ADS-5102 Aided Walking Speed in Select MS Patients in INROADS Trial
An extended-release formulation of amantadine, ADS-5102 was significantly more effective than a placebo at increasing walking speed in multiple sclerosis (MS) patients who had difficulty with this, particularly younger patients with a shorter disease course, the INROADS Phase 3 trial demonstrated.
Further clinical work on this investigative treatment, however, stopped in June 2020, after a comprehensive analysis of INROADS (NCT03436199) data showed that walking speed gains achieved in about 20% of trial participants were low in magnitude, below what was anticipated, its developer, Adamas Pharmaceuticals, announced.
The U.S. Food and Drug Administration also requested an additional Phase 3 trial to support ADS-5102’s approval, which Adamas decided not to pursue.
Trial findings were in the study “A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment,” published in the Multiple Sclerosis Journal.
Most individuals with MS develop mobility and walking impairments, and about half eventually become dependent on walking aids.
ADS-5102, marketed under the brand name Gocovri for Parkinson’s disease, is an extended-release formulation of amantadine. It was seen to improve walking speed in MS patients in a small proof-of-concept Phase 2 trial (NCT02471222).
Based on these data, the company launched INROADS to confirm its potential benefits in a larger group of adult MS patients with difficulty walking.
The 16-week trial evaluated two doses of ADS-5102 — 137 mg and 274 mg — taken orally once a day at bedtime against a placebo capsule.
The study consisted of a screening period, followed by four weeks in which all enrolled were given a placebo. Patients were then randomly assigned to one of the three study arms for 12 weeks, and those who completed the trial could enter an open-label extension and receive the higher ADS-5102 dose for up to one year.
A total of 558 patients entered the trial, and 473 completed it. More patients in the placebo arm stayed until its conclusion (93.5%), than did those randomized to ADS-5102 treatment (88.8% for the lower dose, and 71.9% for the higher dose).
Before entering INROADS, 72 participants had been previously treated with amantadine, and 293 with Ampyra (dalfampridine), the only medicine approved in the U.S. to aid walking in adults with MS.
INROADS’s main goal was to determine if more patients responded to ADS-5102 than to a placebo, with responses defined as a 20% or better increase in speed in the timed 25-foot walk test (T25FW), which measures how quickly a person can walk 25 feet.
Secondary measures included the Timed Up and Go (TUG) test of coordination and balance, the two-minute walk test, and the Multiple Sclerosis Walking Scale-12 (MSWS-12).
Overall, the mean age of participants was 54.4, with a majority being older than 55 and female (67.6%). During the screening period, almost all patients (95.5%) performed the T25FW in less than 26.5 seconds, and about half (55.6%) had an EDSS disability score of 6.0 or 6.5 — meaning they required at least one walking aid, such as a cane or crutch.
Results showed that significantly more patients on 274 mg ADS-5102 experienced a 20% or better improvement in their T25FW speed, compared with those on a placebo (21.1% vs. 11.3%). Of those who completed the study, the proportion of responders was 28.3% with high-dose treatment versus 11.9% with placebo.
An additional analysis showed that the proportion of patients meeting the T25FW goal was similar among those given ADS-5102 at 274 mg regardless of previous Ampyra use (20.0% users vs. 22.5% non-users), and similar among those on placebo (11.0% users vs. 11.6% non-users).
ADS-5102 was found to be more effective in women, patients younger than 55, those with lesser time since diagnosis, patients not using walking aids, and those with an EDSS score of 4 to 5.5, indicating an ability to walk without aid or rest for 100–500 meters (about 330 to 1,640 feet).
A statistically significant change in walking speed — of 0.12 feet per second — was seen in the T25FW test among people given high-dose ADS-5102 relative to placebo. But no significant differences were evident in the TUG assessment or the two-minute walk test.
Among patients given ADS-5102 at its 137 mg dose, the proportion of responders was 17.3%. The mean change in walking speed and the two-minute walk test were not significant relative to the placebo group. Means changes in MSWS-12 scores were small and similar across the different study groups.
“Although significant, the overall improvement in T25FW (0.12 ft/s over placebo) and the low magnitude of treatment differences for other secondary endpoints may seem of questionable clinical relevance,” the researchers wrote.
Adverse events (AEs) of swelling and dry mouth occurred in more than 10% of patients in either ADS-5102 dose group. Other AEs were mostly mild or moderate in severity. Severe treatment-emergent AEs were reported in 2.2% of the placebo group, 4.3% of those on 137 mg of ADS-5102, and 8.1% of the 274 mg group.
Side effects that led to study discontinuation were most frequently due to swelling, visual hallucinations, insomnia, tremor, or dry mouth, many of which occurred in the 274 mg dose group.
Serious AEs were reported by one placebo patient (0.5%), five (2.7%) on ADS-5102 at 137 mg, and 11 (5.9%) in the high-dose treatment group. Serious AEs that caused participants to leave the study included a heart attack, hallucinations, digestive problems, osteoarthritis (bone degeneration), renal cell carcinoma, and blurred vision.
All serious AEs leading to discontinuation, except hallucinations and blurred vision, were considered unrelated to ADS-5102. No deaths, and no relevant changes in vital signs or physical examination findings were reported.
“In conclusion, the INROADS trial met its primary endpoint, demonstrating that a higher proportion of participants achieved a clinically meaningful improvement in walking speed for 274 mg ADS-5102 compared with placebo,” the researchers wrote.
“Although overall responder rates were not large, the results suggest a role for 274 mg ADS-5102 to improve walking in certain patients with MS,” they added.
Adamas continued to give ADS-5102 at 274 mg to the 424 INROADS patients who entered its open-label extension trial (NCT03567057), until its completion in the spring.