153 – Proof-of-Concept Trial of Oral VH4011499 (VH-499), a New HIV-1 Capsid Inhibitor

Background

New long-acting antiretroviral therapy (ART) regimens are needed to expand treatment choices for people living with HIV-1. VH4011499 (VH-499) is a new HIV-1 capsid inhibitor in development as a long-acting antiretroviral agent for the treatment and prevention of HIV-1. Here, we present antiviral effect, pharmacokinetics, safety, and tolerability data for VH-499 from a proof-of-concept, phase 2a trial in people living with HIV-1.

Methods

This randomized, double-blind, placebo-controlled trial evaluated oral VH-499 monotherapy in adults naive to ART with HIV-1 RNA ≥3000 c/mL. In the 10-day monotherapy period, participants received oral VH-499 25, 100, or 250 mg or placebo on Day 1 (baseline) and Day 6. After the monotherapy period, participants initiated locally sourced, standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through Day 11. Secondary endpoints included pharmacokinetics, exposure-response relationships, safety, and tolerability.

Results

A total of 23 participants were enrolled (VH-499, n=20; placebo, n=3), 83% were assigned male at birth, 65% identified as White, and 65% identified as Hispanic or Latin American; median (range) age was 31 (18-62) years. Plasma HIV-1 RNA levels for all VH-499 dose groups declined from baseline through Day 11 (Figure). The 250 mg dose group had a greater mean (SD) maximum change in HIV-1 RNA (−2.2 [0.43] log₁₀ c/mL) than the 25 mg (−1.8 [0.51] log₁₀ c/mL) and 100 mg dose groups (−1.8 [0.45] log₁₀ c/mL). Increasing VH-499 exposures were associated with higher viral load declines. All adverse events (AEs) were grade 1 or 2 in severity, with no trends observed in types of AEs. Each drug-related AE was only reported once. No AEs leading to withdrawal, serious AEs, or deaths were reported. There were no clinically relevant changes in clinical laboratory parameters, electrocardiograms, or vital signs.

Conclusions

VH-499 monotherapy was well tolerated, had a favorable safety profile, and demonstrated highly potent antiviral activity in people living with HIV-1, with up to a mean maximum 2.2 log₁₀ c/mL reduction in HIV-1 RNA over 10 days. A VH-499 exposure-response relationship was established. These results support further development of VH-499 as part of a complete long-acting regimen for the treatment of HIV-1.

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