Decision 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)

Abstract
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)

Novartis 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)

Federal 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)

Multiple 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)

* 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)

Next 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)

* 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)

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)

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 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)

Results 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? 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)

In 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)

Novartis 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)

Initial 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)

Owing 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)

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)

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)

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)

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)

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)

“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)

• 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)

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 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)

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)

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) 

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 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)

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)

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) 

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)

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