DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
Dr. Olaf Stüve
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
Dr. Mitchell T. Wallin
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.