European Approval for Alemtuzumab in MS

Susan Jeffrey


September 17, 2013

The European Medicines Agency (EMA) has granted marketing authorization for alemtuzumab (Lemtrada, Genzyme Corp/sanofi-aventis) for the treatment of multiple sclerosis (MS).

The drug is indicated for the treatment of adult patients who have relapsing-remitting MS with active disease defined by clinical or imaging features.

The approval follows a positive opinion in June by EMA's Committee for Medicinal Products for Human Use (CHMP) supporting marketing authorization for alemtuzumab. "The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Lemtrada and therefore recommends the granting of the marketing authorisation," a statement from CHMP noted.

Alemtuzumab, 12 mg, has a novel dosing and administration schedule consisting of 2 annual treatment courses. The first course is given as an intravenous infusion over 5 consecutive days, and the second over 3 days 12 months later.

The US Food and Drug Administration is now considering the company's supplemental Biologics License Application seeking approval for the treatment of relapsing MS, and action is expected in late 2013, the company statement noted.

In September 2012, Genzyme announced 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" the application, and approval has taken longer than some expected.

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

Teriflunomide was also just approved in Europe on August 30, as reported by Medscape Medical News at that time.

"The approvals of Lemtrada and Aubagio in the European Union represent an important milestone for Genzyme and demonstrate our focus on scientific innovation and commitment to multiple sclerosis patients," said Genzyme CEO and President, David Meeker, MD. "This is particularly exciting as the EU approval is the first for Lemtrada globally. We look forward to making these unique therapies available to MS patients very soon."

"Multiple sclerosis necessitates a highly individualized treatment approach, and the increasing diversity of options is good news," said Hans-Peter Hartung, MD, PhD, professor and chairman of the Department of Neurology at Heinrich-Heine-University in Duesseldorf, Germany. "The Lemtrada clinical trial data support its potential to meaningfully address disability in active RRMS [relapsing-remitting MS] patients, while Aubagio's efficacy, safety and convenient dosing may provide an important alternative to injectable therapies. The approvals of Lemtrada and Aubagio represent a significant step forward in the way we think about treating this disease."

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 Campath in the United States and the European Union to prevent off-label use of it in MS before approval.

Approval for this new indication is based on 2 pivotal phase 3 trials confirming that treatment was associated with reductions in relapse rates in patients with relapsing-remitting MS; in 1 trial, there was also reduced sustained accumulation of disability vs standard treatment with interferon β-1a.

In the phase 3 Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis 2 (CARE-MS II) trial, alemtuzumab significantly reduced relapse rates and sustained accumulation of disability when used as a first-line therapy compared with standard therapy with interferon β-1a in patients with relapsing-remitting MS.

Results from CARE-MS I, a phase 3 comparison of alemtuzumab and interferon β-1a 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. CARE-MS I and CARE-MS II trials were published online November 1, 2012, in The Lancet.

The most common adverse effects of alemtuzumab are infusion-associated reactions, infections (upper respiratory tract and urinary tract), lymphopenia, and leukopenia, the company release notes. Serious autoimmune conditions can occur in patients receiving this drug, so a comprehensive risk management program has been instituted to ensure early detection and management of these autoimmune events.

Long-Term Remission?

In these MS treatment trials, alemtuzumab was given for intravenously at baseline and then again after 1 year. Interim analysis of extension data from the phase 3 trials, presented in March at the American Academy of Neurology's annual meeting and reported by Medscape Medical News at that time, showed relapse rates and sustained accumulation of disability remained low after 1 year, and disability levels remained stable or improved. Further, 80% of patients who participated in the extension did not require retreatment during the third year.

These findings suggest that the benefits of alemtuzumab observed in the phase 3 studies are maintained, even though most patients did not receive further dosing, said Edward Fox, MD, director of the Multiple Sclerosis Clinic of Central Texas, Round Rock, who presented the findings.

Although it's not a cure, these results do introduce the idea of long-term remission for patients with MS, he told Medscape Medical News at that time.

"What I think that 'long-term remission' has meant to oncologists and now to us, is going to be the concept that there are those patients — and we've seen this historically from the open-label experience many years ago and beyond with the phase 2 trial — who have gone many, many, many years without retreatment after an initial dose or 2, or more depending on the trial."


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