Antiviral activity, safety and PK/PD of ACC017 in antiretroviral naïve HIV‐infected adults: A randomized, double‐blind, placebo/dose‐parallel‐controlled short‐term monotherapy study

18 Background: ACC017 is a novel HIV-1 integrase strand transfer inhibitor (INSTI) with potent anti-HIV activity, an in vitro resistance profile different from those of other INSTIs and favourable preclinical safety and pharmacokinetic properties, to evaluate the antiviral activity, safety, pharmacokinetics and pharmacokinetics/pharmacodynamics of ACC017 as short-term monotherapy. Materials and methods: A two-phase design was in this study. In the first phase, antiretroviral-naïve HIV-infected adults were randomized to receive ACC017 (5, 40 or 80 mg) or placebo once daily for 10 days. The randomization ratio was 10:2 (ACC017:placebo) for each dose. The second phase consisted of an open-label combination therapy stage where all subjects continued receiving their originally assigned dose of ACC017 (5, 40 or 80 mg, with no placebo) in combination with FTC/TAF (200 mg/25 mg) for 18 days. Plasma samples were collected to measure HIV-1 RNA levels and evaluate ACC017 pharmacokinetic parameters. The primary outcomes were the log10 reduction in HIV-RNA from baseline on Day 11 and the proportion of participants with plasma HIV-RNA concentrations of less than 50 copies/mL at Day 29. Secondary outcomes included the assessment of ACC017 pharmacokinetics, immunologic changes, safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT06719310. Results: Thirty-six participants were enrolled (n = 12/group). Significant reductions in plasma HIV-RNA from baseline to Day 11 (24 h after the day 10 dose) were observed for all ACC017 dose groups compared with placebo (p < 0.001), with a mean decrease of 1.44–2.34 log10 copies/mL. A well characterized dose–response relationship was observed for viral load decrease. In addition, none of the participants had viral breakthrough. At Day 29, 86.11% (31/36) of the participants had HIV-RNA < 50 copies/mL. Increases in mean AUC0-24h, Cmax and C24h were slightly less than dose-proportional, with median Tmax of 2.53–3.50 h. Steady state was achieved after 3–4 days of once-daily dosing. At steady state, accumulation ratios (Day 10/Day 1) for AUC0-24h, Cmax, and C24h were 1.13–1.26. Plasma HIV-RNA reduction was best predicted by Cτ,ss using an Emax model. ACC017 showed an adverse event profile similar to placebo, and there were no study drug discontinuations due to adverse events. Conclusion: ACC017 demonstrated potent antiviral activity and good short-term tolerability in HIV-1 infected adults. Its pharmacokinetics in HIV-infected individuals were similar to those in uninfected individuals receiving similar doses in prior studies and showed a predictable pharmacokinetics/pharmacodynamics relationship, which supports once-daily dosing in initial treatment patients in future studies.