Fampridine Gets Committee Nod With Caveat: Must Study Lower Doses

FDA's Peripheral and Central Nervous System Drugs Advisory Committee recommended further studies of lower doses of Acorda's MS drug fampridine to reduce risk of seizure.

Acorda may have scored a nearly unanimous vote from the Peripheral and Central Nervous System Drugs Advisory Committee that its multiple sclerosis drug, fampridine SR, is effective, but it more than likely will be required to conduct additional trials on lower doses.

The committee voted 12-1 that fampridine (formerly Amaya) is effective for the proposed indication to improve mobility in patients with MS, but it also voted the 12-1 that Acorda should be required to evaluate lower doses in an attempt to decrease the drug's risk of seizures.

Committee members did not, however, go as so far to vote that Acorda must conduct those trials prior to FDA approval.

During the drug development process, the sponsor tested dosage strengths of 10 mg, 15 mg, 20 mg and 25 mg, all twice daily. While the risk of seizures increased as the dose level increased, there was not a similar increase in efficacy.

Acorda had been developing a 5 mg dose to test during trials, but there were issues with sustainability. The sponsor said during the meeting that it currently is working with Elan (its development partner) on a new 5 mg dose. FDA suggested it also look into developing and testing a 7.5 mg dose.

Novel Claim Meant Novel Endpoint, Concerns About Clinical Significance

The sought-after indication of improving walking ability in MS patients is a novel claim requiring a novel endpoint - which means there is no precedent for how best to assess the effectiveness. That issue came up for the panel, which had some concerns about the clinical meaningfulness of fampridine's effect.

To make up for the lack of precedent, Acorda used the Special Protocol Assessment process to work with FDA to design the two pivotal trials; the primary endpoint they came up with was responder status to a timed 25-foot walking test. A responder in the timed walk was defined as one whose walking speed on at least three of the four on-drug visits was faster than the fastest speed during any of the five off-drug visits.

While a statistically significant number of fampridine-treated patients were responders compared to those in the placebo arm, the magnitude of improvement was small and the clinical significance was uncertain.

For example, in the first pivotal study, 34.8 percent of the fampridine-treated patients qualified as responders compared to placebo-treated patient, of which 8.3 percent responded. However, at the end of two weeks of treatment, the fampridine group only walked 0.8 seconds faster compared to placebo. In addition, there was no difference between the treatment groups in patients' assessment of treatment effects on their physical well-being, according to a Subject Global Impression of Change assessment.

Because of this, both FDA and the committee struggled with weighing the proven effectiveness and the actual quality of life an MS patient would receive against the increased risk of seizures.

Panel Saw Potential For Safe Use, Reinforced By REMS

In the end, members listened to the pleas of those who spoke at the open public hearing, voting 10-2 (one abstention) that there are conditions under which fampridine could be considered safe.

"What I would say to my patients is: 'Well do you want to try and take this drug? You got a 1 in 3 chance of improving your walking speed and there is a risk you'll have a seizure if you take too much.' I think for the patients I attend to ... they'd all say yes," said Nathan Fountain, University of Virginia.

In an unofficial roundtable vote, members further defined its safe use, agreeing that fampridine should be used with caution in patients with mild renal insufficiency and should be contraindicated for patients with moderate to severe renal insufficiency, as well as patients with a history of seizures.

One recommendation to perform EEGs (electroencephalograms) on patients prior to therapy in an effort to curb the rates of seizures, was shot down by those familiar with the test, saying unless an EEG is run in patients with a history of seizures or epilepsy, it would be a waste of time.

Acorda, for its part, presented a Risk Evaluation and Mitigation Strategy aimed at preventing patients from taking higher doses than recommended. Key elements of the REMS include distribution through specialty pharmacies; a MedGuide; a communication plan that includes labeling, a dear prescriber letter, and ongoing health care provider education outreach; enhanced pharmacovigilence and frequent safety reporting to FDA; and ongoing evaluation to ensure effectiveness of the REMS.

The REMS proposal did help committee members to feel more secure about the drug. "I agree that there is a culture among patients that more is better, meaning they will take more and they will get more benefit," said Myla Goldman, University of Virginia. "In this instance, there is actually a mechanism that will help protect against this, and that is the REMS, which is something that is not common in MS."

FDA needs to make a quick turnaround with its decision if it expects to make fampridine's PDUFA date of Oct. 22. In a J.P. Morgan analyst note released during the meeting, Geoffrey Meacham noted that in contrast to the concerns aired before the panel review, the meeting was progressing as "quite favorable" for Acorda, and added that "we feel comfortable with a positive vote and approval now than we did after reading the briefing documents."

-Lauren Smith ([email protected])