Antiviral Effect, Safety, and Tolerability of Oral VH4011499 (VH-499), a New HIV-1 Capsid Inhibitor: Proof-of-Concept Trial

Abstract Background Innovative HIV-1 therapies, especially those with infrequent dosing, are a promising approach to advance progress toward the UNAIDS goal of ending HIV-1 transmission. VH4011499 (VH-499) is a new capsid inhibitor in development as a long-acting antiretroviral agent for HIV-1 treatment. We present the antiviral effect, pharmacokinetics, safety, and tolerability of oral VH-499 from a proof-of-concept phase 2a trial in people with HIV-1. Methods The randomized, double-blind, placebo-controlled CINNAMON trial evaluated oral VH-499 monotherapy in adults naive to antiretroviral therapy (ART) with viremia. During a 10-day monotherapy period, participants received VH-499 25, 100, or 250 mg or placebo on Days 1 and 6. After monotherapy, participants initiated locally sourced standard-of-care ART starting on Day 11. The primary endpoint was maximum change from baseline in viral load through Day 11. Secondary endpoints included exposure-response relationship, safety, and tolerability. Results Twenty-three participants were enrolled (VH-499, n=20; placebo, n=3). Viral load decreased through Day 11 for all VH-499 dose groups (mean [SD] maximum decline: 25 mg, −1.8 [0.5]; 100 mg, −1.8 [0.5]; 250 mg, −2.2 [0.4]). Increasing VH-499 exposures were associated with greater viral load declines. Ninety-five percent (19/20) of participants had no emergent genotypic resistance-associated mutations. Adverse events (AEs) were mild or moderate in severity, and no serious AEs or AEs leading to withdrawal were reported. Conclusions VH-499 monotherapy demonstrated highly potent antiviral activity, was well tolerated, and had a favorable safety profile. These results support further development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment (ClinicalTrials.gov, NCT06039579).