Health Canada has approved alemtuzumab (Lemtrada, Genzyme, a Sanofi Company) for the management of adult patients with relapsing-remitting multiple sclerosis (MS) with active disease defined by clinical and imaging features, and an inadequate response to interferon-β or other disease-modifying therapies, the company announced today.
"Lemtrada is an important new treatment option for Canadians with MS. It has impressive effectiveness following 2 treatment courses for those patients with active relapsing MS," said Dr. Anthony Traboulsee, associate professor of neurology and medical director of the UBC Hospital MS Clinic of Vancouver Coastal Health, British Columbia, in a statement from the company. "Our own local experience in treating 35 patients through clinical trials with Lemtrada has been extremely positive."
Alemtuzumab, 12 mg, has a novel dosing and administration schedule of 2 annual treatment courses. The first treatment course is administered via intravenous infusion on 5 consecutive days, and the second is given on 3 consecutive days, 12 months later.
"Lemtrada is now approved in 30 countries, and we are very pleased that Canadian patients and physicians will have access to this important new treatment option," Genzyme President and CEO David Meeker said in the same statement.
The most common adverse effects of alemtuzumab are infusion-associated reactions (headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, chills, and flushing) and infections (nasopharyngitis, urinary tract infection, and upper respiratory tract infection). Autoimmune conditions, including thyroid disease, cytopenias, glomerulonephritis, and serious infections, can occur in patients receiving this treatment, and a comprehensive risk management program incorporating education and monitoring will support early detection and management of these identified risks, the statement notes.
The Road to Approval
On June 28, The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion supporting marketing authorization for alemtuzumab, and on September 17, the EMA approved alemtuzumab for the treatment of adult patients with relapsing-remitting MS who have active disease defined by clinical or imaging features.
Unlike Health Canada, the EMA did not limit the use of alemtuzumab to second-line treatment.
In the United States, however, the US Food and Drug Administration (FDA) has still not approved alemtuzumab, and the process has taken longer than some expected.
In September 2012, Genzyme announced that the FDA had issued a "Refuse to File" letter on its supplemental Biologics License Application, asking for a revision in the presentation of the data so that regulators might "better navigate" the application.
There was no approval over the summer of 2013, and the decision eventually went before the FDA's Peripheral and Central Nervous System Drugs Advisory Committee. Prior to the committee meeting, FDA's own reviewers raised significant concerns about the drug's safety and the adequacy of the efficacy data.
On November 13, the panel gave alemtuzumab a roller-coaster ride, voting alternately that the 2 pivotal trials upon which approval was based — known as 323 and 324 or Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II — were not adequate or well controlled, but were in favor of the sponsor having provided adequate evidence of effectiveness.
They then voted almost unanimously that the sponsor had not provided sufficient evidence of a reduction in disability with alemtuzumab, but then subsequently decided that, assuming the efficacy results were as they appeared, safety results would not preclude approval. The panel also voted unanimously (with 2 abstentions) that if the drug were approved, it should not be indicated as a first-line agent in MS.
Panel chairman, Nathan Fountain, MD, University of Virginia, Charlottesville, acknowledged that the panel came to no strong resolution.
"I don't know of any other neurology product with such an extreme safety profile," he told Medscape Medical News at that time. "While natalizumab also has safety issues, these relate to one single adverse effect which can be prevented in many cases, while alemtuzumab has a whole variety of concerns with no obvious way of preventing them. Despite this, most members of the committee appeared to be of the opinion that the drug demonstrated enough efficacy to be available for properly selected patients."
The MS therapeutic area has seen approval for 3 new oral agents in the last several years, including fingolimod (Gilenya, Novartis) in 2010 and teriflunomide (Aubagio, Genzyme/Sanofi) and dimethyl fumarate (BG-12, Tecfidera, Biogen Idec), both in 2013.
Alemtuzumab is a monoclonal antibody that targets CD52, present on T and B cells. It is already approved for the treatment of chronic lymphocytic leukemia under a different brand name (Campath, Genzyme). However, the company limited access to the Campath alemtuzumab product in the United States and the European Union to prevent off-label use of it in MS prior to approval.
Approvals for this drug have been based on 2 pivotal phase 3 trials that confirmed treatment was associated with reductions in relapse rates in patients with relapsing-remitting MS, and in 1 trial, there was also reduced sustained accumulation of disability vs standard treatment with interferon-β1a.
In the phase 3 CARE-MS II trial, alemtuzumab significantly reduced relapse rates and sustained accumulation of disability compared with standard therapy with interferon-β1a in patients who had had at least 1 relapse during treatment with interferon-β1a or glatiramer acetate.
Results from CARE-MS I, a phase 3 comparison of alemtuzumab and interferon-β1a in treatment-naive patients, showed a significant reduction in relapse rates at 2 years, but there was no significant effect on sustained accumulation of disability with alemtuzumab.
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Cite this: Canadian Approval for Alemtuzumab (Lemtrada) in MS - Medscape - Dec 13, 2013.