ADS-5102 (amantadine) Extended Release Capsules in Multiple Sclerosis Patients with Walking Impairment: A Phase 2 Proof of Concept Study

Background: Walking impairment is common in MS patients and is a cause of disability and reduced quality of life. There is a need for additional therapies.

Objectives: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime to treat walking impairment in multiple sclerosis (MS) patients.

Methods: This randomized, double-blind, placebo-controlled, 4-week, proof-of-concept study (NCT02471222) was conducted at 14 clinical trial sites in the United States in MS patients with walking impairment (defined by a baseline Timed 25 Foot Walk (T25FW) between 8 to 45 seconds).  Patients were randomized 1:1 to placebo (pbo) or ADS-5102. The primary objective of this study was to evaluate the safety and tolerability of ADS-5102. Exploratory efficacy analyses included the percent change from baseline to Week 4 in the T25FW, Timed Up and Go (TUG), 2 Minute Walk Test (2MWT), and the Multiple Sclerosis Walking Scale-12 (MSWS-12). The T25FW test has previously been used as a basis for product approval in the United States and Europe. Study site training was conducted for all walking performance measures. 

Results: 60 patients were randomized (30 to ADS-5102 and 30 to pbo); 59 of whom were treated. The most frequent adverse events (AEs) (occurring in greater than 2 patients in the ADS-5102 group) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AE. One patient in the ADS-5102 group experienced a serious adverse event (SAE), suspected serotonin syndrome. Efficacy analyses were based on a pre-defined modified intent-to-treat population (n=56). An approximately 15 percent placebo-adjusted improvement in walking speed was seen in the T25FW test (p<0.05). An approximately 10 percent placebo-adjusted improvement in TUG was also observed. The other walking performance measures used in this trial were directionally consistent.

Conclusions: ADS-5102 was generally well tolerated in this study population. These data suggest an effect of ADS-5102 on walking speed. Further clinical development is warranted to confirm these observations.