Deborah Brauser

September 21, 2016

LONDON — Treatment with prolonged-release (PR) fampridine tablets (Fampyra, Biogen) improves not only walking speed in patients with multiple sclerosis (MS) but also mobility and functional measures, new research suggests. The drug is known as dalfampridine-extended release (Ampyra, Acorda Therapeutics) in the United States.

Although this potassium channel blocker has shown improvements in walking ability in past studies, the phase 3 ENHANCE trial is "the largest and longest randomized trial to date," the investigators say.

ENHANCE, with more than 600 patients with MS, showed that those who received PR-fampridine 10 mg twice daily had a "clinically significant" improvement on the MS walking Scale (MSWS-12) after 24 weeks compared with the participants who received matching placebo (the primary endpoint).

The fampridine group also showed greater improvements in transfer and walking speed, self-reported physical impact of MS, and, in subgroup analysis, upper-extremity function.

In addition, the safety profile "was consistent with that observed in other trials," said Jeremy Hobart, MD, Plymouth University Schools of Medicine and Plymouth Hospitals, United Kingdom, during a late-breaking news session here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016.

Dr Jeremy Hobart

"Our findings confirm and expand on the favorable risk-benefit profile established in prior pivotal trials" of the drug, he later told Medscape Medical News.

Session co-chair Hans-Peter Hartung, MD, professor and chair of the Department of Neurology at the Heinrich-Heine University in Dusseldorf, Germany, and director of the University's Klinik für Neurologie, agreed that the study corroborates past results.

"The population was shown to benefit in terms of walking from the active treatment," said Dr Hartung. "This was additional confirmation and tested the utility of this drug in patients who are in the middle range of disability."

Walking Dysfunction Affects 80% of Patients

Dr Hobart noted that roughly 80% of individuals with MS have some type of walking dysfunction.

"Studies show that before there's any demonstrable neurological impairment, gait analyses demonstrate impaired walking ability, which is a deeply challenging problem," he said.

The US Food and Drug Administration approved dalfampridine extended release for walking improvements in patients with MS back in 2010.

And while past research has demonstrated "consistent benefits" from the drug, "doubts have remained as to whether these are clinically meaningful benefits," said Dr Hobart.

"Also, the original studies were conducted over a relatively short period of time. Therefore, there have been some questions about the durability of the effect."

In ENHANCE, 636 patients with MS aged 18 to 70 years were enrolled at centers in 11 countries. After a 2-week screening period, all were randomly assigned to receive, for 24 weeks, fampridine-PR 10 mg twice a day (n = 317; 59% women; mean age, 49 years) or matching placebo (n = 319; 57% women; mean age, 48.8 years).

Inclusion criteria included a score of 4 to 7 on the Expanded Disability Status Scale (EDSS; group mean score, 5.48) and having progressive or relapsing MS for at least 3 months prior.

The primary outcome measure was a mean improvement score of 8 or greater on the MSWS-12 between baseline and end of treatment.

Secondary outcomes included score changes from baseline on the MS Impact Scale physical subscale and the Berg Balance Scale (BBS), improved upper-extremity function on the ABILHAND questionnaire, and improved speed on the Timed Up and Go (TUG) test.

"So there was a mixture of self-report and clinician-report measures," said Dr Hobart.

He added that BBS and ABILHAND baseline mean scores, at 41 and 85, respectively, "were high and well above the midpoint, towards the ceiling effect of the scale."

"Clear Delineation" Among the Groups

At the end of 24 weeks, 43.2% of the fampridine group vs 33.6% of the placebo group achieved at least an 8-point improvement on the MSWS-12 (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2 - 2.3; P = .006).

"This was the proportion of people who met the 8-point threshold for a clinically meaningful change," Dr Hobart explained. "In addition, there was a clear delineation and demarcation between the two groups."

TUG speed improvement of at least 15% was reached by significantly more of the fampridine patients than the placebo patients (43.4% vs 34.7%, respectively; P = .03). This equalled a 1.5 OR (95% CI, 1.0 - 2.1).

Those receiving the active treatment also had a greater mean improvement on the MS Impact Scale (least square mean [LSM] difference, –3.31; P < .001).

Although there were also greater mean changes in BBS and ABILHAND scores for the fampridine vs placebo groups, they were not statistically significant.

"I think this goes back to the high baseline scores. And it may represent a measurement effect rather than a true effect, which is supported by subgroup analyses," said Dr Hobart.

In the participants with an EDSS score of 6 or less, the LSM difference between treatment groups on the ABILHAND was a non-significant 0.10. However, in those with an EDSS greater than 6, the LSM difference was 3.05.

"Here you begin to see that the differences are detected in hand function, which is consistent with our clinical experience."

As for treatment-emergent adverse events (AEs), only 3 members of each group reported "any severe AE" and 18 and 13 members of the fampridine and placebo groups, respectively, reported an AE of any type.

"This brought us no new news from our previous phase 3 studies," said Dr Hobart, adding that each group had one death, "but neither was attributed to the medication."

Overall, "this was one of the only studies to use a priori threshold of clinical meaningfulness as the primary endpoint -- which I believe to be an important, albeit challenging, development for the work," he summarized.

"Pertinent Data"

After the session, Dr Hartung told Medscape Medical News that walking disability is always a great concern for patients with MS and an important factor governing their quality of life.

Plus, the evaluation of hand function was an interesting addition to the research.

"Any intervention that can enhance function is important to the patient, although this doesn't do anything to the underlying pathobiology of the disease," he said. "Still, the data are very pertinent."

Dr Hartung noted that in Germany, use of this drug is widespread and "it's known to have a benign safety profile," although initially it was hampered by a high price.

"When the drug went through evaluation by the GBA [Gemeinsamer Bundesausschuss], which is equivalent to NICE [National Institute for Health and Care Excellence] in the UK, the price had to be significantly reduced. But it's now frequently prescribed by neurologists for patients with both secondary and primary progressive MS with a disability [on the EDSS] of 3 to 6.5," he reported.

The study was funded by Biogen. Dr Hobart has received consulting/advisor fees, honoraria, and/or research support from Acorda, Biogen, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita. Dr Hartung has disclosed no relevant financial relationships.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Parallel Session 14: Late Breaking News, oral presentation 254. Presented September 17, 2016.

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