Phase 1 Evaluation of VH4524184, a Third-Generation Integrase Strand Transfer Inhibitor With an Enhanced Resistance Profile

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) have been fundamental to HIV-1 treatment for over 15 years. VH4524184 (VH-184) is a third-generation INSTI with long-acting potential currently in development for HIV-1 treatment. METHODS: This double-blind, randomized, placebo-controlled, phase 1, first-time-in-human (FTIH) study evaluated oral VH-184 in adults without HIV-1 administered as single ascending doses (10-460 mg; part 1), multiple ascending doses (160-480 mg) for 14 days with concomitant midazolam (480 mg cohort; part 2), and as a single dose (100 mg) under fasted/fed conditions (part 3) to assess safety, tolerability, and pharmacokinetics. VH-184 resistance was evaluated in vitro against pseudotyped viruses containing participant-derived integrase sequences from the SAILING and DAWNING studies that conferred reduced susceptibility to second-generation INSTIs. RESULTS: Eighty-four participants (VH-184, n=63; placebo, n=21) were included in the FTIH study. VH-184 demonstrated a good safety and tolerability profile. Dose-proportional increases in exposures were observed after single doses of 10 to 300 mg, without further increase after 460-mg single or 480-mg multiple doses. Geometric mean half-life was ∼24 hours. Observed accumulation in exposures ranged from 1.3- to 1.9-fold after repeat VH-184 dosing of 480 and 160 mg, respectively. VH-184 had minimal impact on the pharmacokinetics of CYP3A substrates and exhibited a moderate positive food effect. The in vitro resistance profile of VH-184 was enhanced compared with prior INSTIs, retaining antiviral activity against second-generation INSTI-resistant pseudotyped viruses. CONCLUSIONS: These data support the safety and further development of VH-184 as a third-generation INSTI with long-acting potential for HIV-1 treatment (ClinicalTrials.gov, NCT05631704).