Proof-of-Concept Phase 2a Trial of VH4524184 (VH-184), an Emerging Third-Generation Integrase Strand Transfer Inhibitor With an Enhanced Resistance Profile.

BACKGROUND: VH4524184 (VH-184) is an emerging third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs being developed as a long-acting antiretroviral therapy (ART) for HIV-1. We present data from a proof-of-concept phase 2a trial of VH-184 in people with HIV-1. METHODS: This randomized, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults naive to ART with HIV-1 RNA ≥3000 copies/mL. Participants received oral VH-184 10, 50, or 300 mg or placebo on Days 1 (baseline), 4, and 7. On Day 10, participants initiated standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through Day 10. Secondary endpoints included safety, tolerability, exposure-response relationship, CD4+ cell effects, and treatment-emergent resistance. RESULTS: Of 22 participants enrolled (VH-184, n=19; placebo, n=3), 86% were male, 68% were White, and median age was 32 years. Mean maximum change from baseline through Day 10 in HIV-1 RNA was -1.17, -2.15, and -2.31 log10 copies/mL for VH-184 10, 50, and 300 mg, respectively. No adverse events (AEs) leading to withdrawal, treatment-emergent serious AEs, or deaths occurred. There were no clinically relevant changes in safety laboratory parameters, electrocardiograms, or vital signs. No VH-184 genotypic or phenotypic resistance was detected through Day 10. CONCLUSIONS: VH-184 monotherapy demonstrated rapid and potent antiviral activity and a favorable safety and tolerability profile. The established exposure-response model and efficacy and safety results support further development of VH-184 as the core agent in complete ART regimens for HIV-1 (ClinicalTrials.gov, NCT06214052).