FDA Advisory Committee Endorses Fingolimod for Relapsing-Remitting Multiple Sclerosis

June 11, 2010

June 11, 2010 — The US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory Committee has recommended approval for the novel oral agent fingolimod in the treatment of patients with relapsing-remitting multiple sclerosis (MS).

The highly anticipated drug is the first in a new class of disease-modifying agents called sphingosine 1 phosphate receptor modulators. Fingolimod's sponsor, Novartis, was seeking a new drug application for patients with MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

Novartis plans to market fingolimod as Gilena. If approved by the FDA, it will be the first oral agent for patients with MS, giving them a welcome alternative to currently available injectable therapies.

The committee spent hours discussing a long list of questions posed by the FDA but was unanimous in its decision to recommend fingolimod's approval.

Substantial Evidence

Eluen A. Yeh, MD, from the State University of New York at Buffalo, said she was convinced that Novartis had demonstrated substantial evidence of effectiveness for the new drug, adding "Looking at the data upside down and sideways and every other way that you've dissected it, it does appear to reduce relapse frequency and to me when I looked at the data, that was quite impressive."

She was echoed by James E. Udelson, MD, from Tufts University School of Medicine, Boston, Massachusetts, and 1 of 2 cardiologists on the advisory committee panel, who said he found the data "very compelling."

Most panel members expressed the opinion that fingolimod should be available as a first-line treatment.

Jason W. Todd, MD, a neurologist at Northeast Neurology in Concord, North Carolina, said he had a significant subset of patients who would never take an injection therapy. "I think this should be offered first line," he said.

"As a person with MS, I would very much like to have the opportunity to take this drug if I needed therapy with it, albeit with appropriate discussion of all the potential risks," said Judith E. Feinberg, MD, professor of medicine at the University of Cincinnati in Ohio. "I take care of plenty of people who take interferon and that's not a lovely drug either, so I think this should be available to patients, but they should understand that there are unknowns."

Lowest Effective Dose

The panel was also asked to weigh in on whether they thought Novartis should test a lower dose of fingolimod. Most panel members said Novartis should evaluate the effects of fingolimod at doses lower than 0.5 mg once daily, which was the dose used in the clinical trials that it presented to the FDA.

"If 0.5 mg is not the lowest effective dose, why should we accept this as the final answer on the dose for the patient," asked Donald S. Fong, MD, MPH, director of clinical trials research at Kaiser Permanente Southern California, Pasadena, California. "I think we should have scientific evidence that it's the lowest effective dose, and I think that we should be able to reassure our patients that we have asked the sponsor to provide us with evidence that it is the most effective dose."

Dr. Fong also raised the issue of health care costs in general. "From a societal perspective, I think that this drug has some side effects, and if it needs to be monitored, that places resource requirements on our health system. These are costs that the sponsor doesn't see, but these are costs that we as tax payers and as subscribers to insurance plans ultimately have to pay. I think we need to see the lowest effective dose."

First-Dose Effect

Safety concerns were paramount for the panel, and members spent a considerable time discussing how serious adverse events associated with fingolimod — including bradycardia and heart conduction abnormalities linked to receipt of the first dose, as well as macular edema and declining pulmonary function — should be monitored.

With regard to the cardiology effects, the panel felt that patients should be monitored while in the clinician's office after they have been given their first dose of fingolimod.

Dr. Udelson suggested that clinicians be educated about these effects. "I would like to see an education program for clinicians. I would worry that some clinicians seeing a 20 beat per minute, 25 beat per minute drop after the first dose might really be worried, so that patients wouldn't be denied a very efficacious therapy just because of a very expected pharmacodynamic first-dose effect."

The other cardiologist on the panel, Michael J. Domanski, MD, of the Uniformed Services Medical School, Bethesda, Maryland, suggested that patients be monitored when they receive their first dose because of the known effects of fingolimod on the conduction system.

"For now, until the drug is better understood in the postmarketing environment, if they were my patients I would monitor them," he noted. "I would hang on to them long enough to watch what happens to them with the first dose. They don't have to be in a hospital, but they could stay in a setting where you have an EKG [electrocardiogram] monitor."

Dr. Feinberg pointed out that the studies presented by Novartis were done in relatively healthy patients with no comorbidities, so she would feel more comfortable with recommendations to monitor all patients for adverse effects.

The patient representative on the panel, Cynthia Sitcov, from Arlington, Virginia, said she would want to being monitored for all adverse effects. "I have MS, and if I were to go on this drug, I absolutely would welcome getting monitored. To me it's a complete no-brainer."


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