Lemtrada (Alemtuzumab)
Mechanism found for Alemtuzumab side effect(20/05/13)
Researchers think they may have figured out why a drug that is highly effective against one autoimmune disease can sometimes trigger another.
The CD52-targeted biologic drug alemtuzumab (Lemtrada) is in late-stage development for multiple sclerosis, with long-term efficacy shown with just two annual courses of treatment. But, in a few patients, the agent appears to prompt an autoimmune attack on the thyroid or other organs. The mechanism has been unclear.
A new study from researchers in Australia and China, published in Nature Immunology, suggests a possible answer. They found that T cells expressing CD52 downregulated other T cells in vitro. Also, examination of samples from human patients with type 1 diabetes (the autoimmune form) showed low counts of these CD52+ cells as well as impaired function in the few that did exist.
In another set of experiments in diabetes-prone young mice, injecting the animals with lymphocyte populations lacking the CD52+ subset resulted in accelerated development of diabetes.
The researchers suggested that depletion of CD52 T cells -- as occurs after alemtuzumab treatment -- may unleash other T cells to attack host tissues, resulting in autoimmune disease.
Source: MedPage Today © 2013 MedPage Today, LLC (20/05/13)
Genzyme boasts of durable response to MS drug Lemtrada(22/03/13)
Looking ahead to a prospective FDA approval of its experimental multiple sclerosis drug Lemtrada and a new product launch into a competitive and fast-changing market, Genzyme executives today rolled out positive data from a one-year extension study of its pivotal Phase III trial that gives the company some boasting rights for a drug that demonstrated a durable response in most patients.
The bottom line of the extension data backs Genzyme's claim that the majority of the patients in the pivotal two-year trial continued to report that the disease was largely held in check for the following 12 months. Roughly 90% of the late-stage volunteers signed up for the extension study, with the understanding that they could receive additional treatment if they experienced a single relapse or the enlargement of at least two brain or spinal lesions. In the treatment naïve arm of the study, 65% of the patients receiving Lemtrada were relapse-free compared to 55% of the patients in another arm who had previously relapsed while using another treatment.
"In this 1-year extension study 80% of patients did not require an additional course of treatment, over 70% were stable or had improved disability scores," says Mike Panzara, therapeutic area head, multiple sclerosis and neurology. "This sends the message we are not going to be doing things in a me-too way. We're doing things that add value and move the field forward in treating the disease."
Genzyme is building on the successful showdown of Lemtrada vs. Rebif, a standard therapy for MS. Last November investigators reported that in a head-to-head study with Rebif (interferon beta-1a), Lemtrada was better at reducing the annualized rate of relapses, according to the trial results published in The Lancet. Also, the "accumulation of disability" was slower in the Lemtrada arm while an improvement in disability scores "suggested" a reversal of disability in some patients. Lemtrada is the commercial name for alemtuzumab, which had also been approved as Campath to treat leukemia. That cheaper drug, though, was shelved to make way for what is expected to be a far more expensive MS therapy.
If Lemtrada gets a green light from the FDA, though, it will be entering a roiled marketplace. Biogen Idec is likely nearing an OK for the oral MS drug Tecfidera (BG-12), which has been overshadowing Genzyme's new drugs--oral Aubagio and the infusion therapy Lemtrada. Aubagio, approved last September, has been prescribed by 80% of all MS specialists, says Bill Sibold, senior vice president, head of multiple sclerosis for the big Sanofi subsidiary. Most of those new patients are being switched from other treatments, with half coming from Avonex (Biogen Idec) and Copaxone, a mainstay at Teva Pharmaceutical Industries.
"I don't see any effect of Tecfidera on Lemtrada," says Sibold. "I consider them completely different animals." Lemtrada has had a "profound impact on disability, where patients not only slowed (the disease), some had improvements. That's something we haven't seen."
A thumb's up from the FDA in the second half of 2013 would come later than Genzyme had initially expected. Its first application to the agency was handed back last year for a rewrite, shoving the Sanofi drug further back in the queue. The FDA recently accepted the revised NDA for review.
Source: FierceBiotech © 2013 FierceMarkets (22/03/13)
Lymphocyte clue to multiple sclerosis drug, Alemtuzumab response
Patients with rapid recovery of CD4-positive T cells after alemtuzumab treatment for multiple sclerosis (MS) are at risk for disease progression or relapse, research suggests.
The difference was apparent from 3 months after treatment, implying the potential for individualized treatment protocols based on CD4+ counts, say lead researcher Neil Robertson (Cardiff University, UK) and colleagues.
"The association between disease activity and early lymphocyte recovery is not surprising, as MS is primarily a cell-mediated disorder," they write in Neurology. "However, this relationship has not been demonstrated in vivo before."
The researchers assessed 56 patients (40 women) given alemtuzumab 12 mg daily for 5 days to treat symptoms of MS. They observed an initial "profound depletion" of lymphocyte subsets, followed by gradual recovery.
CD19+ cells were the first to recover, reaching the 25th percentile of average pretreatment levels at 3-6 months after treatment. These were followed by CD8+ cells, which reached a similar level after 6-9 months.
Patients' average CD4+ cell counts remained below the 25th of pretreatment levels for up to 24 months of follow up (they received a second alemtuzumab course 12 months after initial treatment). However, recovery of CD4+ cells differed between patients who did and did not exhibit disease activity during follow up.
In all, eight patients had a relapse, five had progressive disability, and four had asymptomatic lesions on magnetic resonance imaging. CD4+ cells were significantly higher at 6 and 24 months in patients with than without clinical relapse, and in those with than without new lesions.
CD4+ counts diverged from 3 months between patients who remained stable and those with any clinical or imaging measure of new disease activity, remaining significantly higher in those with disease activity through 24 months.
Having a 12-month CD4+ count above 400x106/mL was 81.1% sensitive and 73.7% specific for new disease activity by 24 months. "Current practice is to routinely image all patients at 24 months and to base treatment decisions on these scans and available clinical data," say Robertson et al.
They note that the high negative predictive value of a low CD4+ count suggests that retreatment could potentially be restricted to patients with higher counts. "Inevitably this would be attractive in managed care programs and environments where access to imaging is difficult and this economic argument could be built on if larger studies support this assertion."
Source: News-Medical.Net (19/12/12)
Sanofi draws fire over cost of MS drug Lemtrada
Medical journal The Lancet warned that Sanofi's experimental multiple sclerosis drug Lemtrada may be too costly for patients and health insurers once it gets approved by regulators.
The journal, which published the encouraging results of two late-stage Lemtrada tests on Thursday, also criticized the drugmaker's decision to withdraw leukemia therapy Campath, the same drug given at a different dosage, depriving MS patients who had been using it off-label.
In an editorial accompanying the test results, The Lancet voiced concerns that Lemtrada would be priced higher than current MS drugs on the market and said the discontinuation of Campath may mean patients who had used it for MS would not be able to continue their treatment.
The injectable drug, chemically known as alemtuzumab, was sold until September 2012 under the name Campath as treatment for leukemia and given more frequently at a higher dosage.
"There is concern that with a license for multiple sclerosis, the cost of alemtuzumab could rise and might become too expensive for many patients and health systems," the editorial said.
Although Campath remains available free of charge to leukemia patients, Sanofi's rare disease unit Genzyme pulled it off the market in September to prevent its unauthorized use as an MS drug.
Analysts said the move would allow the company to adjust the price to match that of rival MS drugs on the market.
A full course of Campath, which in 2011 had sales of $76 million, cost around $60,000 when given three times a week for up to 12 weeks, according to Genzyme.
Lemtrada, instead, is given at less than half the dose of Campath for 5 consecutive days and then again for 3 days a year later. Since the drug has yet to be approved, it remains unclear how much Sanofi will charge for it.
The drug, which works by resetting a person's immune system, has shown in late-stage trials to be an effective treatment for MS patients who have failed to respond to other therapies.
It has also shown to benefit people not previously treated for the disease, suggesting it could be used as a first-line MS therapy.
But patients need regular monitoring for serious side effects that can include infections and autoimmune diseases.
"It's important that the appropriate safety monitoring is in place for patients who are prescribed Lemtrada," Genzyme's head of MS, Bill Sibold, told Reuters, responding to questions about the Lancet editorial. "Until an approved risk-management program is established, we believe the use of Lemtrada should only occur in clinical trials."
Lemtrada remains available to patients who are taking part in clinical tests.
Sibold declined to discuss pricing plans for Lemtrada, but said Genzyme has set up programs to make its approved drugs available to patients who cannot afford them. "With Lemtrada it would be no different," he said.
DRUG FUNDING
But there are concerns that cash-strapped European governments may balk at funding the drug through their public healthcare systems.
Doug Brown, Head of Biomedical Research at U.K. charity MS Society said that while Lemtrada's results are great news for patients, the drug would only be useful to them if it were available through the country's publicly funded National Health Service.
"We urge Genzyme to price the treatment responsibly so that if it's licensed, it's deemed cost effective on the NHS," he said.
The U.K.'s cost-effectiveness body National Institute for Health and Clinical Excellence (NICE), whose opinions are also watched closely in other countries, initially rejected Novartis' MS pill Gilenya, only to make a U-turn after the company agreed to a discounted price.
Sanofi launched its MS pill Aubagio in the U.S. at a price of $45,000 for a year's treatment, making it cheaper than rivals.
Gilenya - the only other MS pill currently on the market - costs 28 percent more, while injectable treatments such as Biogen Idec Inc's Avonex and Teva Pharmaceutical Industries Ltd's Copaxone are 8 and 6.5 percent higher respectively.
Source: Reuters © 2012 Thomson Reuters (01/11/12)
Alemtuzumab lessens relapses, improves disability in MS - studies
Two new trials offer proof that a leukemia drug long used to treat multiple sclerosis works better than a common treatment.
When compared with the widely used drug interferon beta, the leukemia drug alemtuzumab reduced relapse rates by half, researchers say.
Alemtuzumab Reverses Disability in Some
Alemtuzumab has been used to treat MS for close to two decades, but it has never been approved for this use. It is given by IV infusion.
The drug not only reduced relapses, but improved disability associated with MS, such as loss of coordination or difficulty walking, in some patients.
Side effects include infusion reactions, infections, and potentially serious autoimmune disorders. Patients taking it must be followed closely.
“In the menu of treatment choices for MS patients, I think alemtuzumab falls into the ‘high-reward, high-risk’ category,” says Alasdair Coles, MD, of Britain’s University of Cambridge, who led one of the newly published studies.
“No other drug has been shown to offer the benefits in terms of disability improvement that this drug shows,” he says. "It comes with problems, but these problems are manageable.”
400,000 MS Patients in U.S.
The National MS Society estimates that about 400,000 people in the United States have been diagnosed with multiple sclerosis, and most (85%) have the relapsing-remitting form of the disease, in which symptoms come and go.
These symptoms can include loss of feeling, coordination, and mobility, problems with thinking and vision, and depression.
In one of the two newly published studies, University of Cambridge researchers followed 563 previously untreated patients treated with either alemtuzumab or interferon beta.
Two years later, 22% of the alemtuzumab-treated patients had relapsed, compared to 40% of those treated with interferon beta.
In the second study, which included 840 patients whose MS symptoms were not being controlled with other treatments, treatment with alemtuzumab was associated with 35% of patients relapsing over two years, compared to a 51% relapse rate among those treated with interferon beta.
Patients in this study were also less likely to have additional MS-related disabilities after two years when they took alemtuzumab; 13% had disabilities compared to 20% of interferon-treated patients.
1 in 3 Users Develop Autoimmune Disease
In clinical practice, alemtuzumab has most often been used to treat patients who don't respond to other treatments or are no longer responding to them.
Coles says he believes this is how the drug will continue to be used if it is approved as an MS drug in the U.K. and the U.S.
He adds that about 1 in 3 patients who take the drug for MS develop an autoimmune disorder that affects the thyroid, and about 1 in 100 develop a disorder that involves blood platelets, which are involved in clotting and stopping bleeding.
He says both conditions, while potentially serious, can be easily managed if patients are followed closely.
“Close monitoring is critical because these side effects tend to appear a year or two after treatment, when MS symptoms are often under control and patients want to get on with their lives,” he says.
National MS Society Chief Research Officer Tim Coetzee, PhD, says he does not see this as a big deterrent, since many of the newer drugs for multiple sclerosis also require close monitoring.
“Given the choice between having a treatment that requires aggressive monitoring and not having that treatment at all, I believe that most patients will take the treatment any day of the week,” he says.
Drug’s Cost as MS Treatment in Question
The drug maker Genzyme plans to market alemtuzumab as an MS treatment in the U.S. and Europe, pending approval by government regulators. The drug will not be available to MS patients during the approval process.
In an editorial published with the two studies, editors of the journal Lancet express concerns that the drug will be too expensive for patients and health systems when it is reintroduced as an MS treatment.
“Finding promising treatments such as alemtuzumab is important,” they write. “But so is keeping alemtuzumab accessible and affordable if its early success in these trials proves to be of enduring value.”
Source: WebMD ©2005-2012 WebMD, LLC (01/11/12)
MS drug 'rebranded' to Lemtrada – at up to 20 times the price
Pharmaceutical giant Sanofi withdraws existing treatment to boost profits with rebranded Lemtrada.
A pharmaceutical company stands accused of putting profit before patients after withdrawing a drug used in the treatment of a chronic debilitating disease – ahead of relaunching it at a price predicted to be up to 20 times higher.
Three of Britain's leading neurologists have written to the Health Secretary, Jeremy Hunt, to protest at Genzyme, part of the multinational drug company Sanofi, halting supplies of the drug alemtuzumab for multiple sclerosis.
The drug is currently licensed for the treatment of leukaemia. But it has been known for 20 years also to be effective in MS patients suffering from an aggressive form of the disease.
Neurologists have used the drug in these patients "off label" – prescribing it on their own initiative even though it was not licensed for multiple sclerosis – following encouraging results from a large placebo-controlled trial published in the New England Journal of Medicine in 1998. Alemtuzumab, which is given in two courses a year apart, costs markedly less than other drugs for multiple sclerosis to which it is thought to be superior – around £2,500.
Genzyme has now applied for a licence for the drug in multiple sclerosis to regulators in Europe and the US and is expected to relaunch it under the trade name, Lemtrada, at what could be many times its current price. In the meantime the company has withdrawn the drug from MS patients' off-label treatment, pending the granting of the licence, on the grounds that "any adverse event outside a clinical trial … may complicate the regulatory process".
In the neurologists' letter to the Health Secretary, professors Neil Scolding of the University of Bristol, Neil Robertson of the University Hospital of Wales and John Zajicek of the University of Plymouth say that Genzyme's decision has "serious implications for vulnerable UK patients with MS". They say patients who have already started treatment will "not be able to get their vital second course", and new patients may "miss their window of therapeutic opportunity" putting them at risk of "progressive, severe disability".
When licensed, they say, the drug's price is expected to be "15 to 20 times greater", and its withdrawal sets an "inappropriate precedent". They add: "It shows little regard for patients whose opportunity to alter the course of their disease is time-limited, and may represent an over-enthusiastic attempt by the parent company to profit from the current situation."
Professor Zajicek said he had personally treated about 150 patients with the drug, and 400 to 500 had received it across the UK. "Many of us think it is the best drug for patients with aggressive MS in the early stages of the disease. It's the greedy behaviour of the drug company that upsets me. They are just trying to rebrand it and put the price up. It is morally corrupt."
A spokesperson for Genzyme said: "Our goal is to ensure that Lemtrada is approved by regulatory authorities and made available to multiple sclerosis patients as quickly as possible. Until approved risk-management programmes are established, the use of Lemtrada for MS should occur only in clinical trials. Off-label use of alemtuzumab in MS has always been at the discretion of individual clinicians without reference to the company."
"In the UK, our price for Lemtrada and the value it brings to patients will be subject to the usual health economic evaluation by the National Institute for Health and Clinical Excellence."
Doug Brown, Head of Biomedical Research at the Multiple Sclerosis Society, said: "Alemtuzumab shows real promise as a potentially new medicine for many people with relapsing-remitting MS. There is no good reason why people with MS who have been allowed to benefit from the treatment should now be denied it.
"Genzyme need to come up with a scheme, quickly, that makes their product available to all those people currently being treated and, if it's licensed, price the drug reasonably so it is deemed cost effective on the NHS."
A Department of Health spokesperson said: "We know how important this drug is for some MS sufferers and are working closely with the company and the NHS to help make sure these patients can still access it."
Case study: 'I have seen the way my mother is suffering'
Oritse Williams, 25, of the platinum-selling boyband JLS, knows the suffering caused by multiple sclerosis since his mother, Sonia, 54, was diagnosed over a decade ago. He and his brother pledged when in their teens that they would do all they could to help her.
"We decided that when we grew up, my brother would become a scientist and I would try to make money from my music. That way we would have both the means and the ability to find a cure." Williams cared for his mother through his childhood and until he appeared in the final of The X Factor in 2008.
The drugs company: Sanofi
Sanofi, based in Paris, is the world's fourth-largest pharmaceutical company, employing 113,000 people worldwide.
Last year the company made a profit of almost €6bn on revenue of €33b. Its products include Clomid, for female infertility, the anti-clotting agent Plavix and the cancer drug Taxotere.
The company is the world's largest producer of vaccines through its subsidiary Sanofi Pasteur. It acquired Genzyme, a US biotech company based in Cambridge, Massachusetts, in 2011.
In 2010 Sanofi sacked 1,700 US employees citing growing competition from non-branded generic manufacturers. It denied the action was related to its purchase of Genzyme.
Last week, the Paris-based company announced plans to cut almost 1,000 jobs in France despite protests condemning the move.
Source: The Independent © independent.co.uk (15/10/12)
FDA refuses MS drug Lemtrada filing
Genzyme, a Sanofi company, announced it has received a Refuse to File letter from the U.S. Food and Drug Administration (FDA) in response to the supplemental Biologics License Application (sBLA) for the approval of Lemtrada™ (alemtuzumab) as a treatment for relapsing multiple sclerosis.
After collaborative consultations with the FDA, the agency requested that the company modify the presentation of the data sets to enable the agency to better navigate the application. The FDA has not requested additional data or further studies. Genzyme will work with the FDA over the coming weeks to resubmit the application as soon as possible.
“We have had constructive dialogue with the FDA, and we are very confident in our ability to address the agency’s request and resubmit rapidly,” said David Meeker, President and CEO, Genzyme.
The company’s marketing authorization application submitted to the European Medicines Agency has been accepted and the review process is underway.
Genzyme is developing Lemtrada in MS in collaboration with Bayer HealthCare.
About Alemtuzumab/Lemtrada™
Alemtuzumab is a monoclonal antibody that selectively targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, rebalancing the immune system in a way that potentially reduces MS disease activity.
Genzyme holds the worldwide rights to alemtuzumab and has primary responsibility for its development and commercialisation in multiple sclerosis. Bayer HealthCare retains an option to co-promote alemtuzumab in multiple sclerosis. Bayer HealthCare has notified Genzyme of its intention to co-promote under this option. Upon regulatory approval and commercialization, Bayer would receive contingent payments based on sales revenue.
*LemtradaTM is the proprietary name submitted to health authorities for the company’s investigational multiple sclerosis agent alemtuzumab.
Source: Therapeutics Daily ©2011 UBM Canon (28/08/12)
Campath pulled ahead of possible OK for Lemtrada for MS
Sanofi's rare disease unit Genzyme is pulling leukaemia drug Campath to prepare for its launch under a different dosage and as a multiple sclerosis treatment that will be branded as Lemtrada.
The withdrawal, meant to prevent the off-label use of Campath as a multiple sclerosis drug, is already under way in some European countries and will be effective in the United States on September 4, a Genzyme spokesman said.
Lemtrada, which Sanofi submitted for approval with health regulators in Europe and the United States in June, could be launched in 2013 if it wins approval.
If approved, it will be given far less frequently and in lower doses than Campath, and is one of the new products the French drugmaker is betting on to restore growth after losing several aging blockbusters to generic rivals.
"We think that this stoppage shows Sanofi's confidence in the approval of Lemtrada in multiple sclerosis," said Bryan Garnier analyst Eric Le Berrigaud, who estimates the drug could generate sales of $400 million in 2018, if approved.
The withdrawal will also enable Sanofi to adjust Lemtrada's price closer to that of rival multiple sclerosis drugs, Le Berrigaud said. Rivals include Tysabri, an injectable drug sold by Biogen Idec and Elan, while Novartis markets MS pill Gilenya.
Campath, which last year had sales of $76 million, will continue to be available through patient access programs in the 50 countries where it has been available since its launch in 2001.
"In most countries we will provide the drug for free, where this is permitted," the Genzyme spokesman said.
The news was first reported by trade publication BioCentury.
Source: Chicago Tribune © Chicago Tribune 2012 (22/08/12)
Application submitted to FDA and EMA for approval of Lemtrada(TM) (alemtuzumab) for MS
Genzyme, a Sanofi company , today announced that the company has submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) and a marketing authorization application (MAA) to the European Medicines Agency (EMA) seeking approval of Lemtrada(TM) (alemtuzumab) for treatment of relapsing multiple sclerosis (RMS). Genzyme is developing Lemtrada in MS in collaboration with Bayer HealthCare.
Genzyme's clinical development program for Lemtrada included two Phase III studies in which results for Lemtrada were superior to Rebif(R) (high dose subcutaneous interferon beta-1a) on clinical and imaging endpoints, including a reduction in relapse rate. In addition, as presented last month at the American Academy of Neurology meeting, some patients with pre-existing disability treated with Lemtrada in the CARE-MS II trial were more than twice as likely to experience a sustained reduction in disability over two years than patients treated with Rebif.
"There remains a large unmet treatment need for patients living with active disease and we believe that Lemtrada, given its efficacy and unique dosing schedule, has the potential to transform the lives of patients with MS," said Genzyme President and CEO, David Meeker.
The regulatory submissions for Lemtrada include two-year controlled efficacy and safety data from both treatment-naive patients and those who relapsed while on therapy, with greater than five years of safety follow-up. Common adverse events associated with alemtuzumab were consistent across the Phase III program and included infusion-associated reactions and infections, which were generally mild to moderate in severity. Autoimmune adverse events were observed in some patients with cases being detected early through a monitoring program and managed using conventional therapies.
In addition to Lemtrada, Genzyme's clinical development program for relapsing multiple sclerosis includes the once-daily oral treatment, Aubagio(TM) (teriflunomide), which is currently under review by the FDA and EMA.
Source: MarketWatch Copyright © 2012 MarketWatch, Inc.(12/06/12)
Lemtrada (alemtuzumab) improved disability scores in MS patients over Rebif
Genzyme, a Sanofi company , reports today additional data from the Phase III CARE-MS II trial. Accumulation of disability was significantly slowed in patients with multiple sclerosis (MS) who were treated with alemtuzumab versus Rebif(R) (high dose subcutaneous interferon beta-1a), as measured by the Expanded Disability Status Scale (EDSS), a standard assessment of physical disability progression.
In addition, significant improvement in disability scores was observed in some patients treated with alemtuzumab from baseline and compared to patients treated with Rebif, suggesting a reversal of disability in these patients. In the trial, patients with pre-existing disability treated with alemtuzumab were more than twice as likely to experience a sustained reduction in disability than patients given Rebif. Genzyme is developing alemtuzumab in MS in collaboration with Bayer HealthCare.
CARE-MS II was a randomized Phase III clinical trial comparing the investigational drug alemtuzumab to Rebif in patients with relapsing-remitting multiple sclerosis (RRMS) who had relapsed while on prior therapy. The company announced in November that results for the co-primary endpoints of the trial were highly statistically significant.
Key disability data from the CARE-MS II trial presented today at the 64th Annual Meeting of the American Academy of Neurology include:
-- The mean EDSS score for patients treated with alemtuzumab decreased over a two-year period, indicating an improvement in their physical disability, while the mean score for patients given Rebif increased, indicating a worsening of disability (-0.17 vs. 0.24; p < 0.0001).
-- At two years, 29 percent of patients treated with alemtuzumab had experienced a six-month sustained reduction in disability, meaning their level of disability improved, as compared to only 13 percent with Rebif (p=0.0002).
-- There was a 42 percent reduction in the risk of six-month sustained accumulation (worsening) of disability (SAD) as measured by EDSS in patients treated with alemtuzumab compared to Rebif over two years of study (p=0.0084), as previously reported. This was a highly statistically significant result for this co-primary endpoint.
Key relapse data from the trial presented at AAN include:
-- 65 percent of patients treated with alemtuzumab were relapse-free at two years, meaning they did not experience any relapses in the trial, compared to 47 percent with Rebif (47 percent risk reduction; p<0.0001).
-- A 49 percent reduction in relapse rate was observed in patients treated with alemtuzumab 12 mg compared to Rebif over two years of study (p<0.0001), a highly significant result for this co-primary endpoint, as previously reported.
"To date, a key goal for MS treatment has been to delay the worsening of disability," said Jeffrey Cohen, M.D., Director of Experimental Therapeutics, Cleveland Clinic Mellen Center for MS Treatment and Research; and a member of the Steering Committee overseeing the conduct of the study. "Patients in the study whose prior MS treatment was inadequate at preventing relapses and received alemtuzumab in the CARE-MS ll trial experienced a slowing or reversal of their disability."
In the CARE-MS II trial, alemtuzumab 12 mg was given as an IV administration a total of eight times over the course of the two-year study. The first treatment course of alemtuzumab was administered on five consecutive days, and the second course was administered on three consecutive days 12 months later. Rebif 44 mcg was administered by subcutaneous injection three times per week, each week, throughout the two years of study.
"Alemtuzumab is the first disease modifying therapy to show a significant effect both on relapse and disability endpoints over and above those of Rebif in a comparative trial," said Professor Alastair Compston, Chair of the Steering Committee overseeing the conduct of the study, principal investigator on the Phase II and III clinical trials of alemtuzumab, and Head of the Department of Clinical Neurosciences at the University of Cambridge, United Kingdom. "The efficacy data from the CARE-MS trial program suggest that, if approved, alemtuzumab will be an important new treatment for relapsing MS patients with active disease."
Additional new data from the CARE-MS II study suggest that alemtuzumab provided significant improvement over Rebif across a number of imaging endpoints, consistent with the effects observed in the clinical endpoints. In MS, imaging can be used to track the development of lesions, or patches of inflammation in the central nervous system (CNS). Statistically significant improvement was observed for alemtuzumab over Rebif in the percentage of patients with new or enlarging T2-hyperintense lesions (46 vs. 68; p<0.0001) and with gadolinium-enhancing lesions (19 vs. 34; p<0.0001). The change in T2-hyperintense lesion volume from baseline to year two, a secondary endpoint, was not significantly different (p=0.14). In the trial, patients treated with alemtuzumab experienced less change in brain parenchymal fraction (BPF), a measure of brain atrophy or loss of neurons and the connections between them, compared to Rebif (-0.62 vs. -0.81) median percent change from baseline (p=0.012), a significant result.
"We believe these ground-breaking results from CARE-MS ll, including reversal of disability accumulation in some patients, achieved over the standard therapy Rebif, provide a message of hope for people living with MS," said David Meeker, M.D., President and CEO, Genzyme. "We are on track to submit alemtuzumab for review to U.S. and EU regulatory authorities in the second quarter of this year and are excited about the potential of bringing this important therapy to people living with MS who have unmet treatment needs."
The most common adverse events associated with alemtuzumab in the CARE-MS Il study were infusion-associated reactions, which were generally mild to moderate. Infections were common in both groups, with a higher incidence in the alemtuzumab group. The most common infections included upper respiratory and urinary tract infections, cutaneous fungal infections and oral herpes. Serious infections occurred in 3.7 percent of the alemtuzumab group as compared to 1.5 percent of the Rebif group. Infections were predominantly mild to moderate in severity and none were fatal.
In the trial, 15.9 percent of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event compared to 5.0 percent with Rebif, and 0.9 percent of alemtuzumab-treated patients developed immune thrombocytopenia (ITP) during the two-year study period. These cases were detected early through a monitoring program and managed using conventional therapies. Patient monitoring for ITP and thyroid or renal disorders is incorporated in all Genzyme-sponsored trials of alemtuzumab for the investigational treatment of MS. All data reported above pertain to patients in the trial who received alemtuzumab 12 mg or Rebif 44 mcg.
Alemtuzumab is a monoclonal antibody that selectively targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, rebalancing the immune system in a way that potentially reduces MS disease activity.
The company is on track to file for U.S. and EU approval of alemtuzumab in relapsing MS in the second quarter of 2012. Since it is not yet approved for the treatment of MS, alemtuzumab must not be used in MS patients outside of a formal, regulated clinical trial setting in which appropriate patient monitoring measures are in place.
Source: MarketWatch Copyright © 2012 MarketWatch, Inc(25/04/12)
Sanofi is looking at new compounds to expand MS business
Sanofi, 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)
Alemtuzumab more effective than interferon β-1a at 5-year follow-up
Summary: The authors present 5-year follow-up data from the CAMMS223 study, reporting on the long-term safety and efficacy of alemtuzumab treatment compared with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72%. The annualised relapse rate over the 5 years was 0.11 for alemtuzumab and 0.35 for IFNβ-1a.
Most commonly occurring serious side effects were serious infections occurring in 7% of alemtuzumab treated patients, with 30% developing thyroid problems (compared to only 4% in IFNβ-1a group).
The study shows good evidence for the efficacy in reducing progression of disability and relapse rate reduction in patients with RRMS compared with IFNβ-1a and side effect profile in line with previously published data.
Abstract
OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline).
METHODS: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months.
RESULTS: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab.
CONCLUSIONS: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports.Classification of Evidence:This study provides Class III evidence that alemtuzumab is more effective than interferon β-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.
Authors: Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA.
Source: Neurology. 2012 Mar 21. and Pubmed PMID: 22442431 (28/03/12)
Sanofi faces uphill struggle in MS drug market
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)
