DALLAS—Does alemtuzumab have a favorable risk–benefit profile as a treatment for patients with relapsing-remitting multiple sclerosis (MS)? Neurologists who specialize in the disease debated this question at the 2014 Cooperative Meeting of CMSC and ACTRIMS.
Alemtuzumab is approved in Europe, Canada, and Australia for use in patients with MS. The only first-line therapy for refractory MS available in the United States is natalizumab. Among that drug’s drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham virus antibody.
Finding a Balance Between Safety and Efficacy
Many neurologists have raised concerns about alemtuzumab’s safety, but safety is relative, according to Olaf Stüve, MD, PhD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. For any drug, neurologists must identify a good ratio between efficacy and safety that benefits patients more than it hurts them, he added. “I would argue strongly that alemtuzumab has a good efficacy profile that outweighs potential safety issues.” Because natalizumab, which entails its own safety concerns, is the current first-line therapy for patients with refractory disease, “we need another player for patients who don’t respond to disease-modifying therapies,” said Dr. Stüve.
Blinding in an Alemtuzumab Trial Would Be Difficult
The FDA rejected Genzyme’s bid to market alemtuzumab in 2013, citing the lack of double blinding in the Comparison of Alemtuzumab and Rebif Efficacy (CARE) MS I and II trials, as well as concerns about safety.
“It would have been possible to design a double-blinded trial,” said Dr. Stüve. “However, [nearly all] patients are aware which intervention they are receiving, based on any flu-like symptoms. Similarly, an incidence of 90% to 99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent.” Furthermore, because the relapse rate was “fairly consistent in the phase II and phase III programs,” the risk that outcomes were “substantially affected by the trial design,” was reduced, added Dr. Stüve.
Alemtuzumab May Have Long-Lasting Adverse Consequences
“Alemtuzumab is more poison than good,” said Mitchell T. Wallin, MD, Associate Professor of Neurology at Georgetown University in Washington, DC. “My vote is to not approve it. There is some question about how well this drug actually controls disability progression,” he added, referring to the disparate findings of the CARE MS I and II studies. The former trial failed to show that alemtuzumab changed patients’ progression in Expanded Disability Status Scale scores, but the latter trial did show this effect.
Data from the CARE studies, FDA reviews, and an advisory panel meeting of the FDA indicated that alemtuzumab has “good efficacy … in terms of MRI and relapse rates,” said Dr. Wallin. Results of the extended CARE MS trial “seem to show the stabilization of the MRI out to three years,” he added.
But use of the drug often has lethal consequences. Data from the alemtuzumab trials indicate that the drug is associated with a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), said Dr. Wallin. One case of alemtuzumab-related ITP resulted in death.
Approximately 1% of patients studied also had dangerously low platelet counts, which increased their risk for bleeding complications. Reported adverse events, including opportunistic infections, kidney failure, fetal complications, and suicidal ideation, may persuade neurologists that alemtuzumab should not be a first-line therapy. “You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that,” said Dr. Wallin.
Does Alemtuzumab Compare Favorably to Natalizumab?
Other neurologists believe that the long-lasting effect is precisely what makes alemtuzumab a valuable treatment. “This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy,” said Dr. Stüve. The CARE MS extension data indicated that 20% of patients who had received alemtuzumab received subsequent disease-modifying therapy (DMT) with no increase in adverse events. This result “shows that alemtuzumab could potentially be used as an effective induction therapy up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns,” said Dr. Stüve. “This is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease.”
In addition to ITP, alemtuzumab has been associated with opportunistic infections and various malignancies, including thyroid malignancies. Nevertheless, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to anticipate, monitor, and treat these conditions.