Reports of eleven deaths through November 2011 in patients who were taking fingolimod (Gilenya), the first oral multiple sclerosis drug to be approved, have prompted health officials in the United States and Europe to launch safety investigations.
There is no evidence yet that the drug was responsible for the deaths, according to the US FDA.
The FDA approved fingolimod in September 2010 for patients who fail to respond to a beta-interferon or whose condition is rapidly deteriorating. The European Medicines Agency (EMA) followed suit last March.
Heart rhythm and electrical conductivity abnormalities are both recognized risks within the first six hours after initial dosing, and physician treatment instructions by both the FDA and EMA initially required monitoring patients for cardiac problems during that time frame. After the deaths were reported more comprehensive monitoring instructions were issued by the FDA. (See “FDA Updates Patient Monitoring Rules.”)
These rules now require that clinicians conduct an electrocardiogram before treatment on patients followed by continuous monitoring for the next six hours, including blood pressure and heart rate evaluations on the hour. Patients who continue to show any signs of bradycardia or conductivity problems after six hours must be closely monitored until their symptoms abate.
The FDA began its safety investigation after a 57-year-old man died suddenly after completing the requisite six hours of monitoring without incident after his first dose. He was however also taking metoprolol, a beta-blocker, and amlodipine, a calcium channel blocker, and the FDA's approved label for fingolimod cautions that patients taking these drugs have an increased risk of bradycardia or cardiac electrical conductivity problems.
Three other deaths have been due to sudden heart attacks, one from bradycardia, and the remaining six were from sudden unexplained death.
The EMA has also launched a safety investigation into the deaths, and Novartis Pharmaceuticals, the drug's manufacturer, is providing the agencies with adverse event data from its studies to help clarify any risk.
Sandy Walsh, an FDA spokeswoman, told Neurology Today in an e-mail that there is no evidence that the deaths were due to fingolimod.
“We have been in touch with the EMA about fingolimod and we are still evaluating all data relevant to this issue,” she wrote. “We have not made any determinations about what regulatory actions, if any, are necessary, and have not yet determined whether any new monitoring recommendations are necessary. The FDA will notify the public once our review is complete to communicate any recommendations or possible label changes.”
The agency “continues to believe that fingolimod provides an important health benefit when used as directed and recommends that health care professionals who prescribe the therapy follow the recommendations in the approved drug label.”
Two large phase 3, double-blind trials of patients with relapsing remitting MS — both published in 2010 in the same issue of the New England Journal of Medicine (NEJM) — reported on the efficacy of fingolimod. Investigators on the FREEDOMS (the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) trial found that the annualized rate of relapse was 0.18 for those taking 0.5 mg of fingolimod, 0.16 with 1.25 mg, compared with 0.40 for the placebo group. And the TRANSFORMS (Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) investigators reported that the annualized relapse rate was 0.16 in those who received 0.5 mg of fingolimod, 0.20 among those who took 1.25 mg of fingolimod compared with 0.33 in the interferon group.
But in a review paper about the therapy in the Jan. 26 NEJM, two neurologists from the Yale School of Medicine — Daniel Pelletier, MD, associate professor of neurology and diagnostic radiology and chief of the Multiple Sclerosis Center and Neuro-Immunology Division, and David A. Hafler, MD, the Gilbert H. Glaser Professor of Neurology and Professor of Immunobiology — noted there were two deaths reported during the TRANSFORMS trial, both in the group assigned to the higher-dose regimen. One patient developed a primary disseminated herpes zoster infection after the patient was exposed to chicken pox during the course of intravenous methylprednisolone treatment for an MS relapse and the second patient had herpes simplex encephalitis.
“It is not clear whether fingolimod contributed to the deaths, since both cases involved the use of glucocorticoids in the context of a clinical relapse; however, given the mechanism of action of fingolimod, it is highly plausible that these deaths were attributable to fingolimod therapy,” they wrote.
An estimated 30,000 patients worldwide received the drug from 2003 to December 2011, during clinical trials or after fingolimod was approved, and there have been 31 reported deaths from all causes to date, Novartis spokeswoman Julie Masow told Neurology Today in an e-mail.
“These have been attributed to many different causes, including complications of advanced multiple sclerosis, traffic accidents, drowning, suicides, infections and cardiovascular events, among others, and were communicated to the health authorities according to regulations, the rate of overall deaths and myocardial infarction deaths are in line with background rates in a comparable population,” she said.
“[Novartis] is communicating publicly all-cause mortality with the goal of eliminating any confusion and misinformation in the MS community at this time,” she said. “We remain confident in the benefit/risk profile of fingolimod, and will continue to collaborate with health authorities around the world in the interest of patient safety.”
‘PLAUSIBLE’ BUT UNCERTAIN LINKAGE
“I think a connection between the deaths and treatment with fingolimod is plausible but far from certain,” said Jeffrey A. Cohen, MD, professor of neurology at the Cleveland Clinic Neurologic Center, who has authored several studies on the risks and benefits of fingolimod, and was a lead investigator on the TRANSFORMS trial.
There was concern from the beginning that the drug can affect heart rate after the first dose. The studies found few symptomatic problems, but the patients in these trials were highly selected. “It's not surprising that this issue has emerged now that the drug has reached a larger patient population,” he told Neurology Today in a telephone interview.
However, he emphasized that the details on the deaths and their relationship to the drug “are still sketchy,” noting that the EMA also appeared to have “cherry-picked” the cases in question without any clear association that the deaths may have been caused by treatment.
At Cleveland Clinic, he noted, between 800 and 900 patients have received the drug without any problems.
“We tend to be very selective of patients and practice high vigilance for any cardiologic problems both before and after treatment. We do an electrocardiogram before patients are given the first dose, although not on the actual day they take the drug for the first time, and if we see any potential issues, they are referred to a cardiologist for a consult first to see if there are any abnormalities. Usually there is nothing, though.”
Dr. Cohen also said he is not convinced that continuous monitoring for the first six hours after an initial dose, as the EMA now recommends, would have prevented any of the deaths if, in fact, they might have been in any way associated with treatment.
“The bottom line is that more information is needed before we know how to monitor patients when they start fingolimod and as they continue therapy.”
A BIGGER PROBLEM
According to Fred Lublin, MD, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York City, the deaths highlight an even bigger problem.
“As therapies become more complex, we need better avenues of information about emerging side effects and risks, and right now we just are not getting it from the FDA or the manufacturers,” he told Neurology Today in a telephone interview.
“If you call the manufacturers, they say they can't give out any information without the FDA's approval, and the FDA says they need the manufacturer's approval. It's frustrating. We need better and more timely access to this information, but we aren't getting any.”
He noted that clinical trials of fingolimod raised the issue of the potential risk of heart problems in patients when first taking fingolimod.
“It seemed OK, but now it seems some information is lacking. I think that for patients currently taking it who are doing fine, we don't need to do anything yet, but it is hard to know at this stage. We just don't know enough to make any kind of informed decisions about the reported deaths.”
In response to Dr. Lublin's concerns, Lisa Kubaska, of the FDA Center for Drug Evaluation and Research, said product manufacturers are allowed to provide some information about emerging safety issues without prior FDA approval, but she noted that there were challenges with communicating new and emerging drug risks to health care professionals and the general public — a level of uncertainty about the risk, the consequences to how risk information is disseminated, and the steps that can be taken to mitigate the occurrence of the risk.
“The FDA remains committed to provide the public with timely, accurate, evidence-based safety information. In this particular case, the agency promptly issued a drug safety communication after the report of an MS patient who died within 24 hours of taking the first dose of the product and is actively reviewing the new safety information about fingolimod.”