FDA Advisory Committee Recommends Approval for Fampridine in MS

Susan Jeffrey

October 22, 2009

October 22, 2009 — The US Food and Drug Administration (FDA)'s Peripheral and Central Nervous System Drugs Advisory Committee voted to support approval of a new drug application for fampridine sustained release (fampridine-SR; Amaya, Acorda Therapeutics Inc) 10 mg twice daily for the symptomatic improvement of walking ability in patients with multiple sclerosis (MS).

If approved, this will be a new indication never previously granted by the FDA, an FDA briefing document notes; currently approved MS drugs are indicated to decrease relapse rates or, in some cases, to prevent the accumulation of disability.

The committee voted 12 to 1 that clinical data on the 10-mg twice-daily dose of fampridine-SR demonstrated substantial evidence of effectiveness as a treatment to improve walking in MS patients, and 10 to 2, with 1 abstention, that the improvement is clinically meaningful and the drug can be safe for use.

Because of concerns about adverse effects, particularly seizures, and what they viewed as a narrow therapeutic window, the committee also recommended by a vote of 12 to 1 that the company be required to study doses lower than 10 mg, but also voted not to require these studies before approval. The company is currently developing a 5-mg dose.

A risk evaluation and mitigation strategy program providing healthcare professional and patient education for the appropriate use of fampridine-SR has been proposed by Acorda, the company noted in a statement.

The FDA had set today, October 22, 2009, as the date for the current fampridine Prescription Drug User Fee Act (PDUFA); the PDUFA date is the FDA's target date for completing its review of fampridine-SR. However, Acorda released a second statement today noting that the FDA had extended the PDUFA date to January 22, 2010. The FDA has the option to extend the PDUFA goal date when a sponsor submits a major amendment that provides a substantial amount of new data not previously reviewed by the FDA.

Conditions for Approval

Britt Anderson, MD, PhD, from the University of Waterloo, Ontario, Canada, and acting chair of the advisory committee, summed up the conditions for approval put forward during their discussion.

"It appears to be the consensus that patients with known seizure disorders or believed to be, for whatever reason, at risk for a seizure should not receive this medication," Dr. Anderson said. "[The] issue of renal impairment is an important one, with some difference in terms of how severe the renal impairment should be before it represents a contraindication to its employment."

Although they agreed that an electroencephalogram would not be sufficiently instructive in improving the risk–benefit discussion to be recommended, they did recommend that renal function testing including creatinine and a Cockcroft-Gault glomerular filtration rate (GFR) should be done before use of the drug to rule out preexisting severe renal insufficiency, which even the company agreed should be an exclusion for this drug.

At the suggestion of panelist Sidney M. Wolfe, MD, acting consumer representative on the FDA's Drug Safety and Risk Management Advisory Committee and well-known voice of the watchdog organization Public Citizen in Washington, DC, an additional straw poll was done at the end of the meeting to see whether the panel would also view moderate renal insufficiency (defined as a GFR of 30 – 50 mL/min/1.73m2) as an exclusion to use of this drug.

With the exception of 3 abstentions, panelists agreed with Jason W. Todd, MD, from the Summit Sleep Disorder Center in Winston-Salem, North Carolina, who said that in his view, he would not use the drug in those with moderate renal insufficiency, and "in milds, use with caution and follow the GFR, because renal function will change over time."

Dr. Wolfe was 1 of the nay votes on questions of efficacy of fampridine. He viewed the effect size on walking ability as small, depending on the measure used, and not clinically important.

In addition to the seizure concern, other adverse effects are seen with this drug, including higher rates of balance disorders, insomnia, and dizziness, "and other things that can be very troubling to patients," Dr. Wolfe said. "Even though those don't rise to the level of a seizure, those are on the downside, and are things that would presumably be experienced by people including the two thirds who don't benefit at all," he said. "And we do have this problem of not being able to evaluate at the beginning of the study [which patients] are going to be the responders."

Several panelists made the point, however, that not all MS patients respond to all MS drugs that are currently used. Nathan B. Fountain, MD, director of the Comprehensive Epilepsy Program at the University of Virginia in Charlottesville, thought the risk–benefit ratio as it can be understood to date should be presented to the patient to decide.

"I think for the patients that I have with MS, anyway, if I said, 'you have a 1 in 3 chance of improving your walking speed by 30%,' or if I said, 'well, some respond and some don't, and the average improvement is a 21% increase in walking speed,' I think they'd all say yes," Dr. Fountain said. "And I think if I projected myself to that situation I'd probably say yes, all presupposed on the idea that the risk of seizure doesn't appear to be substantially increased when you take it properly."

Pivotal Studies

Fampridine (also known as 4-aminopyridine) is a potassium channel blocker that has a long history of use in the United States, even though it was never approved by the FDA, according to the FDA briefing document. Before its investigational and off-label use in humans, 4-aminopyridine was been known primarily as a bird poison (trade names Avitrol 200 and Avitroland, classified by the US Environmental Protection Agency as a restricted-use pesticide) and as a research tool to characterize subtypes of potassium channels in bench research, the document notes.

On the basis of nonclinical evidence suggesting that the drug enhances action potential conduction in demyelinated nerve fibers, fampridine has been compounded in pharmacies and used off-label to improve walking in a number of neurological conditions for more than 20 years. "That off-label use was not based on substantial evidence from adequate and well controlled studies," the document notes.

Both pivotal studies of this new drug application met their primary endpoint and met the requirements of their special protocol assessments, the FDA briefing notes. Results on secondary analyses, however, gave inconsistent results and indicated a very limited effect on walking speed.

One of these phase 3 trials, for example, published in The Lancet in February 2009 and reported by Medscape Neurology at that time, showed that fampridine improved walking ability, regardless of MS type or of concomitant therapy, but the response was seen in only some patients, and the researchers were not able to identify any factors that predicted which patients would respond (Lancet. 2009;373:732–738).


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