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    You are here : Home » MS Research News » Drugs » Aubagio® (Teriflunomide)

    Aubagio® (Teriflunomide)

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    Teriflunomide is an immunomodulatory, disease-modifying oral drug with anti-inflammatory properties, and is under investigation for the treatment of relapsing forms of MS.

    Teriflunomide blocks the proliferation and functioning of activated T and B lymphocytes - which are thought to be especially damaging in MS - by selectively and reversibly inhibiting a critical mitochondrial enzyme.

    Genzyme blitzes Australian MS market with free oral drug teriflunomide

    AubagioDrug company Genzyme has launched an aggressive campaign to get its new multiple sclerosis drug teriflunomide prescribed free of charge to patients, in a controversial patient familiarisation program announced the same day the medicine was licensed in Australia.

    Each participating neurologist will be able to sign up 10 patients for the once-daily immune system pill, sold under the brand name Aubagio and intended for people with moderate to severe disease, a spokesman said – about 14,000 mainly young adult Australians.

    Any patient prescribed the drug, which competes with interferons, could continue on it indefinitely while the company awaited a Pharmaceutical Benefits Scheme subsidy ruling.

    But Agnes Vitry, from the University of South Australia’s School of Pharmacy and Medical Sciences, said familiarisation programs were intended to pressure the government into unwarranted subsidies and could have “disastrous consequences”.

    “They can lead to a very rapid uptake of new drugs whose safety is still very uncertain and aim to induce swapping from older drugs without medical need but with potential safety issues,” she wrote in a submission to the Australian Consumer and Competition Commission’s review of Medicines Australia’s Code of Conduct.

    Because teriflunomide was a powerful drug with potentially serious side-effects, “I would not trust information given by the drug company but would wait for independent assessments,” Dr Vitry told Neurology Update’s sister publication, 6minutes.

    Teriflunomide stays in the body for up to two years and may cause liver damage and birth defects.

    Source: Neurology Update (27/11/12)

    Australian TGA approves Aubagio to treat relapsing forms of MS

    AubagioGenzyme, a Sanofi company, has announced that the Australian Therapeutic Goods Administration (TGA) has approved Aubagio® (teriflunomide) 14 mg as a new once-daily, oral treatment indicated for patients with relapsing forms of multiple sclerosis (MS).

    The TGA approval will enable health professionals to prescribe Aubagio 14 mg in Australia, which is now the second country to gain marketing authorization for the treatment, following FDA approval in September.

    "We are very pleased with the TGA approval of Aubagio that makes available a new option for healthcare professionals, and people living with MS in Australia who may benefit from this once-daily, oral treatment," said Bill Sibold, Head of Multiple Sclerosis, Genzyme. "The availability of Aubagio in the U.S. and subsequent registration in Australia not only demonstrates our continued progress, it also reflects our commitment to deliver differentiated treatments and provide access for patients globally."

    The TGA's approval of Aubagio was based on safety and efficacy data from the TEMSO (TEriflunomide Multiple Sclerosis Oral) trial. The ongoing Aubagio clinical development program, involving more than 5,000 patients in 36 countries including Australia, is amongst the largest of any MS therapy. Some patients in extension trials have been treated for up to 10 years.

    "For some people living with MS, the additional burden of injectable therapies administered daily to weekly can sometimes be a struggle," said Associate Professor John King, Senior Neurologist, Royal Melbourne Hospital, who participated in the clinical trials for Aubagio. "It is exciting to see a new oral treatment that has been shown to both reduce relapses and slow the progression of disability. This is an encouraging development for the MS community."

    Aubagio is an immunomodulator with anti-inflammatory properties. Although the exact mechanism of action for AUBAGIO is not fully understood, it may involve a reduction in the number of activated lymphocytes in the central nervous system (CNS).

    "We welcome the advent of a new oral treatment option for MS patients in Australia," said Professor Bill Carroll, Chairman of MS Research Australia. "It is important for people with MS and their clinicians to have access to a range of well-tolerated and convenient therapies that may reduce the impact of the disease on their lives and suit their lifestyle."

    Aubagio is marketed in the U.S. and now Australia. Marketing applications for AUBAGIO are under review by the European Medicines Agency (EMA) and other regulatory authorities.

    Source: News-Medical.Net (22/11/12)

    Oral Aubagio® (teriflunomide) study confirms significant impact on disability

    AubagioGenzyme, a Sanofi company announced today that key data from the TOWER trial were presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In the study, once-daily, oral Aubagio® 14 mg significantly reduced the annualized relapse rate and slowed progression of disability in patients with relapsing forms of multiple sclerosis (MS) compared to placebo. In addition, the proportion of patients treated with Aubagio who were relapse-free was significantly higher compared to placebo.

    TOWER (Teriflunomide Oral in people With relapsing multiplE scleRosis) is a randomized, double-blind Phase III trial that enrolled 1,169 patients with relapsing MS across 26 countries and compared 7 mg or 14 mg once-daily, oral Aubagio against placebo. The company announced positive top-line results in June. In September, the FDA approved AUBAGIO as a once-daily oral treatment for patients with relapsing forms of MS. Marketing applications for Aubagio are currently under review by the EMA and other regulatory authorities.

    “Slowing the progression of disability is a major goal in treating MS and remains a significant unmet need for many patients,” said Ludwig Kappos, M.D., Chair of Neurology, University Hospital Basel, Switzerland, who presented the key TOWER results. “The TOWER study results are consistent with the Phase lll TEMSO data, both in terms of the effect on progression of disability and the manageable safety profile of Aubagio.”

    TOWER data presented for the first time today for the 14 mg dose include:

    A 36.3 percent reduction in annualized relapse rate (ARR=0.319), the primary endpoint of the trial, as compared to placebo (ARR=0.501) (p=0.0001); Fifty-two percent of patients treated with this dose were also relapse-free, meaning they did not experience any relapses during the study, compared to 38 percent with placebo (37 percent risk reduction; p<0.0001).

    A 31.5 percent reduction in the risk of 12-week sustained accumulation of disability, the main secondary endpoint, as measured by the Expanded Disability Status Scale (EDSS), compared to placebo (p=0.0442).

    In addition, a 22.3 percent reduction in annualized relapse rate (ARR=0.389) was observed in patients treated with Aubagio 7 mg compared to placebo (p=0.189); Further, 55 percent of patients treated with 7 mg AUBAGIO were relapse-free, as compared with 38 percent on placebo (p=0.0016). There was no statistically significant difference observed between Aubagio 7 mg and placebo for the risk of 12-week sustained accumulation of disability.

    “Aubagio is the first and only oral MS therapy to significantly slow the progression of disability in two Phase III trials,” said David Meeker, M.D., President and CEO, Genzyme. “The convenience of a once daily oral therapy offers a meaningful alternative for patients wanting to avoid the burden of regular injections.”

    Patients who completed the trial were followed for a period between 48 and 173 weeks. The average duration of Aubagio exposure in TOWER was 18 months.

    Adverse events observed in the trial were consistent with those seen in previous studies of Aubagio in MS. The proportion of patients with treatment-emergent adverse events was similar across all treatment arms. The most common adverse events reported more frequently in the Aubagio arms were headache, ALT (Alanine aminotransferase) elevations, hair thinning, diarrhea, nausea and neutropenia. As previously reported, there was one death from a respiratory infection in the placebo arm and three deaths in the teriflunomide arms from a motor vehicle accident, suicide and sepsis.

    The FDA has approved Aubagio as a once-daily, oral immunomodulator indicated for patients with relapsing forms of multiple sclerosis (MS). The ongoing Aubagio clinical development program, involving more than 5,000 patients in 36 countries, is among the largest of any MS therapy. Some patients in extension trials have been treated up to 10 years.

    Aubagio is an immunomodulator with anti-inflammatory properties. Although the exact mechanism of action for Aubagio is not fully understood, it may involve a reduction in the number of activated lymphocytes in the central nervous system (CNS).

    The U.S. Aubagio label includes a boxed warning citing the risk of hepatotoxicity and, teratogenicity (based on animal data). In MS clinical studies included in the U.S. label, the incidence of serious adverse events were similar among AUBAGIO and placebo-treated patients. The most common adverse events associated with Aubagio in MS patients included increased ALT levels, alopecia, diarrhea, influenza, nausea and paresthesia.

    The labeling for Aubagio was also informed by the estimated 2.1 million years of patient exposure globally since the launch of leflunomide, which is indicated in the U.S. for the treatment of rheumatoid arthritis. Aubagio is the principal active metabolite of leflunomide. Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide.

    About the TOWER Trial

    TOWER is a Phase III, multi-center double-blind parallel-group placebo-controlled study of the efficacy and safety of AUBAGIO in patients with relapsing MS followed by an open-label extension period.

    The TOWER study included patients ages 18 to 55. The primary endpoint was the annualized relapse rate, defined as the number of confirmed relapses per patient-year. The key secondary endpoint was time to disability progression confirmed for a minimum of 12-weeks. Safety variables were defined as adverse events reported by the patients or noted by the investigator during the study period.

    Source: Genzyme (15/10/12)

    Battle lines drawn in the MS oral drugs market

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

    Mopping up the competition

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

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

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

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

    Concerns and answers

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

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

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

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

    Biogen's steady stream of optimism

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

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

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

    Source: Daily Finance © Copyright 2012 AOL Inc.

    Oral multiple sclerosis pill Aubagio® gets U.S. approval

    Oral MS MedicationSanofi SA has won U.S. approval for its multiple sclerosis pill Aubagio - one of the two treatments for the chronic disease that could return the French drugmaker to growth after several blockbuster drugs lost patent protection.

    The drug has been shown to be less effective than some rivals but has milder side effects and analysts say it could find favour among newly diagnosed patients. Around 35 percent to 40 percent of multiple sclerosis (MS) sufferers prefer to take no medication rather than face unwanted side effects.

    "In a clinical trial, the relapse rate for patients using Aubagio was about 30 percent lower than the rate for those taking a placebo," Russell Katz, director of the Division of Neurology Products at the Food and Drug Administration, said in a statement on Wednesday.

    Aubagio is expected to launch on the U.S. market in a few weeks, a spokeswoman for Sanofi unit Genzyme said.

    Multiple sclerosis, which has no cure, affects 2.5 million people worldwide. It is a chronic, often disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision.

    MS drugs Gilenya by Novartis and Biogen Idec Inc's BG-12 are expected to dominate a market that JPMorgan analysts predict growing to $14 billion in 2015 from $9.6 billion last year.

    Aubagio is seen grabbing a much smaller chunk of this market, reaching modest sales of $353 million in the United States and five major European countries by 2020, according to business intelligence firm Datamonitor.

    Cheuvreux analyst Marcel Brand, who has a more optimistic forecast, predicts peak sales of Aubagio of 1.48 billion euros by 2018. "Although Aubagio is not as effective on relapse rates as Gilenya, it's free of its longer-term side effects," he said.

    Patients taking Gilenya have to be monitored because the drug causes the heart rate to slow down in the first hours after ingestion.

    European regulators are expected to give their response to Aubagio in the first quarter of 2013.

    Compared with older therapies for MS, Aubagio has the advantage of being taken orally but it has produced less impressive results in clinical tests than other oral treatments and has failed to show it was better than Merck's Rebif, a commonly used injectable drug for MS.

    In addition to Aubagio, Sanofi has filed for approval for MS injectable drug Lemtrada.

    In a recent setback, the FDA asked Sanofi to refile its marketing application for Lemtrada. If it wins approval, the drug could be launched in 2013.

    The most common side effects associated with Aubagio include increased levels of the enyzme alanine transaminase, which can indicate damage to the liver, as well as hair loss, diarrhea, influenza, nausea and numbness of the skin, Sanofi said.

    The ongoing Aubagio clinical development program involves more than 5,000 patients in 36 countries. Some patients in extension trials have been treated for up to 10 years, the company said.

    Source: Yahoo! News c) Copyright Thomson Reuters 2012 (13/09/12)

    Positive test boosts Sanofi MS drug hopes

    Teriflunomide Sanofi reported positive results from a late-stage trial of its Aubagio multiple sclerosis drug, bolstering its chances of approval by regulators as it seeks to catch up with a fast-selling oral treatment from rival Novartis.

    Sanofi said it found that a daily dose of the treatment, one of two multiple sclerosis drugs it has in late-stage development, reduced the rate of relapse by 36 percent compared with a placebo.

    The study assessed the efficiency and safety of Aubagio in 1,169 patients with relapsing forms of multiple sclerosis.

    The full data from the study will be presented at an upcoming scientific meeting, Sanofi said.

    Cheuvreux analyst Marcel Brand, who has an "outperform" recommendation on Sanofi stock, said the results were positive and consistent with earlier data, "which is reassuring".

    Brand expects Aubagio to generate peak sales of $1.8 billion in 2018, taking around 11 percent of volume market share.

    The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are both reviewing marketing applications for Aubagio as a treatment for relapsing forms of MS.

    The FDA's response is due by July 2012, while EMA is expected to give its feedback in the first quarter of 2013.

    Compared with older therapies, Aubagio has the advantage of being an oral drug.

    But it has produced less impressive results in clinical tests than other oral MS treatments and has failed to show it was better than a commonly used injectable drug for MS, although it did have milder side effects.

    Analysts expect the drug could find a niche among newly diagnosed patients, since around 35 to 40 percent of MS patients prefer to take no medication rather than face unwanted side effects.

    MS pills Gilenya by Novartis and Biogen Idec Inc's BG-12 are seen dominating a market that JPMorgan analysts predict growing to $14 billion in 2015 from $9.6 billion last year.

    MS, which has no cure, affects 2.5 million people worldwide. It is a chronic, often disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision.

    Source: Yahoo Health Copyright © 2012 Yahoo! Inc (01/06/12)

    Sanofi is looking at new compounds to expand MS business

    Oral MS DrugsSanofi, which bought Genzyme Corp. last year, is seeking new treatments to expand its multiple sclerosis business, said Michael Panzara, Genzyme’s therapeutic area head for multiple sclerosis, immune diseases and neurology.

    The drugmaker said today its experimental medicine Lemtrada, which it gained through Genzyme, led to an improvement in disability scores in patients suffering from multiple sclerosis compared with an older treatment in a late-stage trial. The company has another experimental MS therapy, Aubagio, which was under development before the Genzyme purchase.

    Beyond Lemtrada and Aubagio, Paris-based Sanofi has other experimental MS compounds in its pipeline “that we are actively starting to look at, and we’re always looking externally for good opportunities,” Panzara said in a phone interview today.

    Sanofi Chief Executive Officer Chris Viehbacher spent $20.1 billion last year to acquire Cambridge, Massachusetts-based Genzyme, the largest maker of medicines for rare genetic diseases. After the purchase, he folded Aubagio, Sanofi’s own MS therapy, into Genzyme to build up a multiple sclerosis business.

    Aubagio, whose chemical name is teriflunomide, is an oral therapy. Lemtrada, also known as alemtuzumab, is a so-called monoclonal antibody administered to patients through infusions for five consecutive days when they begin the treatment and for another three days 12 months later.

    “Alemtuzumab and teriflunomide we view as a beginning,” Panzara said. “You can’t have a world-class MS organization if you don’t fill up the pipeline at all stages of development.”

    Source: Bloomberg ©2012 BLOOMBERG L.P.(25/04/12)

    EMA accepts oral MS treatment Teriflunomide marketing application

    TeriflunomideGenzyme, a Sanofi company , announced today the European Medicines Agency (EMA) has accepted the filing of the marketing authorization application (MAA) for once-daily oral teriflunomide for the treatment of relapsing forms of multiple sclerosis (MS). Acceptance of the MAA starts the EMA's review process.

    "The filing represents another important milestone for teriflunomide and brings us one step closer to offering a new treatment option to patients with relapsing MS," said Bill Sibold, Senior Vice President, Head of Multiple Sclerosis, Genzyme. "As an oral therapy with a promising clinical profile, teriflunomide is extremely well positioned to provide an alternative therapeutic option to patients who are currently taking injectable therapies. Those injectable therapies make up approximately 80 percent of the MS market today."

    The purpose of the MAA is to secure approval to market and allow prescription of teriflunomide in the European Union based on data from two completed pivotal Phase III trials, TEMSO and TENERE. These trials represent two of five efficacy studies of teriflunomide in MS that are completed or underway, making the clinical program one of the largest and broadest of any MS therapy in development.

    An application to market teriflunomide in the United States is under review by the U.S. Food & Drug Administration.

    About Teriflunomide

    Teriflunomide is an immunomodulatory, disease-modifying oral drug with anti-inflammatory properties, and is under investigation for the treatment of MS. Teriflunomide blocks the proliferation and functioning of activated T and B lymphocytes -- which are thought to be especially damaging in MS -- by selectively and reversibly inhibiting a mitochondrial enzyme. Slowly dividing or resting lymphocytes are generally unaffected by teriflunomide, suggesting that the immune system's response to infection should not be compromised.

    Teriflunomide is being studied in a large clinical program that is expected to include more than 5,000 trial participants in 36 countries. Five efficacy clinical trials are either completed or underway with teriflunomide, making the clinical program one of the largest and broadest of any MS agent under development. In addition to the TEMSO and TENERE trials, the Phase III, placebo-controlled trial TOWER is ongoing in people with relapsing forms of MS. Another Phase III study, TOPIC, is underway in early MS or CIS (clinically isolated syndrome). Teriflunomide is also being evaluated as an adjunct therapy to interferon-B in the Phase III TERACLES trial. With up to 10 years of continuous use in a Phase II extension, teriflunomide has the longest clinical experience of any investigational oral MS therapy.

    Source: Market Watch Copyright Business Wire 2012 (23/02/12)

    Sanofi faces uphill struggle in MS drug market

    Lemtrada (Campath)Sanofi SA risks falling behind in the battle for share of the fast-growing multi-billion euro multiple sclerosis (MS) market, as rivals push ahead with revolutionary treatments while doubts remain over the French drugmaker's own drug candidates.

    Sanofi, which has relied on blood thinners and cancer therapies to drive sales but faces increased competition from generic drug versions, is preparing to submit two MS treatments for approval this year.

    But it faces an uphill battle to catch Novartis AG's Gilenya and Biogen Idec Inc's BG-12, set to dominate a market that JPMorgan analysts see growing to $14 billion (8 billion pound) in 2015 from $9.6 billion last year.

    "Sanofi will remain a small player compared with Biogen or Novartis, but it will still remain on the radar screen," said Beatrice Muzard, an analyst at brokerage Natixis.

    MS, which has no cure, affects 2.5 million people worldwide. It is a chronic, often disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision.

    Standard treatment has involved injected drugs such as Teva Pharmaceutical Industries Ltd's Copaxone, Tysabri - sold by Biogen and Elan Ltd - and interferons. But the approval of Gilenya in 2010 introduced a potent new option in pill form.

    Gilenya and other oral MS treatments in late-stage development such as BG-12 are expected to drive growth in the sector.

    But analysts estimate Sanofi will grab only a modest share, given question marks over its drug candidates Aubagio and Lemtrada. Natixis' Muzard predicts the French firm's MS drugs could have peak sales of just 1 billion euros - not enough to plug the gap left by loss of earnings from the arrival of generic competition to its top blood thinner, Plavix.

    STICKING POINT

    Sanofi acquired Lemtrada through its $20.1 billion takeover of U.S. biotech group Genzyme last year, when it was already developing MS pill Aubagio. If approved, both drugs could end up reaching the U.S. and European markets by the end of the year.

    "It's pretty unusual for a company to come out with two new products at once, and actually cover the spectrum of the disease," Sanofi Chief Executive Chris Viehbacher told Reuters.

    Trouble is, there are doubts about both medicines.

    Lemtrada was the main sticking point in the protracted merger talks between Sanofi and Genzyme and, at the time, Viehbacher's team was keen to talk down its prospects. Genzyme had projected peak Lemtrada sales of $3.5 billion a year, while Sanofi pitched the number at around $700 million.

    The final deal between the two companies included a "contingent value right", a tradeable security that gives payouts to Genzyme investors if certain revenue targets are met, to bridge their differences.

    "When we were acquiring Genzyme, we were rightly sceptical of Lemtrada, because I am not keen on paying for things that are not proven," Viehbacher said.

    "Now that we have seen the clinical trial results - I have seen them but I cannot say more because we are going to publish them in April - we are very excited about this multiple sclerosis franchise."

    Unlike older MS drugs that have to be injected daily or weekly, Lemtrada is given just once a year.

    "I think Lemtrada is going to be completely different than everything else, which makes it difficult for the market to assess," said Viehbacher.

    Certainly analyst views vary widely. Morgan Stanley is forecasting 1 billion euros in peak sales for Lemtrada, while Nomura only sees $360 million.

    Medical experts back Viehbacher's view that a wider choice of treatments is needed given the unpredictable nature of MS.

    "Doctors and patients are looking for multiple options because the disease is so variable," said Tim Coetzee, chief research officer of the U.S.-based National Multiple Sclerosis Society. "A drug that is effective in some patients may not be effective in other patients."

    LATER STAGE

    Yet Lemtrada's prospects remain far from certain. During mid-stage tests the drug showed an unprecedented level of efficacy in reducing relapses over a three-year period, but this outcome was not repeated in a later-stage trial.

    It can also have serious side effects, which make it likely to be prescribed only to treat more severe forms of the disease.

    Compared with older therapies, Aubagio has the advantage of being an oral drug. But it has produced less impressive results in clinical tests than BG-12 and Gilenya - though heart issues have recently cast a shadow over Gilenya.

    In one recent study, Aubagio failed to show it was better than Rebif, a commonly used injectable interferon from Germany's Merck KGaA, although it did have milder side effects.

    "Aubagio won't take a lot of market share ... but it could find a niche on the basis of its safety profile," said Muzard, who is forecasting sales of around 400 million euros in 2018, compared with 2.6 billion for Gilenya.

    That niche could be found among newly diagnosed patients, since around 35 to 40 percent prefer to take no medication rather than face unwanted side effects.

    "Here's the challenge: convincing patients to start therapy," said Kevin Richard, co-founder of U.S. consultancy ClearView Healthcare Partners. "In this case Aubagio could be prescribed to patients who are not on interferons yet and who are hesitant to start injections."

    Sanofi filed Aubagio with the U.S. Food and Drug Administration in October and aims to submit it for approval in Europe in the first quarter of 2012, when it also expects to file Lemtrada with both regulators.

    Source: Reuters © 2012 Thomson Reuters (06/02/12)

    Oral Teriflunomide in relapsing Multiple Sclerosis study reported

    TeriflunomideGenzyme, a Sanofi company , today reported top-line results from TENERE, a Phase III clinical trial comparing the effectiveness, safety and tolerability of once-daily oral teriflunomide to interferon beta-1a (Rebif(R)), an approved injectable therapy, in people with relapsing forms of multiple sclerosis (RMS).

    The TENERE trial, which included 324 patients, is the second completed study of five efficacy studies of teriflunomide in MS, making the clinical program one of the largest and broadest of any multiple sclerosis agent under development.

    No statistical superiority was observed between the Rebif and teriflunomide arms (7mg and 14mg) on risk of treatment failure, the primary composite endpoint of the study. Risk of treatment failure was defined as the occurrence of a confirmed relapse or permanent treatment discontinuation for any cause, whichever came first. In the study, 48.6 percent of patients receiving 7mg of oral teriflunomide (n=109) and 37.8 percent of patients receiving 14 mg of oral teriflunomide (n=111) reached the primary endpoint, versus 42.3 percent of patients receiving interferon beta 1-a (n=104).

    The teriflunomide 14 mg daily dose (0.259) and Rebif (0.216) were not distinguishable on the endpoint of estimated annual relapse rate. The rate was higher in the 7mg arm (0.410). The percentage of patients experiencing any treatment emergent adverse events was similar across all arms of the study. The rate of permanent treatment discontinuation in the study due to a treatment emergent adverse event was higher in the Rebif arm (21.8 percent vs. 8.2 percent in the 7mg teriflunomide arm and 10.9 percent in the 14 mg teriflunomide arm).

    Both the 7mg and 14mg doses of teriflunomide were safe and generally well tolerated. Most adverse events observed in the teriflunomide arms were mild in severity, including nasopharyngitis, diarrhea, hair thinning, and back pain. These occurred with a higher incidence than in the Rebif arm. The most common adverse events observed in the Rebif arm were increases in alanine aminotransferase levels, headache and flu-like symptoms. These occurred with a higher incidence than in the teriflunomide arms. There were no deaths in the trial.

    Genzyme anticipates presenting detailed TENERE study findings at a forthcoming medical meeting. The company will also include the results in its application with the EMA for marketing authorization in the European Union, along with results from its successful Phase III TEMSO trial. The company expects to file an application for marketing authorization with the EMA in the first quarter of 2012. The U.S. FDA application for teriflunomide was accepted for review by the U.S. FDA in October 2011.

    About the TENERE Trial

    TENERE was a two-year, randomized, rater-blinded comparator study that included 324 people with RMS from 53 centers in 13 countries. Trial participants were 18 years of age or older, with an Expanded Disability Status Scale (EDSS) of 5.5 or less at the initial screening visit. Trial participants were randomized to receive oral teriflunomide, 7 mg or 14 mg, once daily, or interferon beta-1a (Rebif(R) 44mcg tiw new formulation) and were followed for 48 weeks. The primary endpoint was risk of failure as defined by the first occurrence of relapse or permanent study treatment discontinuation for any cause, whichever came first. Secondary outcome measures included annualized relapse rate, subject-reported fatigue as assessed by the Fatigue Impact Scale (FIS), and subject satisfaction as assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM). Safety and tolerability evaluations were based on adverse events, physical examinations, vital signs and laboratory investigations. A long-term extension of TENERE is ongoing.

    About Teriflunomide

    Teriflunomide is an immunomodulatory, disease-modifying oral drug with anti-inflammatory properties, and is under investigation for the treatment of MS. Teriflunomide blocks the proliferation and functioning of activated T and B lymphocytes -- which are thought to be especially damaging in MS -- by selectively and reversibly inhibiting a critical mitochondrial enzyme. Slowly dividing or resting lymphocytes are unaffected by teriflunomide, leaving the immune system's response to infection uncompromised.

    Teriflunomide is being studied in a large clinical program that is expected to include more than 4,000 trial participants in 36 countries. Five efficacy clinical trials are either completed or underway with teriflunomide, making the clinical program one of the largest and broadest of any MS agent under development. In addition to the TEMSO and TENERE trials, the Phase III, placebo-controlled trial TOWER is ongoing in people with RMS. Another Phase III study, TOPIC, is underway in early MS or CIS (clinically isolated syndrome). Teriflunomide is also being evaluated as an adjunct therapy to interferon-B in the Phase III TERACLES trial. With up to 10 years of continuous use in a Phase II extension, teriflunomide has the longest clinical experience of any investigational oral MS therapy.

    Source: Genzyme (20/12/11)

    Oral MS drug Teriflunomide study shows lasting efficacy and safety

    TeriflunomideThe investigational oral drug teriflunomide (Aubagio) seems to have maintained its effectiveness during up to nine years of follow-up in clinical trial patients with the relapsing form of multiple sclerosis, and no late safety problems have been noticed, researchers said here.

    The findings came from open-label extensions of phase II and III studies with teriflunomide, which is now under FDA review as a treatment for relapsing-remitting MS. The results were presented in a series of posters at the joint meeting of the European and American Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS).

    Annualized relapse rates during the eight-year extension phase of the phase II study ranged from 0.20 to 0.32, with somewhat lower rates seen with a 14-mg/day dose of teriflunomide relative to 7 mg/day, according to Paul O'Connor, MD, of the University of Toronto, who was a principal investigator for this study and others involving teriflunomide.

    The relapse rates were comparable to those seen in the trial's placebo-controlled phase.

    Also, EDSS disability scores remained stable in patients taking 14 mg/day during the extension and rose only moderately among those on 7 mg/day.

    But with both dosages, other signs of disease activity, such as total MRI lesion burden and brain atrophy, continued to rise during the extension.

    Findings were similar in an extension of the phase III TEMSO trial, for which five years of efficacy data are now available, according to O'Connor.

    Annualized relapse rates were in the range of 0.18 to 0.25, again with slightly lower rates associated with the 14-mg dosage. And, as in the phase II extension, the drug failed to completely arrest progression of brain atrophy or total lesion volume.

    Both of the original studies had randomized patients to placebo or the 7- or 14-mg doses of teriflunomide -- 179 patients originally in the phase II trial and 1,088 in TEMSO.

    Participants were allowed to enter the open-label extensions if they wished, in which those who had been receiving the active drug would continue on the same dosage and the placebo group would be re-randomized to the two teriflunomide doses.

    O'Connor and colleagues therefore reported efficacy and safety results for four groups: the original 7- and 14-mg teriflunomide patients and the former placebo group members who switched to teriflunomide at 7 or 14 mg.

    In all, 147 patients in the phase II study and 742 in TEMSO agreed to participate in the extension. Attrition during the extensions was about 50% and 25%, respectively.

    O'Connor acknowledged that patients who had not done well during the trial or the extension would be more likely to refuse or stop participation, a source of bias in the results.

    But he told MedPage Today that nearly all the dropouts had been quizzed about their reasons. In the phase II extension, only eight of about 70 patients who left the study identified lack of efficacy as their motivation. Similarly, 27 of more than 180 dropouts from the TEMSO extension cited lack of efficacy.

    Adverse effects were a much more common reason given for quitting the studies. As in most long-term drug studies, treatment-emergent adverse events were extremely common -- seen in more than 80% of patients in the TEMSO extension and nearly 100% of those in the phase II extensions, which had four and nine years of safety data, respectively.

    Serious infections and malignancies were rare and gave no sign of being drug-related.

    Hematopoietic deficits including neutropenia and leukopenia were seen in 20% of the 7-mg groups and 32% of the 14-mg groups in the longer phase II extension, and in 6% to 7% of both dosage groups in the TEMSO extension.

    Only four patients across the two studies discontinued treatment because of these problems, the investigators indicated.

    The only adverse event that appeared clearly treatment-related was a gradual and subtle thinning of hair, O'Connor said. He said it fell well short of alopecia, but about 10% of low-dose and 20% of high-dose patients indicated that they believed their hair thickness had decreased during treatment.

    Most patients reporting the problem said it came on during the first six months of the extension phase.

    Otherwise, O'Connor said, there were no new safety problems during the extension.

    In a separate presentation, Bernd Kieseier, MD, of the University of Duesseldorf in Germany, indicated that miscarriages seen in TEMSO may not have been a statistical fluke.

    During the placebo-controlled phase of TEMSO, four of 11 women who became pregnant during the study had miscarriages.

    Kieseier and colleagues analyzed data collected by the drug's sponsor, Sanofi (formerly sanofi-aventis), on all patients participating in teriflunomide trials. The database showed a total of 33 female patients taking teriflunomide who had become pregnant with a known outcome.

    Eight of these pregnancies ended in spontaneous abortion, the researchers found.

    Because the drug's safety in fetal exposure is unknown, women who were pregnant or who planned to become pregnant were excluded. Nevertheless, as is often the case, some participants had failures of birth control and others were unknowingly pregnant at enrollment.

    Kieseier also reported that 10 of the pregnancies ended in healthy delivery. There were no reports of structural or functional abnormalities in any of the babies, he said.

    In eight of these cases, the women underwent treatment with cholestyramine or charcoal immediately after pregnancy was discovered to speed teriflunomide elimination.

    Teriflunomide is the active metabolite of leflunomide, a common drug used to treat rheumatoid arthritis. Leflunomide carries a boxed warning indicating that it is contraindicated in pregnancy.

    All the studies were supported by Sanofi.

    O'Connor reported relationships with Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, and Warburg Pincus.

    Kieseier reported relationships with Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi, Talecris, and Teva.

    Primary source: ECTRIMS/ACTRIMS Triennial Meeting

    Source reference:
    Comi G, et al "Extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: safety outcomes with up to 4 years of follow-up," ECTRIMS/ACTRIMS 2011; abstract P439.

    Additional source:
    ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    Li D, et al "Efficacy of teriflunomide in relapsing multiple sclerosis: phase II extension study with 8-year follow-up,"
    ECTRIMS/ACTRIMS 2011; abstract P440.

    Additional source: ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    O'Connor P, et al "Extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: clinical and MRI data 5 years after initial randomisation," ECTRIMS/ACTRIMS 2011; abstract P924.

    Source: Medpage Today © 2011 Everyday Health, Inc (27/10/11)

    Oral MS therapy Teriflunomide (Aubagio™*) significantly reduces relapses

    TeriflunomideSanofi and its subsidiary Genzyme announced today new data from the pivotal TEriflunomide Multiple Sclerosis Oral (TEMSO) Phase III trial showing that once-daily oral teriflunomide significantly reduced annualized rates of relapses leading to hospitalization. New data also confirmed the safety profile and efficacy of teriflunomide over a six-year period after the initial randomization.

    A total of fifteen presentations on teriflunomide are on the program for the fifth joint triennial congress of the European and American Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS / ACTRIMS) in Amsterdam, Netherlands.

    The companies also announced today that the U.S. Food and Drug Administration has accepted for review Sanofi's new drug application (NDA) for oral teriflunomide as a potential therapy for people with relapsing forms of multiple sclerosis (MS). Sanofi expects to file an application for regulatory approval with the European Medicines Agency (EMA) in the first quarter of 2012.

    "The new results of the TEMSO study show that both 7mg and 14mg doses of teriflunomide could reduce the severity of relapses measured through annual rates of relapses leading to hospitalization as well as deliver encouraging long-term results on safety and efficacy," said Professor Paul O'Connor, Director of the MS Clinic at St. Michael's Hospital, Toronto, Canada, and principal investigator of the TEMSO study.

    New post-hoc analyses showed that teriflunomide-treated patients' annualized rate of relapses leading to hospitalization was significantly reduced by 36% (p=0.015) with 7 mg and by 59% (p<0.0001) with 14 mg compared with placebo. The risk of hospitalization per relapse was also significantly reduced by 43% (p<0.001) for the 14 mg dose and numerically reduced by 6% (p=NS) for the 7 mg dose. These analyses also showed teriflunomide significantly reduced the annualized rate of emergency medical facility visits (a visit to a medical facility/hospital for emergency care not resulting in an admission) by 42% (p=0.004) for the 14 mg dose and numerically reduced by 31% (p=NS) for the 7 mg dose vs placebo.

    "The additional data presented at ECTRIMS further supports the potential of teriflunomide as a new once a day oral therapy that can significantly decrease the number of relapses requiring hospitalizations for patients suffering from this complex and unpredictable disease and who need safer and more effective therapeutic options," said Dr. Elias Zerhouni, President, Global Research & Development, Sanofi.

    Long-term data on safety and efficacy of teriflunomide were also presented at this congress. The results from the extension of the TEMSO study showed that both doses of teriflunomide were well tolerated six years after the initial randomization, with a consistent safety profile to the core two- year study. The beneficial effects of teriflunomide on clinical and MRI endpoints reported in TEMSO also continue to be sustained over five years after the initial randomization.

    In addition to the TEMSO extension, the follow up to the Phase II long-term efficacy and safety study was presented. These new findings showed that teriflunomide was well tolerated up to nine years of continuous exposure, with a safety profile consistent with that reported during the 36 weeks of initial double-blind treatment. The reductions in disease activity observed with teriflunomide in the initial study were maintained for up to eight years of treatment.

    About TEMSO study

    TEMSO was a two-year randomized, double-blind, placebo-controlled multinational study that included 1,088 people with relapsing forms of MS from 126 centers in 21 countries.

    Trial participants were 18-55 years of age, with an Expanded Disability Status Scale (EDSS) of 5.5 or less, and had at least one relapse in the previous year or at least two relapses in the preceding two years. Trial participants were randomized to placebo or teriflunomide, 7mg or 14mg, once daily and followed for 108 weeks.

    The primary endpoint was annualized relapse rate, defined as the number of confirmed relapses per trial participant year; a relapse is a new or worsening of a previous clinical sign or symptom.

    The key secondary endpoint was the time to sustained disability progression, measured by the EDSS. Disability progression was defined as an increase from baseline of at least 1.0 point on the EDSS persisting for at least 12 weeks. Change from baseline in total lesion volume was also a key prespecified MRI endpoint in the study.

    Safety and tolerability evaluations were based on adverse events, physical examinations, vital signs and laboratory investigations. A long-term extension of TEMSO is ongoing.

    About Teriflunomide

    Teriflunomide is an immunomodulatory, disease-modifying oral drug with anti-inflammatory properties, and is under investigation for the treatment of relapsing forms of MS.

    Teriflunomide blocks the proliferation and functioning of activated T and B lymphocytes - which are thought to be especially damaging in MS - by selectively and reversibly inhibiting a critical mitochondrial enzyme.

    With nine years of continuous use in a Phase II extension, teriflunomide has the longest clinical experience of any investigational oral MS therapy. In addition to the TEMSO trial, two other Phase III trials, TOWER and TENERE, are ongoing in people with RMS.

    A Phase III study, TOPIC, is also underway in early MS or CIS (clinically isolated syndrome). Teriflunomide is also being evaluated as an adjunct therapy to interferon-β in the Phase III TERACLES trial.

    (*) Aubagio™ is the proprietary name submitted to health authorities for the investigational agent teriflunomide.

    Source: Sanofi (20/10/11)

    New oral MS drug may reduce relapses in MS patients

    TeriflunomidePeople with multiple sclerosis (MS) may soon have a second needle-free option to control their disease.

    Last year, the FDA approved the first disease-modifying pill, a drug called Gilenya, to treat MS.

    Now a new study shows that a different drug, a once-daily pill called teriflunomide, may also slow the progression of the neurological disease and its disabling attacks better than a placebo.

    Currently, most of the disease-modifying drugs that treat MS are given by injection or intravenous infusion.

    "Some patients have been sitting on the sidelines waiting for effective and safe oral medications," says researcher Jerry S. Wolinsky, MD, a professor of neurology at the University of Texas Health Science Center in Houston. Others with MS have been giving themselves regular injections for more than a decade.

    "Their skin is just not holding up well. It's harder and harder for me to convince them to keep doing this because of the difficulties they have with these long-term injections," Wolinsky tells WebMD. For those reasons, he says, pills that work as effectively as the shots are "very important" options.

    And drugmakers are racing to bring them to market.

    In addition to teriflunomide, three other oral medications have been granted fast-track reviews by the FDA.

    Testing a New Pill to Control MS

    The new study, which is published in the New England Journal of Medicine, enrolled nearly 1,100 patients in 21 countries.

    Ninety percent had the relapsing remitting form of MS -- an early stage of the disease. In this stage there are occasional flare-ups typically followed by partial or complete recovery of function.

    The patients enrolled had at least two relapses in the previous two years, but no relapses in the two months before the study. Nearly 800 patients completed the two-year study.

    The study found that teriflunomide reduced relapses in MS patients by 31% compared to a placebo. At the highest dose, the drug significantly reduced the number of treated patients who experienced worsening disability. It also reduced areas of active inflammation in the brain compared to placebo.

    "People on the drug had fewer attacks," says researcher Paul O'Connor, MD, professor of neurology at the University of Toronto. "So what it meant to a patient is that if you were destined to have three attacks in one year, you would actually only have two."

    "It slowed relapse and reduced the risk of disability progression by about 30%," O'Connor says.

    The drug works by preventing fast-growing immune system cells from activating, multiplying, and responding to the body's own proteins, causing inflammation.

    The most common side effects experienced by patients were diarrhoea, nausea, hair thinning, and elevated levels of liver enzymes.

    Rates of serious infections, a common risk of drugs that subdue an overactive immune system, were similar between the placebo and treatment groups. Serious infections affected 2.2% of those taking the placebo, 1.6% of those on the lower dose of teriflunomide, and 2.5% on the higher dose.

    There were three cases of serious kidney infections in people taking the higher drug dose. One led a person to quit the study.

    Because the drug interferes with fast-growing cells, researchers say women who are pregnant or planning a pregnancy should not take the medication.

    Anita Burrell, a vice president at Sanofi-Aventis, the drug's manufacturer, says the company has applied to the FDA for review. They should know this month if the agency has accepted their application.

    "We know cost is a big issue in the MS environment. But it's clearly too premature at this point to speculate for this product in particular," she says.

    MS drugs are some of the most expensive therapies on the market. A study published earlier this year in Neurology found that the health gains MS patients get from their medications come at extremely high prices.

    Gilenya, the pill that's already available to patients, costs $4,000 a month, or $48,000 annually. By comparison, the injectable drug Copaxone costs between $2,800 and $3,200 a month.

    Experts who were not involved in the study say they think there's a good chance it will be approved by the FDA.

    "It's my opinion that this drug needs to be on the market," says Jack Burks, MD, a neurologist in Reno, Nev., and chief medical officer of the Multiple Sclerosis Association of America. "People should be given the opportunity to take this drug. Whether they take it or not should be up to the patient and the doctor."

    He says teriflunomide appears to be effective and safe, at least in the short term.

    "We don't know the long-term safety. Therefore we're cautiously optimistic that the long-term safety data will be good and people who don't want to take shots anymore won't have to," Burks says.

    "Just because it's a pill doesn't mean it's safer," he says.

    Source: Boots Web MD © ©2005-2011 WebMD, LLC. (06/10/11)

    Oral MS drug Teriflunomide may boost Glatiramer efficacy

    TeriflunomideAdding the investigational, oral drug teriflunomide to glatiramer acetate (GA, Copaxone) in patients with relapsing multiple sclerosis substantially decreased the MRI lesion burden, although the effect on relapse rates was less clear, a researcher said here.

    In a 48-week, phase II trial, patients receiving 7 mg/day of teriflunomide in addition to GA had only about one-third the average number of T1-gadolinium-enhancing lesions seen in patients taking placebo plus GA (P=0.03), said Mark Freedman, MD, of the University of Ottawa.

    This dose of teriflunomide combined with GA also cut the adjusted annualized relapse rate by 38%, but the difference failed to reach statistical significance (P=0.22), Freedman told attendees at the annual meeting of the Consortium of Multiple Sclerosis Centers.

    Oddly, a 14-mg dose of teriflunomide plus GA had a smaller effect on MRI lesion burden relative to the lower dose; annualized relapse rates in this group were actually slightly higher than in the placebo-GA arm of the trial.

    Freedman said the findings were in line with an interim, 24-week analysis reported last year.

    These results were somewhat less impressive than results from an earlier phase II study evaluating teriflunomide as an add-on to interferon therapy. In the phase II trial, both doses of the oral drug cut the lesion burden significantly, and with a better response from the higher dose.

    Nevertheless, Freedman insisted that the combination with GA provided a benefit to patients.

    "Probably teriflunomide has some independent effects on MS that are not completely there with either GA or with interferon," he said.

    "As we start talking about escalation and disease control... the itch is to take [a patient] off that [first-line drug] and put them on another drug like fingolimod, natalizumab (Tysabri), or whatever is coming down the pike. Well, maybe that doesn't have to be."

    For many patients, he suggested, it may be more attractive to keep them on the first-line agent, which they are presumably tolerating adequately, and add another agent, as long as it doesn't introduce new adverse events.

    Teriflunomide, he noted, "has an incredibly good safety record."

    This was confirmed in a separate presentation here from a phase III monotherapy study of teriflunomide called TEMSO, by Paul O'Connor, MD, of the University of Toronto.

    Common adverse events with teriflunomide relative to placebo included diarrhea, hair thinning, nausea, and changes in ALT [alanine aminotransferase] liver function tests, said O'Connor, adding that the changes in ALT levels were not serious.

    He said the drug's safety profile thus far would make it suitable as first-line therapy.

    Freedman pointed out that the combination therapy study he reported here was actually designed primarily to assess safety and tolerability. In that respect, the drug passed with flying colors.

    Among the approximately 40 patients in each study arm, serious treatment-emergent adverse events were somewhat more common in the placebo-GA group: 15% versus 12% for the 7-mg teriflunomide dosing group and 5% for 14-mg teriflunomide dosing group.

    Adverse effects that stood out as more common with teriflunomide were the same ones -- hair thinning, rash, nausea, and reduced neutrophil counts -- seen in monotherapy studies and at similar rates, Freedman said.

    But treatment-emergent events related to immunosuppression were more common in the placebo-GA group, Freedman said. Also, whereas teriflunomide in TEMSO and other trials had been associated with modest increases in ALT levels, this effect did not occur in the current study.

    No patients in the 7-mg group had ALT elevations beyond three times the upper limit of normal, and only one patient in the 14-mg group had this degree of ALT increase, as did one patient in the placebo-GA control group.

    Teriflunomide is the active metabolite of leflunomide, a standard rheumatoid arthritis drug. Its specific mechanism of action is to inhibit pyrimidine synthesis, which in turn reduces proliferation of certain immune cells.

    Specific effects on mean MRI lesion counts in the current trial after 48 weeks were as follows:

    Placebo plus GA: 0.333
    7 mg/day teriflunomide plus GA: 0.120 (P=0.031 versus control)
    14 mg/day teriflunomide plus GA: 0.178 (P-0.193 versus control)
    Adjusted annualized relapse rates for the three study arms were as follows:

    Placebo plus GA: 0.420
    7 mg/day teriflunomide plus GA: 0.262 (P=0.217 versus control)
    14 mg/day teriflunomide plus GA: 0.497 (P-0.574 versus control)
    A phase III trial testing teriflunomide in combination with GA and with interferon, called TERACLES, began earlier this year. Results are expected in 2014.

    The study was funded by sanofi-aventis.

    Freedman reported consulting fees or other payments from Genzyme, Bayer, Biogen Idec, Teva, Merck Serono, Novartis, and sanofi-aventis.

    O'Connor reported such fees or payments from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, Teva, and Warburg Pincus.

    Source: MedPage Today © 2011 Everyday Health, Inc. (07/06/11)

    Oral Teriflunomide study recruiting relapsing MS patients
    TeriflunomideEfficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta (TERACLES).

    Summary: Investigators in the United States and others around the world are recruiting 1455 people with relapsing multiple sclerosis for a study comparing two doses of oral teriflunomide (HMR1726), an investigational medication, or inactive placebo, in people taking any type of approved interferon beta. The study is sponsored by Sanofi-Aventis.

    Rationale: Multiple sclerosis occurs when the immune system attacks the brain and spinal cord. Teriflunomide is a novel oral compound that inhibits the function of specific immune cells. Results from a two-year, phase III trial in 1,088 people with relapsing MS (the TEMSO trial), comparing two doses against placebo, showed that both doses significantly reduced the rate of MS relapses by up to 31.5% relative to placebo. The most common side effects were nausea, diarrhea, mildly elevated liver enzymes and thinning of the hair. Combining this experimental oral therapy with a moderately effective standard therapy may boost therapeutic benefits. Other studies of teriflunomide in MS are ongoing.

    Eligibility and Details: People eligible for participation include individuals 18-55 years of age with relapsing forms of MS. Participants must have received a stable dose of any approved type of interferon beta for at least six months, and have had disease activity in the previous 12 months, sometime after the first three months of interferon treatment.

    Participants will be randomly assigned to receive – in addition to interferon – either 7 mg teriflunomide, 14 mg teriflunomide, or placebo once daily for 24 weeks. The main goal of the study is to determine the effectiveness of this combination on reducing the relapse rate. Other goals include evaluating disease activity as observed on MRI, safety and tolerability, and measures of fatigue and quality of life.

    Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please refer to the site listing and contact information on clinicaltrials.gov: http://clinicaltrials.gov/ct2/show/NCT01252355.

    UK Locations

    Investigational Site Number 826006
    Liverpool, United Kingdom, L9 7LJ
    Not yet recruiting

    Investigational Site Number 826004
    Plymouth, United Kingdom, PL6 8BX
    Not yet recruiting

    Source: Clintrials.Gov (04/05/11)

    Phase III Teriflunomide adjunct therapy with interferon beta study

    TeriflunomideSanofi-aventis announced today the initiation of a multinational Phase III study evaluating the efficacy and safety of two doses of once daily teriflunomide (7mg or 14mg) versus placebo in patients with relapsing multiple sclerosis (RMS) treated with interferon beta (IFN beta).

    Teriflunomide is a novel oral disease modifier developed by sanofi-aventis which is being investigated in a large Phase III clinical development program. It includes studies of teriflunomide in monotherapy for the treatment of RMS and in clinically isolated syndrome as well as adjunct therapy.

    "Initiation of the TERACLES study is a tremendous milestone as it is the first ever Phase III study of an oral drug in adjunct therapy to be launched in multiple sclerosis, " said Marc Cluzel, M.D., Ph.D., Executive Vice President, Research & Development, sanofi-aventis. "We are confident that teriflunomide is an excellent candidate for assessing innovative adjunct therapy in multiple sclerosis considering the positive effect observed when it was used in adjunct with interferon beta in the Phase II study."

    Specifically, the TERACLES study will evaluate whether once daily oral teriflunomide 14 or 7mg, in patients treated for at least 6 months on a stable dose of IFN beta prior to randomization, can reduce the annualized relapse rate (primary endpoint) compared to IFN beta plus oral placebo tablets. The main secondary endpoints of the study are to document the disease activity measured by MRI, the time to disability progression and overall safety.

    "The purpose of the TERACLES study is to assess the clinical benefits of teriflunomide as an adjunct therapy in patients with relapsing multiple sclerosis, " said Mark S. Freedman, HBSc, MSc, M.D., Professor of Neurology, Department of Medicine, and University of Ottawa, Ontario, Canada.

    "We hope that this study will replicate the additional efficacy and safety profile we observed in the Phase II trial with teriflunomide in adjunct with interferon beta, and bring an innovative therapeutic approach to this patient
    population."

    The Phase II study results presented this year during the ACTRIMS congress showed that teriflunomide in adjunct with IFN beta significantly improved disease control (evaluated by MRI activity) beyond IFN beta plus oral placebo at one year, with a trend towards fewer clinical relapses and with a consistent safety profile with the data from a Phase II monotherapy study.

    Approximately 240 study sites in 28 countries are targeted for participation in the TERACLES study which will involve 1455 RMS patients. The first patient is expected to be enrolled before the end of this year and the trial will end once the last patient recruited has received at least 48 weeks of treatment.

    Source: Sanofi-aventis (26/10/10)

    TEMSO phase III study results for relapsing MS
    TeriflunomideSanofi-aventis announced today the results from the two year phase III TEMSO study of teriflunomide, a novel oral disease modifier investigated for the treatment of relapsing multiple sclerosis (RMS).

    In this study, both doses of teriflunomide (7 and 14mg) significantly reduced annualized relapse rate (primary study endpoint) by 31% vs. placebo (p is less than or equal to 0.0005). The risk of disability progression (sustained for 12 weeks) was also significantly reduced by 30% for the 14mg dose

    "We are very pleased with the successful results of the TEMSO study which are an important step forward in multiple sclerosis clinical research," said Marc Cluzel, M.D., Ph.D., Executive Vice President, Research & Development, sanofi-aventis. "These exciting results with teriflunomide represent a new real hope to delivering an oral therapy to patients who live with this serious condition and are eager for new treatment options, and more convenient product forms in-line with our sanofi-aventis commitment to multiple sclerosis."

    The results of the TEMSO trial are the first study findings from a large phase III clinical development program on teriflunomide. These results were presented today during the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress, in Gothenburg, Sweden.

    "Multiple sclerosis is a complex disease, and it often has an unpredictable and highly disabling disease course, therefore leading to important health care needs in this relatively young patient group ", said Dr. Paul O'Connor, Director of the MS Clinic at St Michael's Hospital, Toronto, Canada and principal investigator of the TEMSO study. "We were very satisfied to see how TEMSO demonstrated that teriflunomide successfully reduced relapse rate but also reduced the time to disability progression for the highest dose with a favorable safety profile for multiple sclerosis patients with relapses and emerges as a potential new first-line treatment option in this patient population."

    Teriflunomide also significantly reduced the brain disease activity on a range of magnetic resonance imaging (MRI) measures including a significant reduction of the burden of disease (total lesion volume), by 39%>

    Teriflunomide was well tolerated with no major safety concerns. Adverse events occurring at a higher rate in the teriflunomide groups were diarrhea, nausea, alanine transferase increases that were mainly mild and asymptomatic with no dose effect and mild hair thinning and hair loss which rarely led to treatment discontinuation. No serious opportunistic infections occurred in patients treated with teriflunomide.

    In addition to the TEMSO results, data on long-term safety of RMS patients, from eight years of follow-up of the open-label extension of a phase II study were also presented at the ECTRIMS congress. These data showed that teriflunomide was well tolerated during eight years of continuous use with a safety profile consistent with that reported during the first 36 double-blind phase weeks of the study.

    Source: Sanofi-aventis (15/10/10)

    Oral Teriflunomide significantly reduced MS relapse rates

    TeriflunomideSanofi-aventis announced today that the investigational once-daily oral drug teriflunomide significantly reduced annualized relapse rate (ARR) at 2 years versus placebo in patients with relapsing multiple sclerosis (RMS), thus achieving the primary endpoint in the TEMSO phase III trial.

    Both the 7mg and 14mg doses of teriflunomide were well tolerated with a similar number of patients reporting either treatment-emergent adverse events (TEAEs) or TEAEs leading to treatment discontinuation in the treatment arms versus placebo.

    Effects on other clinical and MRI related outcomes further support the primary outcome. The safety profile was in line with previous clinical experience.

    The TEMSO trial is the first study of a large phase III clinical development program to produce results on teriflunomide as monotherapy. Study findings from TEMSO will be presented during the platform presentation scheduled for October 15, 2010, starting at 9:15 a.m. CET at the 26th Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Gothenburg, Sweden. The TEMSO study results are embargoed until this oral presentation.

    About Teriflunomide

    Teriflunomide is a new oral disease modifier for RMS that blocks de novo pyrimidine synthesis thus reducing T- and B-cells proliferation with no cytotoxicity. A comprehensive clinical development program for teriflunomide has been launched in monotherapy.

    First Phase II study results of the safety and efficacy of teriflunomide monotherapy in MS were published in Neurology in 2006. In addition to the TEMSO trial, two other Phase III trials, TOWER and TENERE, are ongoing in RMS.

    A Phase III study, TOPIC, is also underway in early MS or Clinically Isolated Syndrome (CIS). Teriflunomide has also been evaluated as an adjunct therapy to either interferon 1-beta or glatiramer acetate in two Phase II studies.

    Results of these studies were presented earlier this year during the American Committee for Treatment and Research in Multiple Sclerosis meeting (ACTRIMS) congress, and the American Academy of Neurology (AAN) meeting respectively. Phase II studies with teriflunomide (7mg and 14mg) in adjunct with interferon 1-beta demonstrated an improvement in outcomes, with a consistent safety profile in patients treated with the adjunct treatment compared with patients treated with IFN-beta and receiving placebo. In the other Phase II study, teriflunomide in adjunct to glatiramer acetate (GA) was well-tolerated compared to patients receiving GA and placebo. Although there was a numerical trend for the reduction in number and volume of gadolinium enhancing T-1 brain MRI lesions in the adjunct arm compared to placebo with GA, the relative effect was not as robust as that observed for teriflunomide with IFN-beta.

    About TEMSO Study

    TEMSO is a 2-year randomized, double-blind, placebo controlled study including 1088 RRMS patients worldwide, aged 18-55 years, with an Expanded Disability Status Scale (EDSS) <= 5.5 and at least one relapse over the previous year or at least 2 relapses over the preceding 2 years. Patients were randomized to placebo or teriflunomide, 7mg or 14mg, once daily. The primary endpoint was annualized relapse rate defined as the number of confirmed relapses per patients-year. The key secondary endpoint was the time to disability progression measured by EDSS. Safety and tolerability evaluations were based on treatment emergent adverse events, physical examinations, vital signs and laboratory investigations.

    Source: Sanofi-aventis (30/08/10)

    Interferon adjunct reduces MS lesions

    TeriflunomideThe oral drug teriflunomide demonstrates short-term safety and reduces lesions in multiple sclerosis for up to one year when used in combination with interferon beta, according to a study presented here.

    Treatment-emergent adverse events were similar to placebo for patients on combination therapy, and the relative risk reduction for gadolinium-enhancing lesions on active treatment was more than 80% at 1 year, compared to patients on interferon beta alone.

    "Adjunctive therapy with teriflunomide is superior to interferon beta monotherapy for disease control," according to lead researcher Mark Freedman, MD, professor of medicine and director of the MS Research Unit at the University of Ottawa, who spoke 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 was a six-month, double-blind extension of a six-month trial whose results have been previously announced. Those results showed that teriflunomide as an adjunct to interferon beta reduced MRI activity by 56% for the 7 mg/day dose and by 81% for the 14 mg/day dose.

    Teriflunomide blocks new synthesis of pyrimidines, and has antiproliferative and anti-inflammatory properties. It inhibits proliferation and function of activated, but not resting, lymphocytes.

    Patients entering the original trial had a mean age of 40 years, were 70% female, mostly had the relapsing-remitting form of MS, and had an Expanded Disability Status Scale (EDSS) of 2.5. Forty percent of patients had been relapse-free in the previous year. Patients were asked at the end of the 6 months if they wanted to continue on blinded treatment for an additional 6 months. Of 116 original patients, 86 chose to continue. Demographic and disease characteristics of the continuers were similar to those in the entire cohort.

    Eight patients had treatment-emergent adverse events that led to discontinuation during the six-month extension, equally divided among the two groups. Events related to immunosuppression were somewhat higher in those receiving teriflunomide (approximately 55% vs. 39% for placebo), but none led to discontinuation.

    While the study was primarily designed to assess short-term safety, results from neuroimaging were gratifying, Dr. Freedman said. In both active treatment arms, gadolinium-enhancing lesions were reduced relative to placebo, with relative risk reduction of 84.6% for the low dose (p=0.0005) and 82.8% for the high dose (p<0.0001) compared to placebo.

    However, annualized relapse rates were not significantly different between active treatment and placebo groups, although there was a dose-dependent trend in reduction of relapse, Dr. Freedman said.

    "The message is that this combination needs further examination," he said. "This study provides further evidence that teriflunomide is effective in treating relapsing-remitting MS."

    "I think these results are very encouraging," said Peter Calabresi, MD, Director of the Multiple Sclerosis Center and Professor of Neurology at Johns Hopkins University in Baltimore, MD. "It almost looked like a synergistic effect, rather than an additive one, between the two treatments, and that is always appealing."

    However, he noted, the relapse rates did not differ between active treatment and placebo, which is cause for further investigation. "The MRI data is going in the right direction, but the relapse rate needs more study. The real question is how do the patients feel on this treatment."

    Source: Medpage Today © 2004-2010 MedPage Today, LLC (07/06/10)

    Oral Teriflunomide or placebo added to glatiramer acetate for 6 Months in patients with relapsing Multiple Sclerosis: safety and efficacy results

    TeriflunomideMount Sinai researchers took part in a Phase II study of teriflunomide, an investigational oral medication for relapsing-remitting multiple sclerosis (RRMS), the most common form of the disease.

    The study analyzed teriflunomide added to ongoing treatment with glatiramer acetate, a currently prescribed medication, and determined that teriflunomide was safe and effective as part of combination therapy.

    Researchers evaluated 123 patients with RRMS over 24 weeks. Patients were given teriflunomide in doses of seven mg/day or 14 mg/day, while a control group received a placebo. Study participants were evaluated through physical examination, laboratory data, electrocardiogram, pancreatic ultrasound, and MRI.

    Teriflunomide had a positive safety profile, with only seven treatment emergent adverse events (TEAE) leading to treatment discontinuation. MRI studies revealed that teriflunomide also proved to be effective at reducing the size and volume of lesions on the brain.

    "While our study was designed to evaluate the safety of teriflunomide, we determined that in addition to being safe it was also effective in reducing the size and number of lesions in people with RRMS," said Aaron Miller, MD, Professor of Neurology, and Medical Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine. "Further data are required to evaluate efficacy of this combination therapy, but the results are promising."

    Source: Science Codex (14/04/10)

    Oral MS drug, Teriflunomide, promising in mid-stage trial

    TeriflunomidePatients given an experimental multiple sclerosis tablet from Sanofi-Aventis showed a significant improvement compared to those on placebo in a mid-stage test, researchers said on Friday.

    Teriflunomide, which was used as an add-on therapy to interferon beta in the Phase II clinical trial, is one of a number of MS drugs in development that are designed to be given by mouth rather than injection or infusion.

    In the 24-week study, patients on the new drug experienced a 56 percent and 81 percent reduction in cerebral inflammatory lesions compared to those on placebo, as measured by MRI scan, on two different doses of the drug, which was well tolerated.

    "These results encourage longer-term studies to establish the clinical benefit of combination treatment in this disease where effective new therapies are eagerly awaited," investigator Mark Freedman of the University of Ottawa said in a statement.

    Teriflunomide is currently being evaluated in final-stage Phase III studies.

    Oral treatments are seen as an important advance in the treatment of multiple sclerosis, a chronic and degenerative neurological disease, and are being pursued by several companies.

    The most advanced product is Merck KGaA's cladribine, which also reported encouraging clinical trial results on Friday.

    The data on teriflunomide and cladribine was presented at the European Committee for Treatment and Research in Multiple Sclerosis congress in Duesseldorf.

    Source: Reuters © Thomson Reuters 2009 (11/09/09)

    © Multiple Sclerosis Resource Centre (MSRC) 

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