Second Phase 3 Trial Positive With Alemtuzumab in MS

Susan Jeffrey

November 14, 2011

November 14, 2011 — Genzyme, a sanofi-aventis company, has reported positive top-line results for the still-investigational alemtuzumab (Lemtrada) vs standard therapy with interferon beta-1a (Rebif, EMD Serono/Pfizer) from a second phase 3 trial in patients with relapsing-remitting multiple sclerosis (MS).

The trial, called the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) met both coprimary endpoints of reductions in relapse rate and sustained accumulation of disability in treated patients with relapsing-remitting MS.

Results of CARE-MS I, a similar phase 3 comparison of alemtuzumab and interferon beta-1a, had shown a significant reduction in relapse rates at 2 years, but no significant effect on sustained accumulation of disability with alemtuzumab, an effect the researchers attributed in part to an "unexpectedly low number of disability events in the comparator group."

Patients in CARE-MS I were treatment naive, whereas participants were required to have experienced a relapse while on a prior therapy to be eligible for CARE-MS II.

In this second phase 3 randomized trial, which included 840 patients, a 49% reduction in relapse rate was observed in patients treated with alemtuzumab 12 mg compared with interferon beta-1a during 2 years of study (P < .0001). There was also a 42% reduction in the risk for sustained accumulation of disability as measured by the Expanded Disability Status Scale (P = .0084).

"Analysis of the full CARE-MS II data is ongoing and results will be presented at a forthcoming scientific meeting," a statement from the company notes. The CARE-MS I results were presented in October at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), and reported by Medscape Medical News at that time.

"CARE-MS ll represents the culmination of many years of clinical and laboratory research aimed at demonstrating the potential for alemtuzumab as a highly effective treatment for MS, and understanding mechanisms involved in the complex natural history of the disease," said Professor Alastair Compston, PhD, chair of the steering committee overseeing the conduct of the study and head of the Department of Clinical Neurosciences at the University of Cambridge, United Kingdom, said in the statement. "Taken together, the phase 2 and 3 clinical trial data illustrate the promise that alemtuzumab holds as a transformative treatment for people with relapsing MS."

CARE-MS II compared treatment with alemtuzumab 12 mg given daily as an intravenous administration for 5 days, and then again for 3 days 1 year later, to treatment with interferon beta-1a 44 μg given by injection 3 times per week throughout the 2 years of study.

"The superior efficacy results for alemtuzumab, particularly the slowing of disability, are very promising, since this was a head-to-head comparison trial with high-dose subcutaneous interferon beta-1a," said Jeffrey Cohen, MD, professor of medicine (neurology) at the Cleveland Clinic Lerner College of Medicine and director of experimental therapeutics at the Mellen Center for MS Treatment and Research, Case Western Reserve University, Ohio, and a member of the steering committee overseeing the conduct of the study. "These results suggest alemtuzumab's potential to offer patients with MS a new and effective treatment option."

The safety profile observed in the trial was consistent with previous alemtuzumab use in MS, and adverse events continued to be manageable, the company reports.

The most common types of adverse events associated with alemtuzumab in CARE-MS II were infusion-associated reactions, including headache, rash, nausea, hives, fever, itching, insomnia, and fatigue.

Infections were common in both groups, with a higher incidence in the alemtuzumab group. The most common infections in patients receiving alemtuzumab included upper respiratory and urinary tract infections, sinusitis, and herpes simplex infections. Infections were predominantly mild to moderate in severity, and there were no treatment-related life-threatening or fatal infections.

Approximately 16% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and approximately 1% developed immune thrombocytopenia during the 2-year study period. These cases were detected early through a monitoring program and were managed using conventional therapies. Patient monitoring for immune cytopenias and thyroid or renal disorders is incorporated in all Genzyme-sponsored trials of alemtuzumab for the investigational treatment of MS, the authors note.

Presenting the CARE-MS I data at ECTRIMS/ACTRIMS, lead investigator Alasdair Coles, MD, senior lecturer in the Department of Clinical Neurosciences at the University of Cambridge, said monthly monitoring for autoimmune thyroid disease or immune thrombocytopenic purpura will be required with alemtuzumab treatment.

"What I think this drug offers is high efficacy, reasonable ease of administration — reasonable — and quite intense safety monitoring," Dr. Coles told Medscape Medical News. "It's very much down to patient choice as to how attractive they find that package. I anticipate, though, that it will be patients for whom efficacy is the chief determinant of treatment who will opt for this."

In the company statement, David Meeker, MD, president and chief executive officer of Genzyme, said that based on these positive results, they are on track to submit alemtuzumab for review to the US and European Union regulatory authorities in the first quarter of 2012.

Alemtuzumab has been granted fast track designation by the US Food and Drug Administration. Genzyme has the worldwide rights to alemtuzumab and has primary responsibility for the development and commercialization of alemtuzumab in MS. Bayer HealthCare has been codeveloping the drug in MS with Genzyme. "Bayer HealthCare retains an option to co-promote alemtuzumab in MS and upon regulatory approval and commercialization would receive contingent payments based on sales revenue," according to the release.


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