FDA Declines Approval for Alemtuzumab (Lemtrada) in MS

Susan Jeffrey

December 30, 2013

The US Food and Drug Administration (FDA) has declined approval for alemtuzumab (Lemtrada, Genzyme, a Sanofi Company) for its supplemental Biologics License Application in relapsing-remitting multiple sclerosis (MS).

Genzyme announced this morning that the company received a complete response letter from the agency.

"FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects," the company notes in a release. "Genzyme understands that the conclusion is related to the design of the completed phase 3 active comparator studies of Lemtrada in relapsing-remitting MS patients. FDA has also taken the position that one or more additional active comparator clinical trials of different design and execution are needed prior to the approval of Lemtrada.

"Genzyme strongly disagrees with the FDA's conclusions and plans to appeal the agency's decision," the release states.  

"We are extremely disappointed with the outcome of the review and the implications for patients in the U.S. suffering with multiple sclerosis who remain in need of alternative therapies to manage a devastating disease," said Genzyme President and CEO, David Meeker, MD, in the statement. "We strongly believe that the clinical development program, which was designed to demonstrate how Lemtrada compares against an active comparator as opposed to placebo, provides robust evidence of efficacy and a favorable benefit-risk profile. This evidence was also the basis for the approvals of Lemtrada by other regulatory agencies around the world."

Alemtuzumab is already approved in the European Union, Canada, and Australia, and additional marketing applications are under review by other regulatory agencies, the company 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 with active disease defined by clinical or imaging features. The EMA did not limit the use of alemtuzumab to second-line treatment.

On December 13, Health Canada also approved alemtuzumab for management of adult patients with active disease defined by clinical and imaging features, but in Canada, it is limited to those with an inadequate response to interferon-β or other disease-modifying therapies.

In the United States, the approval process has taken longer than some expected. Genzyme announced in September 2012 that the FDA had issued a "Refuse to File" letter on its application, asking for a revision in the presentation of the data so that regulators might "better navigate" it.

There was no approval over the spring and summer of 2013, and the decision eventually went before the FDA's Peripheral and Central Nervous System Drugs Advisory Committee. Prior to the meeting, the 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 on 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 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.

CARE-MS Trials

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 (CLL) 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.

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 on 3 consecutive days, 12 months later. Early results suggested that many patients might not require further treatment, out to 3 years at least, raising the possibility that the drug could offer long-term control of the disease.

The main safety concerns include autoimmune thyroid problems and idiopathic thrombocytopenic purpura (ITP) for which patients would have required monitoring.

The MS therapeutic area has seen approval for 3 new oral agents in the last several years, including fingolimod (Gilenya, Novartis) in 2010, teriflunomide (Aubagio, Genzyme/Sanofi) in September 2012, and dimethyl fumarate (BG-12; Tecfidera, Biogen Idec) in March 2013.

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