Alemtuzumab: Mixed Review From FDA Advisory Committee

November 13, 2013

The US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory Committee today gave the new multiple sclerosis (MS) drug alemtuzumab (Lemtrada, Genzyme) a roller coaster ride, not reaching definite conclusions at the end of the day as to whether it should be approved or not.

Despite voting 11 to 6 (with 1 abstention) that the 2 pivotal trials — known as 323 and 324 or CARE-MS I and CARE-MS II — were not adequate or well controlled, the panel then voted 12 to 6 in favor of the sponsor having provided adequate evidence of effectiveness.

To add to the confusion, the panel voted 14 to 2 (2 abstentions) that the sponsor had not provided sufficient evidence of alemtuzumab on reduction of disability, but voted 17 to 0 (1 abstention) that, assuming efficacy results are as they appeared, safety results would not preclude approval.

Finally, the panel voted 16-0 (2 abstentions) that if the drug were approved, it should not be indicated as a first-line agent.

Panel chairman, Nathan Fountain, MD, University of Virginia, Charlottesville, acknowledged that the panel came to no strong resolution.

"I don’t know of any other neurology product with such an extreme safety profile," he told Medscape Medical News. "While natalizumab also has safety issues, these relate to one single adverse effect which can be prevented in many cases, while alemtuzumab has a whole variety of concerns with no obvious way of preventing them. Despite this, most members of the committee appeared to be of the opinion that the drug demonstrated enough efficacy to be available for properly selected patients."

Potential Bias in Pivotal Trials

Most of the day's proceedings were taken up discussing whether the 2 phase 3 studies — both comparing alemtuzumab with interferon β (Rebif) — were adequately controlled because of potential bias due to their open- label design. Although patients and treating physicians were aware of who was taking which drug, the physicians assessing the results were blinded, a design known as rater-blinded.

Several FDA officials gave lengthy presentations emphasizing the shortcomings of such a design, mainly that it introduced a high potential for bias. Eric Bastings, MD, acting director, Division of Neurology Products at the FDA, stressed that the agency strongly discouraged Genzyme from using open-label trials. "We have consistently indicated discomfort about the trial designs," he said.

Presenting an analysis of the efficacy results, FDA reviewer John Marler, MD, concluded that "the applicant has not submitted evidence from adequate and well-controlled studies to support the effectiveness of alemtuzumab for treating multiple sclerosis." He added: "The applicant reports positive results but the design of the studies creates uncertainty as to the extent of the effects. But there is certainty that there are many serious and life-changing side-effects."

Explaining the agency's concerns, Dr. Marler noted: "A patient's knowledge of treatment could influence relapse and disability outcomes because these outcomes are subjective. The phase 2 results were already known so there would have been a high expectation of alemtuzumab benefit."

He pointed out that the consent form stated that the patient could be withdrawn if disease worsened considerably. "As patients knew which treatment they were on and would be expecting a better response from alemtuzumab, they may have minimized reports of symptoms so as to continue on the drug. This would not have been the case for patients in the interferon arm. So there is bias."

Another point raised was that the baseline assessment was conducted after randomization in about half the cases, Dr. Marler reported. Because this could be subject to bias, using screening data for the baseline assessment might provide a more reliable result. He added: "So if we reanalyze the data using the screening assessment as the baseline, then we see approximately 10% more SAD [sustained accumulation of disability] in alemtuzumab groups and 10% fewer in the interferon arm."

Dr. Marler maintained that if the trials had been well controlled, then the difference between screening and baseline assessments would have been much less. "This could have a dramatic effect on the overall results."

Discussing their votes on the question as to whether the 2 phase 3 trials were "adequate and well controlled," panel members had obviously struggled with these issues. Voting "no" to this question, with the majority, Robert Clancy MD, Children's Hospital of Philadelphia, Pennsylvania, said, "I am very worried about unblinding. The fundamental principles of clinical trials have been violated. I can't trust the results."

The FDA built a nice case on why these trials did not measure up. Dr. Mark Woods

And Mark Woods, PharmD, St Luke's Hospital, Kansas City, Missouri, said, "The FDA built a nice case on why these trials did not measure up."

But voting "yes," David Blumenthal, MD, Case Western Reserve University School of Medicine, Cleveland, Ohio, said,; "It's a tough call. But at the end of the day, even with a double-dummy design, patients would know which treatment they were on because of side effects."

Consumer representative Richard Hoffman, who also voted "yes," added: "The trials were not ideal in design but they are all we have to work with. The European Medicines Agency seemed to like them and The Lancet published them."

And Justin Zivin, MD, professor emeritus, University of California, San Diego, said, "Studies like this can't be blinded, but if raters are blinded that's ok for me."

Adequate Evidence of Effectiveness

On the second question of whether the sponsor had provided adequate evidence of effectiveness, the majority voted in favor.

Dr. Fountain commented: "Despite the fact that most panelists believed the trials were not adequate and well controlled, we didn't allow for any gray area in the first question. And it appears that there is support for a benefit."

Ann Yeh, MD, University of Toronto, Ontario, Canada, said, "Alemtuzumab was not worse than Rebif even in the FDA's reanalysis."

Dr. Blumenthal added: "There was sufficient evidence of efficacy from the MRI data for me. That would not have been biased." And Ying Lu, PhD, Stanford University School of Medicine, California, pointed out that the brain atrophy data also showed a consistent reduction, as well as hospitalizations. "It is hard to be biased on these."

Voting "no," Caleb Alexander, MD, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, said, "If the clinical trials are not adequate or well controlled, I can't see how you can say there is adequate evidence of effectiveness."

On the question of whether there was sufficient evidence of a substantial effect of alemtuzumab on disability, most panelists voted "no," citing inconsistent results between the 2 studies on this endpoint, as well as the bias. Going against the tide on this one, Dr. Zivin said he thought the effect on disability was at least as substantial as other drugs available, and thus worthwhile.

On the question of whether safety would preclude approval assuming the drug was effective, there was a strong negative reaction, with 17 "no" votes.

Most comments reflected the opinions that the individual patient and neurologist should decide on whether they wanted to risk the adverse effects. Dr. Fountain said he wouldn't want to deny the drug to patients with severe disease.

Dr. Blumenthal commented: "Safe use is going to cause big problems. People are going to have bad outcomes. You can't just stop it and wait for effects to wear off. But at the end of day I could not interpose myself between the patient and their neurologist. It is for them to decide whether it is the right choice." He also pointed out that patients can obtain alemtuzumab anyway because it is already marketed for leukemia.

Panel member Paul Rosenberg, MD, Johns Hopkins University School of Medicine, added: "The risks are substantial but this is a really bad disease."

Finally, the panelists were asked to vote on whether, if the data supported approval, alemtuzumab should be indicated as a first-line agent. Again, there was a big "no" to this question.

Dr. Fountain said he felt the drug was not for patients with simple, early MS because of the adverse effects, but it would clearly be appropriate for those with later-stage, more severe disease.

FDA Wanted Double-Dummy Study

On the design of the studies, the FDA requested that Genzyme use a double-dummy design to ensure blinding. But Dr. Blumenthal said he didn't think this would have helped much. "As 92% of patients on alemtuzumab had infusion reactions, patients are going to know what they are being given." But the FDA representatives still insisted a double-dummy design would have been better, pointing out that not all patients would be unblinded, so there would be still be a level of uncertainty.

If issues of bias applied to Avonex, Betaseron, and Copaxone, we wouldn’t have any drugs. Dr. Richard Rudick

Giving testimony to the panel, Richard Rudick, MD, from the Cleveland Clinic in Ohio, who has been involved in several MS trials, said the requirement to have a double-mask design precludes many studies from going ahead.

"If issues of bias applied to Avonex, Betaseron, and Copaxone, we wouldn’t have any drugs. And the differences in those studies between active drug and placebo were smaller than alemtuzumab and Rebif here," he argued.

Safety Issues

In a safety review of alemtuzumab prior to the meeting, Evelyn Mentari, MD, from the FDA, highlighted the many serious adverse effects that could occur with the drug. These included an array of autoimmune diseases, including immune thrombocytopenia, autoimmune hemolytic anemia, immune pancytopenia, anti–glomerular basement membrane disease, membranous glomerulonephritis, thyroid disorders, endocrine ophthalmopathy, acquired hemophilia A, type 1 diabetes mellitus, acute epitheliopathy of the retina, autoimmune skin disease, and undifferentiated connective tissue disorders, along with the incidence of malignancies, notably thyroid cancer and melanoma.

Because these concerns are serious and potentially fatal, Dr. Mentari concluded that she did not recommend approval of alemtuzumab unless substantial clinical benefit exists. "The safety concerns cannot be prevented by monitoring and prophylaxis. They can occur years after the treatment is given, and the risk will be higher after approval as the drug will be used in a broader range of patients.”

Genzyme has proposed making the drug available under a Risk Evaluation and Mitigation Strategy (REMS), similar to the one currently used for natalizumab (Tysabri). This would include monthly complete blood counts and creatinine levels and quarterly thyroid checks. In addition, prophylactic acyclovir would be given for 1 month after infusion and patients would receive methylprednisolone for infusion reactions.

Nyedra Booker, PharmD, MPH, also with the FDA, said the proposed REMS program would not mitigate many of the risks with alemtuzumab, but it will ensure that patients and prescribers are aware of them. "However, the nature of the serious risk with alemtuzumab will not ensure benefits will outweigh the risk of treatment," she added. A Genzyme spokesperson responded that the REMS "was not about mitigation but early intervention."

Adding to the view that it was up to the individual patient and neurologist to decide on the risk/benefit for their own case, 10 public speakers, including representatives of MS organizations and patients themselves, all urged the panel to vote for approval. Several patients described how their disease symptoms had improved dramatically with alemtuzumab. Many said they would run the risk of developing thyroid problems or thrombocytopenia in exchange for a reduction or delay in the disability.

The patient representative on the panel, Cynthia Sitcov, urged the FDA to consider the "the incredibly moving testimony from patients." She noted that numerous letters from patients and advocacy groups have been sent to the FDA. "They are remarkable. Every single one describes this drug as life changing."

Therapeutic Index

Asked by the panel to try and come with a therapeutic index to help with figuring out whether the benefits outweighed the risk, the FDA suggested a therapeutic index of 0. This was calculated by balancing an absolute difference of 8% in relapse rates — "an optimistic estimate from the sponsor's analysis" — with a risk for serious adverse events, which was also around 8%.

But a Genzyme spokesperson presented a different analysis suggesting a number need to treat of 5 to prevent 1 piece of evidence of disease activity, including relapse, disability, or MRI lesions, and a number needed to harm in terms of serious adverse effects of 217 for thyroid issues, 107 for immune thrombocytopenia, and 217 for nephropathy.


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