Alemtuzumab Investigators Protest FDA Decision

Several multiple sclerosis (MS) experts who were involved in the clinical development program for alemtuzumab (Lemtrada, Genzyme) have voiced their disappointment and frustration over the recent decision by the US Food and Drug Administration (FDA) not to approve the drug.

Stephen Krieger, MD, from Mount Sinai Medical Center, New York; Edward Fox, MD, from the Multiple Sclerosis Clinic of Central Texas, Round Rock; and Jeffrey Cohen, MD, from Cleveland Clinic, Ohio, all told Medscape Medical News that they strongly disagree with the FDA decision and are worried about the consequences, which could include patients sourcing the drug from other countries but not being monitored for the serious safety issues.

"It's a huge enterprise to do these trials," Dr. Krieger commented. "A lot of doctors are involved, and we have all seen patients do extremely well who probably wouldn't have done so without alemtuzumab. There is a lot of disappointment among MS specialists."

The company announced that FDA had declined approval for alemtuzumab on December 27, saying that Genzyme had not submitted evidence from adequate and well-controlled studies demonstrating that the benefits of alemtuzumab outweigh its serious adverse effects. The concerns are understood to relate to the open-label design of the 2 phase 3 Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis trials, CARE-MS I and CARE-MS II.

The agency has also stated that 1 or more additional active comparator clinical trials of different design and execution are needed for approval.

"Genzyme strongly disagrees with the FDA's conclusions and plans to appeal the agency's decision," the company said in a statement released December 30 after the FDA issued a Complete Response Letter.

Prior to that, the drug was the subject of an advisory panel meeting of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee, which did not reach a clear consensus. Dr. Krieger told Medscape Medical News that he thought the advisory panel was in favor of approval. "The spirit of the panel was that it was approvable," he said.

But chair of that advisory committee, Nathan Fountain, MD, University of Virginia, Charlottesville, defended the FDA's decision.

"It is likely that the FDA did not approve alemtuzumab for MS because some adverse events that occurred were potentially fatal; in addition, some of them did not occur for years after administration of the drug," Dr. Fountain told Medscape Medical News. "It would be very difficult to insure that patients would be monitored for these problems for an adequate duration."

Many MS researchers looking at the data to date with this drug had been hopeful that the dosing schedule of 2 treatments a year apart, with many patients apparently not requiring any further treatment, might represent an opportunity to move MS into the category of a controlled chronic disease. Others had even used the "C" word — cure — in discussions of its potential impact.

"If alemtuzumab were truly curative, then I imagine the benefits might outweigh the risks," Dr. Fountain said. "However, the clinical trials submitted did not allow determination of whether alemtuzumab altered the natural history of MS. Only through a longer, well-designed, double-blind, randomized, adequately powered study could it be determined whether alemtuzumab is curative.

"Although this type of study is not popular among industry or NIH [National Institutes of Health] sponsors, a curative therapy for MS would be worth the seemingly high risk of a drug like alemtuzumab and would represent a foundational breakthrough in MS therapy," Dr. Fountain concluded.

While the advisory panel did not appear to reach a clear consensus, the assessment of FDA's own reviewers, released before the meeting, was more clear, bordering on blunt. In documents provided to the panel in advance of the meeting, Billy Dunn, MD, acting deputy director of the Division of Neurology Products, summarizes 3 reports from reviewers: from Evelyn Mentari, MD, of the drug's safety; from John Marler, MD, of its clinical efficacy, and from Sharon Yan, PhD, of the clinical statistics supporting the supplemental Biologics License Application for alemtuzumab.

"As discussed by Drs. Mentari, Marler, and Yan, significant concerns exist regarding the safety profile of alemtuzumab and the adequacy of the efficacy data," Dr. Dunn says in the memo.

Playing Politics?

For his part, Dr. Fox believes the issue is more about Genzyme not following FDA requests.

"I knew the FDA had an issue regarding trial design," he said. "There had been a large amount of communication between Genzyme and the FDA which I thought had been resolved. But it appears that the FDA wanted a double-dummy design, Genzyme didn't do it, and now the FDA is putting its foot down. They appear to be making a point. But I don't believe they ever said the drug would not be approved with that trial design. They allowed it to be filed and fast tracked."

Dr. Fox says he "isn't taking no for an answer" at the moment, and he is organizing an open letter from the alemtuzumab investigators to the FDA explaining the reasons for the trial design and the need for the drug. "Individuals from the FDA made this decision, but they cannot dispute the overriding nature of the results. I want this drug available for patients with aggressive MS," he commented.

Dr. Fox was a member of the international steering committee for the development program for alemtuzumab and an investigator in the phase 2 and both phase 3 trials of the drug. He says the steering committee included specialists from many different countries, and there was international consensus on the study design.

Dr. Krieger, who was a site principal investigator for the CARE-MS 2 trial, takes a similar view. "The FDA did request several times that Genzyme conduct the studies with a double-dummy design, but Genzyme set a higher bar of efficacy by using an active comparator and that in itself made a double-dummy design difficult. But why then did the FDA let them go ahead and give them fast track status for the drug approval process?"

The FDA concerns revolve around the fact that the patients were not blinded, Dr. Krieger explains. But he maintains this was accounted for by other factors. "There were blinded evaluators and there were regular assessments to make sure the evaluators remained blinded."

Dr. Cohen echoes these opinions. "The open design of the study was very vigorously discussed on the steering committee of the CARE-MS program, of which I was a member. The hypothetical concerns about bias are well known," he said.

"I have 2 disagreements with the FDA," Dr. Cohen added. "I don't think the double-dummy design would have been feasible as patients would know which drug they were on because of the side effects. And there was enough evidence presented to assuage the concerns about bias."

Dr. Krieger made the point that alemtuzumab is given as an infusion over a few days, whereas interferon β-1a (Rebif, EMD Serono/Pfizer) is administered as an injection 3 times a week, so a double-dummy trial would involve patients being given sham injections 3 times a week for the 2-year trial period or undergoing a sham infusion for several days, which he said was "impractical and unethical."

"Every single person knows what drug they are on, even with a double dummy," Dr. Fox agreed. "With all the effort involved to make a double dummy happen, it would have been a sham."

He further pointed out that most other MS drugs have been tested against placebo, which makes blinding easier. "Because of safety concerns with alemtuzumab, it was felt that the only way to justify its use was to compare with an active drug routinely used for MS. This is a higher standard than applied to any other MS drug, but it is this that has caused them problems because of the lack of blinding. But alemtuzumab is very clearly more effective than Rebif on reducing relapses, slowing disability, and reducing MS lesions on MRI."

Accessing the Drug From Canada or Europe?

Alemtuzumab is already approved in the European Union, Canada, and Australia, and additional marketing applications are under review by other regulatory agencies.

All 3 experts were also uncomfortable about the situation that may now arise, with alemtuzumab being available in Canada and Europe but not in the United States. They point out that this could lead to unsupervised use and big safety concerns.

Dr. Krieger commented: "It is highly likely that some patients will travel to Canada to get it. It is relatively easy to undergo the 2 single administrations 1 year apart in a different country, but the problem is that there won't be any safety programs set up in the US to monitor patients. This drug has some dangerous side effects. Patients need to be monitored closely. This won't happen if they get the drug abroad. This is a very risky situation."

"This was never going to be a medicine for everyone but it is a powerful product for those with the most active form of MS," he added. "And there is a big unmet need here. But these are not the patients I would choose to send to another country for treatment. These are the patients I would want to keep close."

Recent experience with the use of angioplasty to address chronic cerebrospinal venous insufficiency (CCSVI) in MS shows without a doubt that knowledgeable, motivated patients with MS have been known to take matters into their own hands. After the first studies relating to a possible link between CCSVI and MS came out, hundreds of patients used their own resources to fly to centers, sometimes in different countries, to obtain treatment despite the lack of data to support efficacy or safety, and issues with follow-up care once they returned.

One possible scenario now would be that MS centers in the United States may collaborate with hospitals in Canada or Europe and together offer a program under which, if a patient obtains alemtuzumab treatment in a country where it is available, they will undergo monitoring back home at the US hospital.

Dr. Cohen says he has discussed this very possibility. "That is not an ideal situation but it would be feasible if it is the only option," he added.

The National Multiple Sclerosis Society, which describes itself as a "collective of passionate individuals who want to do something about MS now," testified before the FDA advisory committee on alemtuzumab, addressing "the need for more therapeutic options for people with MS and the importance of empowering people with MS to make their own informed treatment decisions," the society notes in a statement reacting to the FDA's decision not to approve alemtuzumab.

"This is disappointing news, given the need for more therapeutic options for people with MS living in the United States," Timothy Coetzee, PhD, chief advocacy, services and research officer at the National Multiple Sclerosis Society, said in the statement.

"The Society will continue to monitor this process and update its constituents of any news," the release concludes.

Dr. Fox reports receiving consultancy fees, honoraria, travel, and research support from Genzyme; Dr. Krieger has served as a consultant and on advisory boards for Genzyme; and Dr. Cohen reports research support paid to his institution from Genzyme.

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Cite this: Alemtuzumab Investigators Protest FDA Decision - Medscape - Jan 16, 2014.