FDA panel gives mixed message on Lemtrada

 
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PostPosted: Fri Nov 15, 2013 6:59 pm    Post subject: FDA panel gives mixed message on Lemtrada Reply with quote

From MedPage Today, November 13, 2013:

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FDA Panel Gives Mixed Message on Lemtrada


By Joyce Frieden, News Editor, MedPage Today

SILVER SPRING, Md. -- An FDA advisory committee voted overwhelmingly Wednesday that alemtuzumab (Lemtrada) has been shown to be adequately effective for the treatment of relapsing/remitting multiple sclerosis (MS).

However, that 12-6 vote by the Peripheral and Central Nervous System Drugs Advisory Committee was balanced by a separate vote -- 14-2, with two abstentions -- that Genzyme, the drug's sponsor, has not provided substantial evidence of improvement in disability. That vote came mainly from questions about inconsistent results in the two studies of the drug, as well as concerns about bias that may have been introduced into the study because of unblinding of patients and physicians to the treatment regimen.

Alemtuzumab, a monoclonal antibody targeting the CD52 protein, is already well-known in the oncology field as a leukemia drug, sold for many years under the name Campath. After studies indicated that it reduced MS relapses, Genzyme acquired rights to the drug. Last year, it halted commercial sales of Campath so that it could make alemtuzumab available exclusively as an MS treatment (although Genzyme is providing the drug free of charge to those leukemia patients who continue to do well on it).

In MS, the drug would be administered in two courses 1 year apart. Genzyme's two pivotal trials, CARE-MS-I and CARE-MS-II, both showed that the drug cut the annualized relapse rate in patients with relapsing-remitting MS by about 50% compared with beta-interferon (Rebif) treatment, one of two standard therapies for the condition (the other is glatiramer acetate, trade name Copaxone).

On the strength of these trials, the European Union approved alemtuzumab as an MS treatment in September.

FDA reviewers expressed many reservations about the drug. John Marler, MD, clinical reviewer for the FDA, said that the trials' design introduced a possibility of bias, most notably because the trials were unblinded for patients and physicians, and patients were able to find out whether they were assigned to the study drug before they began receiving treatment.

"A subject's knowledge of the treatment assignment could easily influence both the relapse and SAD [sustained accumulation of disability] primary outcomes because they are subjective inter-related patient-report measures," he said.

For example, patients who knew they were on the study drug might under-report relapses because they wanted to stay on the drug and continue getting its benefits; the study's consent form included a standard clause saying that if the patient's disease worsens during the study, they may be told they are being dropped from the study and that alternative treatment will be considered, he noted. Conversely, patients who knew they were on the comparator drug might over-report relapses in hopes of getting out of the study or being switched to alemtuzumab.

In addition, Marler was concerned that knowing the treatment assignment may have affected dropout rates. In one of the studies, 13% of patients in the interferon group dropped out before being treated, as compared with 2% of patients in each of the two alemtuzumab dosing groups.

Marler also noted that the results of MRI testing in the trials did not support the positive findings of reduced relapse rates, a finding that appeared to concern several committee members.

Clinical safety reviewer Evelyn Mentari, MD, outlined several serious adverse events that occurred during the trials. In the two controlled trials of the drug, 18.5% of patients in the alemtuzumab group experienced thyroid adverse events -- including hyperthyroidism, hypothyroidism, Basedow's disease, and autoimmune thyroiditis -- versus 5.4% of the interferon patients. If the extension trial is included, 22% of all alemtuzumab patients developed Graves' disease, compared with 1% of patients on interferon.

Other side effects Mentari mentioned included immune thrombocytopenia (occurring in 2% of all patients treated with alemtuzumab versus none of the patients on interferon) and pneumonitis (0.5% versus 0%). In addition, five cases of thyroid cancer occurred in female patients taking alemtuzumab who were seen at sites in the U.S., which is equivalent to a rate of 298 cases per 100,000 person-years. The Surveillance, Epidemiology, and End Results (SEER) database reports that thyroid cancer incidence among all U.S. females is 18 per 100,000 person-years, she noted.

"These safety concerns cannot be prevented by monitoring or prophylactic measures," Mentari concluded. "Because the post-marketing setting involves a broader range of patients and less structured monitoring, there may be an increased risk of serious and fatal outcomes."

On another question posed by the FDA, committee members seemed sympathetic to testimony from patients on the drug that the medication had made a big difference in their lives, and voted 17-0, with one abstention, that the many safety issues raised by FDA reviewers did not preclude FDA approval.

"There are potentially serious side effects but given the disease course, the patient should be able to decide what their risks are and determine for themselves" whether to take the drug, said panel member Michelle Mielke, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minn.

"The risks are really substantial but this is a really bad disease," said committee member Paul Rosenberg, MD, associate professor of geriatric psychiatry and neuropsychiatry at Johns Hopkins University.

The agency is not required to follow the advice of its advisory committees, though it often does.



The article can be seen here.
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