Safety, Tolerability, and Pharmacokinetics of ALKS 8700, a Novel Oral Therapy for Relapsing-Remitting Multiple Sclerosis, in Healthy Subjects
Objectives: To evaluate the safety, tolerability, and pharmacokinetics following single oral administration of ALKS 8700 and its comparison to an approved drug product, dimethyl fumarate (DMF).
Methods: This Phase 1, randomized, double-blind, placebo-controlled study was conducted in 2 parts. Part 1 was a sequential, single-ascending dose design in healthy subjects with 7 cohorts. In each cohort, 6 subjects received a single oral dose of ALKS 8700 and 2 subjects received placebo (8 subjects/cohort). Part 2 was a 2-treatment, 2-period, cross-over design with a washout period of 7 days and 2 active treatment sequences. In each period, 6 subjects received a single dose of either ALKS 8700 or 240 mg DMF and 4 subjects received placebo.
Results: All randomized subjects completed the study. In Part 1, doses of ALKS 8700 ranging from 49 mg to 980 mg were evaluated. ALKS 8700 was not detected in plasma as a result of being rapidly converted to MMF. MMF exposure increased with increasing ALKS 8700 dose levels. The ALKS 8700 dose selected for Part 2 was 420 mg. The Cmax of MMF after treatment with ALKS 8700 was 34% lower than after treatment with DMF, while AUC was comparable between both treatments. The median lag time for absorption was longer in subjects treated with ALKS 8700 compared to DMF (1.5 hour vs. 0.5 hour, respectively). ALKS 8700 treatment resulted in less variability in MMF exposure than DMF. Throughout the study, all dose levels of ALKS 8700 were generally well tolerated. The most common adverse events (AEs) were flushing and gastrointestinal (GI)-related (for both ALKS 8700 and DMF); all AEs were mild or moderate in severity. In Part 2, the percentage of subjects with GI-related AEs was notably lower for ALKS 8700 (8.3%) compared to DMF (41.7%). No serious AEs or discontinuations due to AEs were observed.
Conclusions: ALKS 8700 treatment was well tolerated and provided MMF exposure comparable to DMF. Less variability in Cmax and AUC, and lower rates of GI-related AEs were observed following treatment with ALKS 8700 compared to DMF. The results of this study support further clinical investigation of ALKS 8700 for the treatment of RRMS.