Background
VH4524184 (VH-184) is a third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs. Previously, oral VH-184 demonstrated potent antiviral activity in people with HIV-1 in a proof-of-concept study. Here, we present results from the first-time-in-human study of injectable formulations in adults without HIV to assess the long-acting potential of VH-184.
Methods
In this ongoing phase 1, double-blind, placebo-controlled, randomized study (ClinicalTrials.gov, NCT06310551), we are evaluating the safety, tolerability, and pharmacokinetics (PK) of parenterally administered VH-184 in adults without HIV for up to 52 weeks. PK data were collected after subcutaneous (SC) or intramuscular (IM) administration of escalating doses of VH-184 formulations. Observed PK data were integrated into a population PK (PopPK) model to simulate multiple dosing regimens including monthly (Q1M), every 2 months (Q2M), and every 6 months (Q6M).
Results
In the first 7 study cohorts, 39 participants (33 male) received a single dose of 1 of 2 formulations (A and B) under evaluation. The majority of injection site reactions (ISRs) were grade 1, with fewer grade 2 ISRs and 2 grade 3 ISRs. The most common ISRs were erythema, pain, and nodules. Formulation A reached maximum plasma concentration (Cmax) a median of 3 days after SC or IM injection, and terminal half-life after SC dosing was a median of 7 weeks. Formulation B showed a wider range of time to reach Cmax due to slow absorption and maintained a flat PK profile through Month 7; thus, terminal half-life has not been defined. The PopPK analysis adequately characterized the observed PK profile for both formulations, and simulation results suggest that VH-184 long-acting injectable (LAI) formulations may maintain VH-184 PK above clinically effective concentrations with Q1M or Q2M dosing for formulation A and Q6M dosing for formulation B.
Conclusions
VH-184 LAI formulations were well tolerated and demonstrated a favorable PK profile, with both formulations showing an extended half-life, supporting long-acting dosing. The emerging safety profile of VH-184 is similar to that of marketed INSTIs. Data from the ongoing study and the PopPK model will be used to further optimize dosing regimens and inform the phase 2b LAI VH-184 study design.
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