May 7, 2012 (New Orleans, Louisiana) — Full results of a second phase 3 trial of alemtuzumab (Lemtrada, Genzyme/Sanofi) in patients with relapsing-remitting multiple sclerosis (MS) who had relapsed while receiving previous treatment show that the still-investigational treatment met both co-primary endpoints of reductions in relapse rates and sustained accumulation of disability compared with standard therapy with interferon beta-1a (Rebif, EMD Serono/Pfizer).
The findings, from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis 2 (CARE-MS 2) trial, were presented here at the American Academy of Neurology's 64th Annual Meeting. Topline results were released in November 2011 and reported by Medscape Medical News at that time. The study was funded by Genzyme.
"This study shows superior efficacy of alemtuzumab compared to interferon beta-1a across multiple outcomes, including relapses, disability — not only reduced risk of worsening, but increased likelihood of improvement — and on MRI lesion activity and brain volume loss," said Jeffrey Cohen, director of experimental therapeutics, Cleveland Clinic Mellen Center for MS Treatment and Research, Ohio, and a member of the Steering Committee, who presented the results here.
CARE-MS 2 is the third positive study comparing alemtuzumab with an active comparator, interferon beta-1a, "which itself is effective against relapses, disability, and MRI [magnetic resonance imaging]" activity, Dr. Cohen noted. "The adverse event profile was consistent with previous studies, he added, and a program to monitor for development of thyroid issues and immune thrombocytopenia (ITP) was successful in early detection of these known complications.
Alasdair Coles, MD, senior lecturer in the Department of Clinical Neurosciences at the University of Cambridge, United Kingdom (UK), was principal investigator of the CARE-MS 1 trial that compared alemtuzumab with interferon beta-1a in treatment-naive patients. Results of that trial showed a significant reduction in relapse rates at 2 years but no significant effect on sustained accumulation of disability with alemtuzumab.
Dr. Coles told Medscape Medical News that results of these studies now form the basis for a new drug application to the US Food and Drug Administration (FDA) and to the European Medicines Agency (EMA).
Overall, alemtuzumab reduced lesions and delayed or even improved disability and in all trials was compared with active comparator; this, Dr. Coles noted, "has never been done before."
The package of alemtuzumab data is expected to be submitted to the FDA and EMA sometime in the second quarter this year, he said.
CARE-MS 1 results were first 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 were reported by Medscape Medical News at that time. Several subanalyses from CARE-MS 1 were also presented here.
Alemtuzumab is an anti-CD52 humanized monoclonal antibody that targets lymphocytes and monocytes, causing a depletion in these cells, which then reconstitute over time. It is already approved to treat leukemia or T-cell lymphoma and is used in conditioning regimens for bone marrow or kidney transplantations.
CARE-MS 2 compared treatment with alemtuzumab, 12 mg given daily as an intravenous administration for 5 days, and then again for 3 days 1 year later, with interferon beta-1a, 44 ?g given by injection 3 times per week throughout the 2 years of study. The trial initially included a third arm of 24-mg alemtuzumab, he noted. "This arm was terminated early to accelerate enrollment."
To help block infusion-related adverse effects, alemtuzumab patients received 3 days of intravenous methylprednisolone in addition to each infusion course so the same treatment was also administered annually to the interferon patients, Dr. Cohen noted.
"Because of the distinct mode of administration and side effect profile, it was felt blinding was not going to be feasible, so patients and treating physicians were not blinded," Dr. Cohen said. However, he continued, blinded raters assessed patients on the Expanded Disability Status Scale (EDSS) every 3 months and at the time of suspected relapse, as well as on the Multiple Sclerosis Functional Composite (MSFC) every 6 months. Central reading of MRI findings was also blinded.
The co-primary efficacy endpoints were annualized relapse rate and time to 6-month sustained accumulation of disability on the EDSS. The study was considered positive if either or both endpoints were met, he noted.
Patients were included if they had relapsing-remitting MS; an EDSS score of 5 or less (mean, 7); and active disease, defined as at least 2 relapses in the prior 2 years. Included patients actually had an average of 1.5 relapses in the prior year. Approximately 80% had previously received interferon, 30% had received glatiramer acetate, and 20% had received both.
Study retention was good overall, although less so for interferon, Dr. Cohen noted: 76% of interferon recipients completed the study vs 95% for alemtuzumab.
For the co-primary endpoint of annualized relapse rate, the rate was 0.52 with interferon vs 0.26 with alemtuzumab, a 49% reduction that was highly statistically significant (P < .0001). Time to first relapse showed an early divergence of curves and an increase in the number of relapse-free patients, from 47% with interferon to 65% with alemtuzumab, a 47% reduction in risk (P < .0001).
Time to 6-month accumulation of disability was reduced from 21% with interferon to 12.7% with alemtuzumab, Dr. Cohen noted, "representing a hazard ratio of 0.58 or 42% treatment effect."
Average EDSS score over 2 years of the study showed an average increase of 0.24 EDSS steps in the interferon group vs an average decrease in the alemtuzumab group of 0.17, an improvement. The differences were significant compared with baseline and between groups at month 24, a net difference of 0.41 EDSS step.
That analysis was supported by the time to 6-month sustained reduction of disability, that is, improvement, showing an increase in the risk for improvement from 13% in the interferon group to 29% with alemtuzumab, representing a hazard ratio of 2.6 (P = .0002).
T2 lesion volume decreased in both groups, and the difference between them was not significant, Dr. Cohen noted, but the proportion of patients with new or enlarging T2 lesions over 2 years was decreased significantly. The proportion of patients with gadolinium-enhancing lesions was also reduced.
Brain parenchymal fraction, a measure of brain atrophy, was also reduced with alemtuzumab relative to interferon, Dr. Cohen said.
CARE-MS 2: MRI Endpoints
|T2-hyperintense lesions (%)||46||68||<.0001|
|Gadolinium-enhancing lesions (%)||19||34||<.0001|
|Brain parenchymal fraction (median % change from baseline)||-0.62||-0.81||.012|
The overall incidence of adverse events was similar between groups, as were serious adverse events. A somewhat greater proportion of interferon recipients either discontinued therapy because of an adverse event or discontinued the study, he noted.
Two patients died, both in the 12-mg alemtuzumab group: One patient died in a motor vehicle accident, and another with severe disability died of aspiration.
Infusion reactions were common with alemtuzumab; most were mild to moderate and were reduced by pre-medication.
Infections, including serious infections, were increased with alemtuzumab; the most common infections with this treatment included nasopharyngitis, sinusitis, upper respiratory tract infection, and urinary tract infection. Serious infections seen in more than 1 alemtuzumab recipient included pneumonia, appendicitis, and herpes zoster. There was 1 case of tuberculosis and none of progressive multifocal leukoencephalopathy. There were few malignancies in this trial, and no pattern in cancer types.
As has been reported previously with alemtuzumab, thyroid disorders were increased with treatment; 15.9% of treated patients developed autoimmune thyroid-related adverse events vs 5% of interferon-treated patients.
ITP, also a known effect of this drug, was seen in 7 patients receiving alemtuzumab over the 2-year follow-up. Four cases were detected during monthly monitoring of complete blood count and 3 by patient-reported symptoms. One of the patients responded without therapy, and 6 responded to therapy with steroids or intravenous immunoglobulin. One patient subsequently relapsed, and another had to undergo splenectomy, Dr. Cohen noted.
Monitoring Part of the Deal
Monitoring for the occurrence of thyroid issues and ITP has been a proscribed part of trials of alemtuzumab since these effects were first seen in earlier studies. Such monitoring is likely to be part of any postapproval use of the drug, similar to the programs already in place monitoring for progressive multifocal leukoencephalopathy with natalizumab (Tysabri, Biogen Idec/Elan), Dr. Coles said.
"I think the good news about safety from our phase 3 trials is that there is no news," he said. Taking alemtuzumab, though, will necessarily involve taking part in a monitoring program to help mitigate the risk of thyroid and ITP problems. "The FDA will decide what to do, but I imagine it will consist of something like monthly blood draws."
Dr. Coles also reported some experience they have had with retreatment with alemtuzumab from extension studies. Patients in trials had 2 cycles of alemtuzumab separated by 12 months, he said, "but we have a local experience in the UK of 87 patients treated since 1999. They've all had 2 cycles of therapy, and half of them haven't needed any more," he noted. Some patients have required 3 or even 4 cycles over that time period; 2 have required 5 cycles.
"We've not seen any unusual side effects with repeated treatment, although of course we're talking about quite small numbers now so I don't think we could be confident that there is not a problem," Dr. Coles said. "Every time we give alemtuzumab, antibodies are generated to the drug, but the beauty of alemtuzumab in lots of respects is that the next cycle is not the next day or the next month, it's several years down the track, by which time any antibodies that have been formed have gone."
CARE-MS 1 and CARE-MS 2 were funded by Genzyme, a Sanofi Company. Alemtuzumab is being developed in collaboration with Bayer HealthCare. Dr. Cohen reports he has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. He has also received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Coles reports he has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. He has also received research support from Genzyme Corporation.
American Academy of Neurology 64th Annual Meeting: Abstracts #S01.004, S01.006. Presented April 24, 2012.
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