Deborah Brauser

March 01, 2017

ORLANDO — An extended-release (ER) formulation of amantadine hydrochloride known as ADS-5102 (Adamas Pharmaceuticals) may be safe and effective for patients with walking impairment from multiple sclerosis (MS), according to new research.

The phase 2 proof-of-concept study, which included 60 participants, showed that those who received the ER capsules daily for 4 weeks had a 17% adjusted improvement in walking speed, which was greater than for those who received matching placebo.

The investigational drug group also had greater improvement in walking distance and functional mobility than the placebo group, although the differences were not statistically significant.

In addition, the drug was well tolerated (the primary outcome measure). Altogether, the data "warrant further development," note the researchers.

"The results even in this small study are exciting and very encouraging," principal investigator, Jeffrey Cohen, MD, director of the Mellon MS Center at the Cleveland Clinic, Ohio, told Medscape Medical News.

Dr Jeffrey Cohen

"The plan is to now take it to a more definitive trial," he said, adding that amantadine is a drug that most clinicians are already familiar with. "And in this new formulation, it shows great promise for improving walking ability."

Dr Cohen presented the findings here at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017.

"Important Target"

"Gait impairment is a very common manifestation of multiple sclerosis, and it's one of the most disabling symptoms, so it's an important target," said Dr Cohen.

"Currently, there's only one drug available that improves walking, and that's dalfampridine [Ampyra, Acorda]," he added. "It's effective but really only helpful in about a third of patients. So there's certainly an unmet need there."

Initial development of ADS-5102 was focused on treating levodopa-induced dyskinesia in patients with Parkinson's disease. In fact, a New Drug Application for this indication is under review at the US Food and Drug Administration. A Prescription Drug User Fee Act (PDUFA) date is set for August 24, 2017.

In addition, "there was some preliminary data that this particular compound of amantadine might be beneficial for treating MS. So this pilot study was to look for any suggestion of benefit on walking and to look at several aspects of mobility," reported Dr Cohen.

All the participants had impaired walking, defined as a score of 8 to 45 seconds at baseline on the timed 25-foot walk test (T25FW) and were aged 18 to 70 years. In addition, 78% had relapsing-remitting MS, 10% had progressive relapsing MS, and 12% had progressive MS.

They were randomly assigned 1:1 to receive at bedtime 340 mg of ADS-5102 (70.4% women; mean age, 53.3 years; mean of 11 years since MS diagnosis) or matching placebo (69% women; mean age, 52.3 years; mean of 13.8 years since diagnosis) for 4 weeks. They also continued their current MS medications.

The primary outcome measure was safety and tolerability, as assessed by treatment-related adverse events (AEs), study drug discontinuations, and laboratory tests.

Secondary measurements of efficacy included the MS Walking Scale-12, speed on the T25FW, endurance/distance on the 2-minute walk test, and mobility on the Timed Up and Go (TUG) test.

Walking Improvements

Results showed a 16.6% placebo-adjusted improvement on the T25FW for those receiving the study drug (P < .05). In addition, about 30% of the study drug group vs 17% of the placebo group had a change on the T25SFW of 20% or greater.

Walking speed worsened in 7% vs 41% of patients, respectively.

Those receiving the experimental formulation had a 3-second placebo-adjusted change on the TUG and a 5-meter improvement on the 2-minute walk test, but these comparisons weren't significant (P < .10 and P = .23, respectively).

On the MS Walking Scale-12, the mean total score decreased by a similar 8.4 and 8.2 in the treatment and placebo groups.

No effects were found on the measures of fatigue, depression, or cognitive function.

As for AEs, they were "consistent with the known safety profile of amantadine," write the investigators.

Of those receiving ADS-5102, 12 reported at least one treatment-related AE compared with 6 of those receiving placebo. Dry mouth (23.3% vs 3.4%, respectively), constipation (10% vs 6.9%), and insomnia (10% vs 3.4%) were most common. In addition, 5 treatment-related discontinuations occurred in the study drug group vs none in the placebo group.

The one serious AE, suspected serotonin syndrome, was reported in the ADS-5102 group.

"Most AEs were mild to moderate intensity," note the investigators. "No clinically significant findings were noted for safety laboratory parameters, vital signs, and physical examinations in either treatment group."

"This…study of ADS-5102 has generated encouraging data across several performance measures in multiple sclerosis patients," Rajiv Patni, MD, chief medical officer for Adamas, said in a release.

"If these data are confirmed in longer duration, controlled clinical trials, [it] may offer an additional treatment option for…patients experiencing impairments in walking ability," Dr Patni added.

Dr Cohen reported that a phase 3 trial is in the planning stages, with these same endpoints, as well as others. "There's no reason to think that this only works on walking; it may improve other symptoms of MS, so we'll probably explore those in a preliminary way."

Attempts Welcomed

"Walking impairment is one of the hallmark challenges that people with MS experience," ACTRIMS 2017 co-chair Andrew Goodman, MD, University of Rochester Medical Center, New York, commented to Medscape Medical News.

"When patients hear that they may have MS, one of the things they'll ask is, 'Am I going to be in a wheel chair?' It's what people worry about and is potentially one of the most devastating, physically and emotionally, aspects of MS," said Dr Goodman.

"So any attempts at trying to improve gait function are welcomed, especially because there's only one drug approved by the FDA for that indication."

Dr Goodman, who was not involved in this research, was an investigator in trials for dalfampridine.

"And yet, dalfampridine is effective in only a portion of people with MS. Obviously, any sort of addition to our ability to help people with MS walk better would be a great advance," he said.

"Perhaps it would be synergistic with the existing treatment or perhaps it would help people who are not helped as much as we would like or at all by dalfampridine," concluded Dr Goodman.

The study was funded by Adamas Pharmaceuticals. Dr Cohen is an advisor to Adamas and has received compensation from the company. Dr Goodman reports that he has been a consultant to Acorda.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017. Abstract P027. Presented February 24, 2017.

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