Fampridine May Improve Walking Ability in Some MS Patients
Treatment with fampridine (4-aminopyridine) in a sustained-release (SR) form generates hope for improving gait disorders in multiple sclerosis (MS), according to results of a phase 2 trial published online July 30 in Neurology ahead of print.
The multicenter, double-blind, randomized, placebo-controlled, parallel-group study failed to meet its primary endpoint — significant increase in walking speed on the Timed 25-Foot Walk test (T25FW) — and also failed to show significant improvement on seven of eight other predefined endpoints. However, fampridine significantly improved leg strength more than placebo.
“Currently, no therapies improve walking impairment in MS,” said the lead study author Andrew Goodman, MD, director of the MS Center at the University of Rochester in Rochester, NY. “Fampridine-SR could be an important new strategy to treat this aspect of the disease.”
The authors' optimism about the drug was based on a post-hoc analysis that used a definition of consistent response. “Our definition was someone whose walking speed for at least three visits during the double-blind treatment period was faster than the maximum speed measured in the five non-treatment visits [four before treatment and one at two weeks after],” he continued. “The visits before treatment provided a baseline, while the follow-up visit helped exclude participants who experienced unrelated improvement over time.”
In the responder analysis, walking speed improved by more than 25 percent over baseline during the treatment period, Dr. Goodman said.
Since submission of the report for a phase 2 study for publication in Neurology, two phase 3 trials started using the 10 mg twice daily dose of fampridine-SR, and the consistent responder definition was used prospectively to assess the benefits of fampridine. (The studies have not yet been published, but results of one trial were reported at the 2007 AAN annual meeting, and Dr. Goodman is presenting the second trial results this month in Montreal at the MS World Congress.)
ARTICLE IN BRIEF
Investigators reported that walking speed improved in patients taking fampridine over placebo in a post-hoc analysis.
MECHANISM OF ACTION
The drug's presumed mechanism as a potassium channel blocker in the CNS is to allow conduction of impulses through areas of myelin damage.
Fampridine-SR was developed to provide more sustained and safer drug levels, because of reports of occasional seizures and other side effects (such as paresthesia, nausea, and insomnia) encountered with the compounded and immediate-release formulations of 4-aminoypridine, Dr. Goodman explained.
The phase 2 study randomized 206 patients equally to four different groups: placebo, fampridine 10 mg twice daily, fampridine 15 mg twice daily, and fampridine 20 mg twice daily. The first two weeks of the double-blind phase included dose escalation for the latter two groups, followed by a 12-week, stable-dose phase. Participants — aged 18 to 70 years — completed two trials of the timed walking test in an average of eight to 60 seconds at screening.
People who had recent exacerbations of MS or changes in medication were excluded to minimize instabilities in MS symptoms during the trial. Dr. Goodman explained that these patient groups are “moving targets,” because it would not be clear whether improvement was the resolution of a relapse or from benefit of the drug. No significant differences were observed in the four treatment groups in baseline demographic or clinical characteristics. Compliance with study medication was more than 96 percent in all four groups.
All three fampridine treatment groups showed larger increases in walking speed than the placebo group, but these differences did not reach statistical significance. The Lower Extremity Manual Muscle Test (LEMMT) mean score improved for patients receiving twice daily doses of fampridine 10 mg and 15 mg, but not fampridine 20 mg twice daily, during the stable-dose period.
POST HOC RESPONDER ANALYSIS
Using the criterion of consistent improvement in walking speed, the response rate in the placebo group was 8.5 percent compared with twice daily fampridine 10 mg (35.3 percent), 15 mg (36 percent), and 20 mg (38.6 percent) groups. A consistent mean improvement of 25- to 29-percent in walking speed was observed in responders, while the mean change for placebo group on this measure did not exceed 4 percent at any visit.
Dr. Goodman said that the improvement in walking speed among famprimide responders was significantly greater than in the placebo group at every visit, for the pooled group and for each dose group considered individually.
The rates of adverse events in the 10-mg twice daily group were similar to those in the placebo group, but were higher in the 15- and 20-mg groups. No clear dose relationship was observed for most events, although each of the common adverse events were more frequent in fampridine-treated subjects than with placebo. Adverse events in more than 5 percent of fampridine patients included falls, asthenia, insomnia, headache, fatigue, urinary tract infection, dizziness, and nausea.
The drug was not discontinued because of adverse events in the 10-mg group. Seizures were the most worrisome adverse event, occurring in two participants in the 20-mg group. Dr. Goodman said that previous studies have reported seizures associated with high doses of fampridine, but exposures are too few to estimate the risk of seizures at the lower doses of fampridine.
In an accompanying editorial, Richard Kryscio, PhD, professor of statistics and chair of biostatistics at the University of Kentucky's Sanders-Brown Center On Aging in Lexington, questioned the validity of the post-hoc analysis in the phase 2 trial. “Is this a true positive finding or an example of data massaging?” he wrote.
When contacted by telephone, Dr. Kryscio learned about the two prospective phase 3 studies. “Hats off to the investigators for confirming the responder analysis prospectively,” he said. “I am looking forward to seeing these new results in print.”
He noted that it is unclear why responses were seen in more than one-third of patients in the phase 2 trial regardless of the dose used.
“This phase 2 study was disappointing because it was negative for virtually all of the associated outcomes. It is surprising that it is so difficult to demonstrate a benefit,” said Patricia K. Coyle, MD, who is Professor and Acting Chair of the Department of Neurology at SUNY at Stony Brook in Stony Brook, NY.
Fampridine is a symptomatic treatment rather than a disease-modifying drug, she continued. Neurologists have been using a compounded formulation of 4-aminopyridine for years and believe it benefits patients with MS. However, it has not been rigorously scientifically validated as an effective treatment in published studies.
“This study does not yet establish the benefits of fampridine-SR for MS. I look forward to reviewing the subsequent two prospective phase 3 studies mentioned by Dr. Goodman,” Dr. Coyle said.
Dr. Coyle suggested that heat-sensitive MS patients may derive a benefit from fampridine-SR. These patients experience symptom worsening when body temperature rises because nerve conduction fails, she said, and we would expect improvement from a drug that improves nerve conduction. •