C. H. Nelson, D. Gossage, S. West, A. Zari, S. Ramanathan; Gilead Sciences, Foster City, CA

BACKGROUND: GS-6637 is a prodrug of GS-548351, a reversible ALDH2 inhibitor, under clinical development as an aid for smoking cessation. The aim of this first-in-human study was to evaluate pharmacokinetics (PK), safety and food effect following GS-6637 dosing in healthy non-smokers and smokers.
METHODS: This was a double-blinded, randomized, placebo-controlled, single and multiple (for 10 days) oral dose-study. Healthy male and female non-smokers and smokers were enrolled sequentially in escalating dose cohorts (100 mg to 900 mg; n = 6 to 9 active, 2 to 3 placebo per cohort). GS-6637 was administered fasted, except for fed state dosing (high-fat meal) in food effect cohort. Serial blood and urine PK samples were collected up to 48 hrs post last dose. Safety evaluations were assessed by adverse events (AEs), clinical laboratory tests, vital signs, and ECG data.
RESULTS: GS-6637 was rapidly converted to its active form GS-548351 and was typically absent in plasma or urine. GS-548351 exhibited dose-proportional PK following single doses and slightly less than dose-proportional PK after multiple doses of GS-6637. There were no differences in GS-548351 PK between non-smokers and smokers. The median half-life of GS-548351 was 16.4 to 19.5 hrs across dose levels. There was a slight decrease in Cmax (23%) of GS-548351 when GS-6637 was administered in the fed state as compared to the fasted state that is unlikely to be clinically relevant. Most AEs were mild; 4 serious laboratory AEs (abnormal liver tests) were reported in 1 subject during the post-treatment follow-up.
CONCLUSION: GS-6637 single and multiple dosing was generally well-tolerated and can be dosed once-daily based on GS-548351 plasma half-life. The overall data support continued clinical development of GS-6637 as an aid for smoking cessation.