154. Pharmacokinetics and Safety of GS-1720 Following Multiple Ascending Doses in a Phase 1a Study in People Without HIV-1

Abstract Background Long-acting antiretrovirals for HIV-1 treatment may improve adherence by reducing treatment fatigue. GS-1720 is an oral integrase strand transfer inhibitor (INSTI) with potent anti-HIV-1 activity. Pharmacokinetics (PK) and safety of single ascending GS-1720 doses in participants without HIV-1 have been previously reported. Here, we report preliminary PK and safety of multiple ascending doses (MAD). Methods In this Phase 1a, randomized, blinded, placebo-controlled, multicohort study, oral GS-1720 or placebo (6:3/cohort) was administered under fasting conditions in 3 once-weekly (QW) and 2 once-daily (QD) MAD cohorts. Participants received 150, 450, or 1350 mg of GS-1720, or placebo, for 6 weeks or 450 or 900 mg of GS-1720, or placebo, for 7 or 14 days, respectively. Primary endpoints were plasma PK parameters (including AUC, Cmax, and accumulation ratios) and incidence of adverse events (AEs) and laboratory abnormalities. Participants were followed up to Day (D) 105. Results Overall, 45 participants were enrolled: median age, 29–40 years; 47% female. For QW doses of 150, 450, or 1350 mg at Week 6, respectively, mean (coefficient of variation [CV]%) Cmax was 19.9 (21.3), 39.6 (23.3), and 60.6 (25.8) μg/mL, and median (range) Tmax was 6 (4–8), 4 (3–4), and 4 (2–6) hours. Accumulation ratios ranged from 2.4–2.9 for AUC and 2.0–2.2 for Cmax. For QD doses of 450 and 900 mg at D7 and D14, respectively, mean (CV%) Cmax was 64.5 (13.6) and 126 (13.6) μg/mL, and median (range) Tmax was 4 (2–8) hours. Accumulation ratios were 5.3 and 6.8 for AUC and 4.2 and 5.4 for Cmax at D7 and D14, respectively. AEs related to GS-1720/placebo (blinded data) were reported in 12/45 participants (27%); most AEs (16/20; 80%) were Grade 1. One AE in the 450 mg QW cohort led to GS-1720/placebo discontinuation. Conclusion GS-1720 exhibits a PK and safety profile supportive of oral QW dosing. The data support the development of GS-1720 as part of a first INSTI-containing oral QW regimen. Disclosures Haeyoung Zhang, PharmD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ines Mendes, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Eva Mortensen, MD, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Hui Wang, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Aaron Share, B.Sc, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Monika Sobczyk, M.Sc, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ramesh Palaparthy, PhD, Gilead Sciences, Inc.: 1475-US-PSP, 1475-WO-PCT, 1474-US-PSP, 1515-US-PSP, 1515-WO-PCT|Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Dhananjay Marathe, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)