Safety and efficacy of ADS-5102 (amantadine) extended release capsules to improve walking in multiple sclerosis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS). OBJECTIVE: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment. METHODS: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed. RESULTS: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE-suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed. CONCLUSION: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia.

BACKGROUND: Preclinical and clinical studies suggest amantadine immediate-release (IR) may reduce dyskinesia in Parkinson's disease (PD), although higher doses are associated with increased CNS adverse events (AEs). ADS-5102 is an extended release amantadine capsule formulation, designed for once-daily dosing at bedtime (qhs) to provide high concentrations upon waking and throughout the day, with lower concentrations in the evening. The pharmacokinetics (PK) of ADS-5102 were assessed in two phase I studies in healthy subjects, and a blinded, randomized phase II/III dose-finding study in PD patients. METHODS: The first phase I study assessed single ADS-5102 doses (68.5, 137, and 274 mg) in a crossover design, whereas the second phase I study evaluated ADS-5102 137 mg for 7 days followed by amantadine IR 81 mg twice daily (or reverse order). In the phase II/III double-blind study, PD patients with dyskinesia were randomized to ADS-5102 (210, 274, or 338 mg) or placebo for 8 weeks. RESULTS: Single ADS-5102 doses resulted in a slow initial rise in amantadine plasma concentration, with delayed time to maximum concentration (12-16 h). Amantadine plasma concentrations were higher in PD patients versus healthy volunteers. The steady-state profile of once-daily ADS-5102 was significantly different from that of twice-daily amantadine IR, such that the two formulations are not bioequivalent. PK modeling suggested the recommended daily ADS-5102 dosage (274 mg qhs) resulted in 1.4- to 2.0-fold higher amantadine plasma concentrations during the day versus amantadine IR. CONCLUSIONS: ADS-5102 can be administered once-daily qhs to achieve high amantadine plasma concentrations in the morning and throughout the day, when symptoms of dyskinesia occur.