Safety, Tolerability, and Pharmacodynamics of <scp>GS</scp> ‐4224 in Healthy Participants and Participants With Chronic Hepatitis B

BACKGROUND & AIMS: This Phase 1a/b clinical study evaluated the safety, tolerability, pharmacodynamics (PD) response, and antiviral activity of GS-4224, a first-in-class, programmed death-ligand 1 (PD-L1)-binding orally bioavailable small molecule. METHODS: Participants were randomised to single and multiple ascending doses (S/MAD) of GS-4224 or placebo-to-match (PTM). Healthy participants (HPs; 5 cohorts) received once-daily GS-4224 doses for 10 days, escalating from 20 to 1 000 mg. Participants with chronic hepatitis B (CHB; 5 cohorts) received once-daily GS-4224 100, 300, or 700 mg for 28 days. The primary objective was GS-4224 safety and tolerability. PD markers in peripheral blood cells and the mean change in hepatitis B surface antigen (HBsAg) were measured. RESULTS: Overall, 60 HPs and 42 participants with CHB received GS-4224, and 15 and 10 received PTM. There were no Grade ≥ 3 adverse events (AEs), serious AEs, or deaths among HPs. No participants with CHB experienced serious AEs or death. Grade ≥ 3 AEs occurred in 2 viremic participants (unrelated Grade 3 AE of acute exacerbation of hepatitis B [detected prior to GS-4224 dosing] leading to study discontinuation; related Grade 3 AE of increased alanine aminotransferase). PD-L1 receptor occupancy on cells with low PD-L1 expression was dose-dependent and peaked at 38% among HPs who received MAD of GS-4224 1 000 mg and 35% among participants with CHB who received MAD of GS-4224 700 mg. No changes in HBsAg levels were observed in participants with CHB who received GS-4224. CONCLUSIONS: In all participants, GS-4224 was generally safe and well tolerated; however, no antiviral effect was detected at the doses evaluated.