ARTICLE IN BRIEF
Despite safety concerns raised by an FDA panel about alemtuzumab for multiple sclerosis, an FDA Committee unanimously voted that this should not preclude the approval of the drug for use in certain MS patients — particularly those who had failed other therapies. They also agreed, however, that the clinical trials did not provide adequate evidence of efficacy and that alemtuzumab should not be used as a first-line therapy.
The number of available, approved therapies for relapsing multiple sclerosis (MS) continues to grow — currently, there are 10 — but still patients and clinicians recognize a considerable void when it comes to treatment options which are both safe and effective in patients over the long term. The most recent therapy under U.S. Food and Drug Administration (FDA) review is alemtuzumab (Lemtrada), manufactured by Sanofi. (Alemtuzumab is the first fully humanized monoclonal antibody, and works peripherally to disable circulating T and B cells, leading to profound and prolonged changes in the immune system. The active ingredient was previously approved by the FDA in 2001 for treating leukemia.)
Two days before the Nov. 14 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee to discuss alemtuzumab, the FDA released a briefing document compiled by three experts, analyzing clinical safety (Evelyn Mentari, MD, medical officer of the Division of Neurology Products,), clinical efficacy (John Marler, MD, medical officer of the Division of Neurology Products), and statistics (Sharon Yan, PhD, statistician) of the drug. In the document, the reviewers pointed to “serious and potentially fatal safety issues” with alemtuzumab and called the relative benefit of the treatment into question when compared with substantial risks. The advisory committee was charged with providing independent, expert advice to the FDA on two main points: “whether the applicant has provided adequate and well-controlled studies that demonstrate substantial evidence of effectiveness” and whether the serious potential risks of the drug should preclude approval.
In the two pivotal trials, CAMMS 323 and CAMMS 324, investigators reported a nearly 50 percent reduction in the annual relapse rate of relapsing-remitting MS patients taking alemtuzumab, when compared with beta-interferon (Rebif) treatment. [See “Alemtuzumab: Trial Data” for more on the findings.] But Drs. Yan and Marler pointed to the unblinded and open-label nature of these trials, claiming this may have introduced bias into the interpretation of the results. For instance, Dr. Marler noted a higher drop-out rate among patients using interferon after patients became aware of their assignment, but before treatment, which may have skewed data. Dr. Mentari also did not recommend the approval of alemtuzumab “unless substantial clinical benefit exists” because of the incidence of an array of autoimmune disease, along with the incidence of malignancies, including thyroid cancer and melanoma.
Still, despite the serious concerns raised, the FDA advisory committee voted (17 to 0, with one abstention) that this should not preclude the approval of the drug for use in certain MS patients — particularly those who had failed other therapies. They also agreed, however, that the clinical trials did not provide adequate evidence of efficacy and that alemtuzumab should not be used as a first-line therapy. The FDA has not yet issued final approval of the drug, and does not necessarily have to comply with the advisory committee recommendations.
These votes “reflected the complexity of the questions at hand and probably reflected the FDA's confusion on the matter, and that is why they brought it to a committee,” explained Nathan B. Fountain, MD, professor of neurology and director of the F.E. Dreifuss Comprehensive Epilepsy Program at the University of Virginia School of Medicine, who chaired the FDA advisory committee. “The committee seemed to think alemtuzumab could be approvable for very limited use with an adequate degree of surveillance. This was different than the original proposal for use in all types of MS.”
The committee “recognized what I think all of us in the world of MS understand: number one, MS is a bad disease; number two, there remains unmet need for these patients,” said John Corboy, MD, neurology professor at the University of Colorado School of Medicine, who was not involved in the advisory committee review.
Citing the briefing document, Robert J. Fox, MD, staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, said that it raised the important issue of balancing the risks of therapies like alemtuzumab “with the risk of impairment and injury from MS itself. We don't have a cure for this disease yet, but we are looking for one, so until then, we have to balance out the risk of the disease with the potential benefits and risks of the treatment options.”
Drs. Fox and Corboy acknowledged that there are particular difficulties involved in performing clinical trials of MS at this time. Especially, said Dr. Fox, “when the treatments that one is developing — in this case alemtuzumab — have a different mode of administration from treatments that are considered standard at that point, such as interferon.” Inasmuch as interferon is given by injection subcutaneously three times a week, whereas alemtuzumab is given by IV infusion several times a year — it raises an issue about the complexity of doing “properly blinded clinical trials in MS when the treatment modalities are so dramatically different.”
Dr. Corboy added that the world of trial design in MS is changing, and regulatory agencies are demanding more comparison trials. For example, he said, one of the “major criticisms that the three-person FDA panel had was that the trial design was not a double-dummy trial design, which has many implications: it dramatically increases the cost of the study and it also substantially increases the effort on the part of the patients,” he said.
But even in double-blinded trials, said Dr. Fox, side effect profiles (such as injection-site infection) can result in unblinding. In progressive MS, he added, “we still embrace placebos because we have no effective therapy for progressive MS. But in relapsing MS, we have 10 FDA-approved therapies now and so we have moved past the time when a placebo for the full two years or three years of a trial in relapsing MS is considered ethical.”
The reality of MS, as reflected by the recent FDA review and the advisory committee vote, noted Dr. Corboy, “remains that we still have an unmet need and the management of these potentially risky agents will only become more complicated. But that should not dissuade us from doing everything we can to have an early impact on patients to diminish their risk of disability down the road.”
WHICH PATIENTS MIGHT BENEFIT FROM ALEMTUZUMAB?
Dr. Fountain said this will be an important question for the FDA and MS specialists to answer. “My opinion is that the potential for long-delayed occurrence of serious life threatening problems, such as ITP [idiopathic thrombocytopenic purpura] and malignancies is sufficiently high that alemtuzumab should generally be reserved for those with severe or refractory MS.”
Perhaps those patients “who need more aggressive therapy than some of our standard first-line therapies,” added Dr. Fox, or a patient for whom natalizumab is not an appropriate treatment option because they are seropositive for the PML virus, have an allergic reaction, or because they have developed anti-natalizumab antibodies could benefit from alemtuzumab.
As we gain more experience with already approved FDA agents, said Dr. Corboy, “it's becoming clearer that not all the medications are equivalent to one another. But it is also clear that there are various issues with regards to tolerance, adherence, and risk. Patients' interpretations of side effects and risk, and physicians' interpretations of risks are going to be variable. It is the norm in our world for patients to fail one, two, or more medicines,” he said.
One of the more alarming features of this drug's risk profile, said Dr. Fountain, is that side effects may not occur for many months — or even years — after treatment. So, it is incumbent upon clinicians and their patients to monitor for these potential adverse events for a very long time. “The risk is that patients will get a 5-day treatment once and possibly a 3-day treatment one year later and then forget about the monitoring that needs to be done for continued risk,” he said.
It remains to be seen what, if any, risk mitigation strategy is put in place for this medication, for example the use of a biomarker like cytokine IL-21 for predicting risk of developing autoimmune disorders in patients using alemtuzumab, Dr. Corboy said. He pointed to the development of strategies to identify and stratify risk of PML in patients considering the use of natalizumab, which has “enhanced the usage of natalizumab substantially, and it will be interesting to see if a similar strategy evolves for the use of alemtuzumab over time.”
There still needs to be more research to determine whether or not alemtuzumab will arrest or even reverse MS disease progression, said Dr. Fountain. “This will require a well-designed, double-blind, long-term study,” which is very difficult to conduct.