph nodes, reducing the number of inflammatory T-cells circulating in the bloodstream and in the CNS.

    One of the preclinical studies presented at AAN evaluated FTY720's ability to activate S1P receptors on astrocytes in cell culture. Astrocytes are known to play an active role in nervous tissue repair, and to regulate the permeability of the blood brain barrier. The study findings indicate that FTY720 activates S1P receptors on astrocytes, stimulating intracellular pathways that regulate a variety of functions, such as cell proliferation and migration. (Muellershausen et al)

    A second study, also conducted in cell culture, demonstrated that FTY720 improved the survival and increased the number of immature and mature oligodendrocytes - cells that help form myelin in the CNS. Stimulation of S1P receptors on oligodendrocytes may help limit demyelination and/or promote myelin repair. (Barske et al)

    In the third study, conducted in an established animal model of MS [experimental autoimmune encephalomyelitis (EAE) in rats], researchers found that FTY720 directly administered in the rat brain significantly suppressed the severity of clinical EAE, suggesting additional mechanisms of action independent of lymphocyte depletion. In imaging studies, enhanced myelination and axonal protection associated with the clinical effects were confirmed in animals receiving oral FTY720. (Schubart et al)

    Clinical results in depression (Kappos et al)

    Data from the six-month placebo-controlled Phase II study of once-daily oral FTY720 in patients with MS found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups at six months compared to placebo. Depression is a common co-morbid condition in people with MS; the presence of depression in MS may reduce adherence to disease-modifying therapy and lead to higher rates of treatment discontinuation.

    The Phase II study included 281 patients, randomised to receive FTY720 1.25 mg, FTY720 5 mg, or placebo. Depression was evaluated in 239 patients using the Beck Depression Inventory - Second Edition (BDI-II). BDI-II scores of 14 or more suggest clinical depression. At baseline, mean BDI-II scores were 9.3 for patients randomised to receive FTY720 1.25 mg, 8.0 for patients randomised to receive FTY720 5 mg, and 9.1 for patients randomised to receive placebo. At month six, patients receiving FTY720 1.25 mg had the most improvement in depression symptoms (BDI-II = 7.9, mean change from baseline = -1.45). Patients receiving FTY720 5 mg had no change in mean BDI-II scores, and patients receiving placebo showed worsening (BDI-II=10, mean change from baseline = +0.94). The proportions of patients with BDI-II scores indicating clinical depression were significantly lower in both FTY720 groups when compared with the placebo group at month six: 33% of patients receiving placebo versus 17% of patients receiving FTY720 1.25 mg (p=0.0176) and 19% of patients receiving FTY720 5 mg (p=0.0407).

    Source: Novartis (05/05/07)

    The Roskamp Institute is Participating in a New Phase III MS Study to Evaluate the Efficacy and Safety of FTY720, a Novel, Investigational, Once-Daily Oral Medication

    The Roskamp Institute announced today that it is now screening patients for enrollment in a new Phase III study to evaluate the efficacy and safety of FTY720 (fingolimod), a novel, investigational, once-daily, oral medication, in relapsing-remitting multiple sclerosis (RRMS).

    The 12-month, double-blind, randomised, active-comparator study, called "TRANSFORMS" (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS) is sponsored by Novartis and will include approximately 1275 MS patients in more than 170 study centers worldwide.

    "If the Phase III study program confirms the data demonstrated in the Phase II study program and leads to FDA approval, FTY720 may represent an improvement when compared to currently-available injectable medications," said Dr. Andrew Keegan, Principal Investigator.

    The TRANSFORMS study will include patients with RRMS between the ages of 18 and 55. Upon study entry, enrolled participants will be randomly assigned to either receive FTY720 1.25 mg (1 capsule/day), FTY720 0.5 mg (1 capsule/day) or interferon-beta-1a (i.m. once weekly) in a double dummy design. Qualified participants will receive the study medication and study related care at no cost for the duration of up to 12 months. The primary endpoint will be the relapse rate at 12 months.

    In MS, inflammatory lymphocytes (T-cells) are believed to be responsible for the destruction of the protective myelin coating, which surrounds the nerves in key areas of the brain and spinal cord. This destruction hinders the ability of nerves to send electrical signals, resulting in problems with muscle movement, coordination, balance and cognition.

    FTY720 has a novel mode of action different from all available therapies. It binds to the sphingosine 1-phosphate receptor-1 (S1P1) on circulating lymphocytes and reversibly traps a proportion of them in the lymph nodes. As a result, FTY720 lowers the number of activated T-cells circulating in the bloodstream and central nervous system.

    The Phase II 12-month results, recently published in the New England Journal of Medicine, demonstrated that FTY720 reduced the rate of clinical relapses and inflammatory disease activity as measured by MRI over the first six months of the study compared to placebo. After six months placebo patients were switched to active therapy. The Phase II 24-month data presented at the ECTRIMS meeting in September, 2006 showed that many patients taking once-daily oral FTY720 remained free of relapses over two years. They also maintained a low rate of inflammatory disease as measured by magnetic resonance imaging (MRI). Patients who received placebo for the first six months also experienced an improvement after switching to FTY720, and the improvement was sustained through month 24.

    Over two million people worldwide, and approximately 400,000 in the US, are estimated to have from multiple sclerosis, which is the leading cause of neurological disability in young adults. MS has a significant impact on the patient's social activities, employment and overall quality of life. MS is the most common chronic, disabling disease of the central nervous system affecting twice as many women than men. The relapsing-remitting (RRMS) course is the most common form of the disease. Patients suffer acute self-limiting attacks (relapses) of neurological dysfunction followed by complete or incomplete remission in function. Over time, transmission of electrical nerve impulses is disrupted, nerve cells are destroyed, and patients experience symptoms ranging from fatigue, tingling, numbness and blurred vision to poor muscle control with partial or complete paralysis, speech or mental impairment.

    Source: The Roskamp Institute (01/05/07)

    Sarasota's Roskamp Institute Announces Participation in Multiple Sclerosis Study
    Roskamp Institute Looking for Volunteers for Multiple Sclerosis Research Study.

    The Roskamp Institute announced today its participation in a pharmaceutical sponsored research study for relapsing-remitting Multiple Sclerosis (MS) patients.

    While the Roskamp Institute's primary focus is on Alzheimer's disease, Roskamp researchers have a significant interest in MS due to findings that suggest there are some captivating similarities when studying the immune system response in the brain of persons with Alzheimer's disease and MS.

    "The white blood cells, also known as T-cells, contain a surface marker called CD40 that may play an important role in both Alzheimer's disease and MS," said Dr. Andrew Keegan, an investigator in Neurosciences at the Roskamp Institute's clinical trials division. "Our commitment to finding cures to neurodegenerative disorders, such as MS, has led us to participate in this study sponsored by Novartis that will examine the use of a new investigational drug called fingolimod."

    Research scientists want to determine whether the investigational drug Fingolimod, which is currently not approved by the US Food and Drug Administration, can help people with relapsing-remitting MS. The study drug comes as capsules you take by swallowing once a day, and has been given by researchers to more than 2,300 people in studies that have included healthy people, patients with MS, and kidney transplant patients.

    Fingolimod may act on certain types of white blood cells that are responsible for immune reactions. Researchers want to determine if the investigational drug makes these cells move away from areas of inflammation and redirects them toward lymph nodes and other places in the body where they rest. Scientific researchers believe these white blood cells play an important role in the inflammation process associated with MS and this investigational oral medication may be able to help people with inflammation caused by MS.

    "We are looking for volunteers to participate in this pharmaceutical sponsored research study to assess the effectiveness and safety of the investigational drug fingolimod, used to treat patients with relapsing- remitting MS," said Dr. Michael Mullan, director of the Roskamp Institute. "We hope by working with Novartis we may be able to provide our patients and their families with another treatment option."

    The Roskamp Institute is devoted to understanding causes of and finding cures for diseases of the mind like neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilises a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer's disease.

    Source: Roskamp Institute (13/12/06)

    Novartis Pharmaceuticals initiates new world-wide Phase III study for Fingolimod (FTY720)
    Following a two-year phase II clinical study, in which Novartis Pharmaceuticals reported a relapse rate reduction of more then 50%, compared to placebo, with 77% of people taking Fingolimod (FTY720) remaining relapse-free over two years. Novartis has announced the initiation of a world-wide Phase III study in more than 3000 people with MS.

    The FREEDOMS multi-centre study, is to evaluate the effectiveness and safety of two different doses of Fingolimod(FTY720), compared to placebo over 24 months. It will be recruiting people between the age of 18 and 55 with relapsing-remitting MS that must have experienced 1 relapse in the last year or 2 relapses in the last 2 years.

    Source; Novartis Pharmaceuticals (13/10/06) 

    Researchers Uncover A Novel Mechanism Of Action Of A Potential New Drug For The Treatment Of Multiple Sclerosis
    Virginia Commonwealth University researchers have identified a unique mechanism of action of a new drug that shows great promise for the treatment of multiple sclerosis.

    The researchers report the unique action of FTY720, or Fingolimod, an immunosuppressant drug that was already known to affect the functioning of the immune system by preventing the egress of white blood cells from the lymph nodes into the blood. The article was pre-published as a First Edition Paper in Blood, The Journal of the American Society of Hematology, which appeared online on Sept. 28.

    In this study, the research team observed that FTY720 also inhibited the activity of a key enzyme called cPLA2, which is necessary for the production of inflammatory mediators, known as eicosanoids. Eicosanoids drive inflammatory disorders such as asthma and multiple sclerosis.

    According to Sarah Spiegel, Ph.D., professor and chair in the VCU Department of Biochemistry, and lead author on the study, the inhibition of cPLA2 would shut down the entire inflammatory pathway, possibly without the side-effects caused by medications such as Vioxx, that have been withdrawn from the pharmaceutical market.

    FTY720, a drug developed by Novartis, has shown considerable therapeutic effects in a recent small, placebo-controlled clinical trial involving patients with relapsing-remitting  multiple sclerosis. The study was published in the September 2006 issue of the New England Journal of Medicine by an international research team.

    "With its novel mode of action and the added benefit of an oral formulation, further clinical development of FTY720 might have a major impact on treatment of MS".

    "By clearly understanding the mechanism of action of drugs such as FTY720, we can develop more optimal treatments for inflammatory disease such as asthma or MS. This drug may prevent both inflammation and axonal damage, including demyelination, which are characteristic of MS," said Spiegel.

    This work was supported by grants from the National Institutes of Health, and the National Science Foundation.

    The research team included Shawn G. Payne, Ph.D., a researcher in the VCU Department of Biochemistry, who made the discovery of the novel actions of this drug; researchers Carole A. Oskeritzian, Ph.D., Rachael Griffiths, Preeti Subramanian, all in the VCU Department of Biochemistry; Suzanne E. Barbour, Ph.D., and Charles E. Chalfant, Ph.D., both professors in the VCU Department of Biochemistry who contributed vital reagents and expertise; and Sheldon Milstien, Ph.D., a neuroscientist with the NIH.

    Source: Science Daily Copyright © 1995-2006 ScienceDaily LLC (13/10/06)

    Phase II Data Showing Clinical Benefits of Novel Once-Daily Oral Multiple Sclerosis Therapy FTY720 (Fingolimod) Published in New England Journal of Medicine
    * One-year data show significant reductions in inflammatory disease activity and clinical relapse activity with daily oral FTY720 were maintained for up to one year

    * Phase III program investigating FTY720 now being implemented in the U.S.

    Clinical trial results published in the New England Journal of Medicine showed that FTY720 (fingolimod), a novel once-daily oral compound, demonstrated significant benefits in the treatment of various relapsing forms of multiple sclerosis (MS). Based on the positive Phase II study results, Novartis has launched a Phase III pivotal study program to further evaluate FTY720's benefits in patients with the relapsing-remitting form of multiple sclerosis (RRMS).

    The Phase II data show that during the initial six months of treatment, oral FTY720 taken once-daily reduced the rate of inflammatory disease activity, measured by magnetic resonance imaging or MRI, by up to 80% compared to placebo and also reduced the rate of clinical relapses by more than 50%. In patients who continued FTY720 treatment during the subsequent six-month extension, low levels of disease activity were maintained as measured by both MRI and relapses, and both these measures decreased in patients who switched from placebo to FTY720.

    "These results demonstrate that once-daily oral FTY720 provides a significant and rapid improvement in MRI measures of inflammation, as well as in relapse-related clinical endpoints in patients with relapsing multiple sclerosis," said Chief Investigator Professor Ludwig Kappos, MD, of the Department of Neurology at the University Hospital in Basel, Switzerland. "If the magnitude of benefits shown in this Phase II study are confirmed in the larger-scale Phase III study program, oral FTY720 could represent a major improvement in the way MS will be treated in the future."

    The recently launched global Phase III pivotal study program called FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) will include over 100 study centers and over 2,000 patients worldwide with RRMS. The randomised, double-blind, placebo-controlled study will evaluate the efficacy and safety of two orally-administered doses of FTY720 (1.25 mg and 0.5 mg) as compared to placebo in reducing the frequency of relapses in patients treated for up to 24 months. Other objectives include evaluation of efficacy on disability progression, Magnetic Resonance Imaging (MRI) lesion parameters as well as safety and tolerability of FTY720 (1.25 mg and 0.5 mg) compared to placebo.

    Phase II study results

    The Phase II study described in the New England Journal of Medicine was conducted at 32 centers in 11 countries (in Europe and Canada) to evaluate the effect of FTY720 on disease activity as measured by MRI and relapses as well as its safety and tolerability.

    In the initial placebo-controlled phase, 281 patients were randomised equally to receive FTY720 1.25 mg, FTY720 5 mg or placebo once-daily for six months. Of the 255 patients who completed this part of the study, 98% volunteered to continue in the extension phase. Patients in the placebo group were then re-randomised to receive either FTY720 1.25 mg or 5 mg blinded for an additional six months, while those already on the study drug continued with their original treatment.

    This study showed that once-daily oral FTY720 provides significant improvement in MRI measures of inflammation and in relapse-related clinical endpoints in patients with relapsing MS. Inflammatory disease activity as measured by the total cumulative number of gadolinium (Gd)-enhancing MRI lesions was significantly reduced by up to 80% (p<0.001 in FTY720 1.25 mg, p<0.006 in FTY720 5 mg) compared to placebo over six months of treatment. At six months, the proportion of patients free of Gd-enhancing lesions was also greater in both FTY720 groups compared to placebo (p<0.001 for both groups) with a separation between the curves becoming evident from two months onwards.

    In both the groups taking FTY720 (1.25 mg or 5 mg), patients who had experienced a reduction in their annualised relapse rate of more than 50% compared to placebo during the first six months of the study maintained this low relapse rate during the subsequent six-month extension study.

    In patients who switched from placebo to either dosage of FTY720 after six months, the annualised relapse rate was reduced by at least 70% during the six-month extension study compared to the period on placebo.

    Relapse rates were reduced by 55% in the FTY720 1.25 mg group (p=0.009) and by 53% in the FTY720 5 mg group (p=0.014) compared to placebo. Time to first confirmed relapse was also significantly prolonged in both FTY720 groups compared to placebo (p=0.007 in FTY720 1.25 mg, p=0.01 in FTY720 5 mg). More than 80% of patients who received FTY720 for up to 12 months were free from lesions showing active inflammation on MRI at month 12, irrespective of their treatment dose.

    In the six-month placebo-controlled phase of the study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis), and dyspnea plus diarrhea, and nausea. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and increase in blood pressure were also observed. There were no unexpected safety findings during the six-month extension phase as compared to the six-month placebo-controlled phase. The ongoing Phase III study program includes comprehensive safety monitoring which will provide further assessment of the safety profile.

    An analysis of two-year phase II data with FTY720 will be presented at the European Congress for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Madrid later this month.

    About FTY720

    FTY720 is the first in a new class of disease-modifying treatments called sphingosine 1-phosphate receptor (S1P-R) modulators and has a novel mode of action different from all currently marketed MS therapies. FTY720 has been developed by Novartis and licensed from Mitsubishi Pharma Corporation.

    Source: Novartis Pharmaceuticals Corporation (14/09/06)

    Novartis MS pill efficacy sustained for 18 mths
    Drugmaker Novartis AG said on Thursday its experimental multiple sclerosis pill FTY720 showed sustained efficacy and good tolerability after 18 months in patients with a relapsing form of the disease.

    Data from a Phase II test, to be presented at a meeting of the American Association of Neurology (AAN), showed that patients taking the drug who had seen their relapse rate reduced by 50 percent after 6 months, maintained the low relapse rate during the following 12 months.

    Currently marketed multiple sclerosis treatments reduce relapse rates by 30 percent on average over 2 years, Novartis said in a statement.

    Novartis hopes that FTY720 could be the first oral drug for multiple sclerosis on the market, beating a similar product under development by Serono maker of one of the world's top-selling MS drugs, Rebif.

    Current treatments for the disease are administered by frequent, deep injections.

    Over 2 million people worldwide have the disabling neurological disease which generally strikes young adults and often in a form where attacks are followed by a period of total or incomplete remission.

    Many then go on to develop the secondary progressive form of multiple sclerosis within 10 years.

    Novartis said the most frequently reported side effects in patients treated with FTY720, or fingolimod, for up to 18 months were infections such as colds, and headache.

    The firm also said there were no unexpected safety findings during the 12-month extension compared to the six-month placebo-controlled phase.

    All patients in the test were continuing to take a lower 1.25 mg dose of the drug. A higher dose of 5 mg had a higher rate of side-effects but showed no difference in treating the disease.

    Novartis said it had begun enrolling patients in several European countries for Phase III trials of the drug in MS and was in talks with the U.S. Food and Drug Administration on starting a Phase III test in the United States.

    Source: Yahoo News Copyright © 2006 Reuters Limited. All rights reserved. (06/04/06)

    Novartis: FTY720 offers gold standard MS potential
    Novartis drug to become preferred front-line agent for the treatment of multiple sclerosis.

    Phase II trial results have already highlighted the potential of Novartis' oral multiple sclerosis drug FTY720. Assuming that phase III results confirm this efficacy data, the drug candidate has the potential to dominate the MS market over the longer-term.

    Multiple sclerosis (MS) is characterised by significant unmet need, with no cure currently available. Treatments are used to modify the disease's course, treat exacerbations, and manage symptoms. However, most patients still suffer from some attacks and subsequent disability. Furthermore, the efficacy of currently approved MS agents tends to diminish over time and the American Academy of Neurology (AAN) estimates that 35-50% of MS patients do not have an optimal response and, therefore, may benefit from alternative therapies.

    Novartis' FTY720 was highlighted for particular attention after the once-daily, oral agent demonstrated a 55% reduction in relapse rates and an 80% reduction in lesions compared to placebo after six months.

    The potential market opportunity awaiting new MS agents has increased following the market withdrawal of Tysabri. Although the FDA recently ruled that Biogen Idec and Elan can resume sales of Tysabri, questions still surround the drug and its future role in the treatment of MS.

    FTY720 also stands to gain as a result of its delivery method. With a superior administration profile compared to currently injectable MS agents, it is expected that oral pipeline agents to gain significant market share upon their approval. Use of beta-interferon agents for the treatment of relapsing-remitting MS (RRMS) will decline sharply upon the approval of oral MS formulations, with oral MS agents accounting for 43% of the RRMS market by 2014.

    FTY720 is the most promising of the five oral MS agents currently in the late stages of development, some of which may yet struggle with significant regulatory and development hurdles. In addition, where data is available, efficacy associated with all other oral MS agents in development have thus far been inferior compared to phase II FTY720 results.

    Providing that data from the phase III trials, scheduled to start in early 2006, are comparable to those shown in phase II, FTY720 is set to become the preferred front-line agent for the treatment of RRMS post-approval in 2010.

    Source: Pharmaceutical Business Review ©2006 Business Review Ltd (16/03/06) 

    Novartis MS drug shows promising results
    Data from the extension of a Phase II study to 12 months confirm the significant effects of FTY720, a novel oral medication, for the treatment of patients with relapsing multiple sclerosis (MS).

    The data, presented at the ECTRIMS/ACTRIMS meeting in Thessalonica, Greece, showed that both patient groups taking FTY720 (1.25 mg and 5 mg) who had experienced a reduction in their annualized relapse rate of more than 50% during the first six months of the study compared to placebo maintained this low relapse rate during the subsequent six-month extension.

    In patients who switched from placebo to either the 1.25 mg or 5 mg dosing of FTY720 after six months, the annualized relapse rate was reduced by at least 70% during the second six-month study phase compared to the first six months on placebo.

    More than 80% of patients who received FTY720 for up to 12 months were free from lesions showing active inflammation on magnetic resonance imaging (MRI) at month twelve irrespective of their FTY720 treatment dose (1.25 mg or 5 mg).

    "We are excited by these full-year study results confirming the significant effect of oral FTY720 on reducing both clinical relapses and inflammatory disease activity that we first saw during the six-month placebo-controlled phase of the study," said chief investigator Professor Ludwig Kappos, MD, Department of Neurology at the University Hospital in Basel, Switzerland, "We hope that the magnitude of benefits shown in Phase II will be confirmed in the larger scale Phase III study program expected to be launched soon." Based on the positive Phase II study results, Novartis is in discussions with regulatory authorities about the FTY720 Phase III program, which is expected to be launched by the end of 2005.

    Over two million people worldwide are estimated to suffer from multiple sclerosis, which is the leading cause of neurological disability in young adults. MS is the most common chronic, disabling disease of the central nervous system affecting twice as many women than men.3 MS has a significant impact on the patient's social activities, employment and overall quality of life. Currently marketed MS therapies afford an average reduction in relapse rates of 30% in two-year studies and require frequent injections ranging from daily to weekly. , , ,

    FTY720 Phase II study results
    The results are from a large Phase II study conducted at 32 centers in 11 countries (Europe and Canada). In the initial, placebo-controlled part of this study, 281 patients were randomized in equal numbers to receive either placebo, 1.25 mg or 5.0 mg FTY720 orally once-daily for six months. The study evaluated the effect of FTY720 on disease activity as measured by MRI and clinical relapses as well as its tolerability and safety. After six months, patients in the placebo group were re-randomized to receive either FTY720 1.25 mg or 5 mg blinded for an additional six months, while patients already on FTY720 continued their originally-assigned treatment. A total of 98% of the 255 patients who completed the first six months volunteered to continue in the extension phase evaluating the longer-term effects of FTY720.

    In the 12-month analysis, both patient groups on FTY720 (1.25 mg and 5 mg) who had experienced a reduction in their annualized relapse rate of more than 50% during the first six months compared to placebo maintained this low relapse rate during the subsequent six-month extension. In those patients who switched from placebo to either 1.25 mg or 5 mg of FTY720 after six months, the annualized relapse rate was reduced by at least 70% during the second six-month study phase compared to the first six months on placebo.

    The MRI results at 12 months showed low levels of inflammatory disease activity in all FTY720 groups. In patients who switched from placebo to FTY720, the mean number of inflammatory (Gd-enhancing) lesions on MRI (at the 12th month) was reduced by more than 80% compared to the sixth month. More than 80% of patients who received FTY720 for up to 12 months were free from lesions showing active inflammation on MRI at the 12th month irrespective of their FTY720 treatment dose (1.25 mg or 5 mg).

    FTY720 appeared to be well tolerated, with 91% of patients who entered the extension phase completing the 12th month on the study drug. There were no unexpected safety findings during the extension as compared to the six-month placebo-controlled phase. The most frequently reported adverse events in patients treated up to twelve months were non-serious infections (colds, influenza), headache, diarrhoea and nausea.

    About FTY720
    Oral FTY720 has a novel mode of action different from all available therapies. It reversibly sequesters lymphocytes away from blood and susceptible target organs such as the central nervous system (CNS), thereby reducing neuroinflammation in MS. FTY720 has been developed by Novartis Pharma and licensed from Mitsubishi Pharma Corporation.

    References
    21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)/10th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS)

    A relapse refers to the appearance of new symptoms or the aggravation of old ones, lasting for at least 24 hours. (01/10/05)

    © Multiple Sclerosis Resource Centre

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