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

Background: Long-acting antiretroviral therapy offers people with HIV-1 more convenient and sustainable treatment options, improving quality of life and adherence. VH4524184 (VH-184) is a third-generation integrase strand transfer inhibitor (INSTI) that has potent antiviral activity, long-acting potential and an enhanced in vitro resistance profile compared with second-generation INSTIs. Since VH-184 may be administered concomitantly with combined oral contraceptives (COCs), it is important to understand any clinically relevant drug–drug interactions. In this study, we assessed the impact of VH-184 on the pharmacokinetics (PK) of a common COC containing ethinyl estradiol (EE) and norethindrone acetate (NEA).

Material and Methods: We conducted a phase 1, open-label, single-sequence, 1-way study in female participants without HIV aged 18 to 45 years. Participants received once-daily oral EE 30 μg/NEA 1.5 mg alone (treatment period 1; Days 1–10) or with once-daily oral VH-184200 mg (treatment period 2; Days 11–20) after a 21-day run-in period of EE/NEA followed by a 7-day washout period. The primary endpoint was maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 to the end of the dosing interval (AUC₀-τ) for EE and NEA. Secondary endpoints included VH-184 PK parameters, safety and tolerability.

Results: Of the 26 participants enrolled, 20 completed the study. Five participants discontinued before treatment Period 1, and one participant withdrew after completing treatment Period 2 but before the follow-up visit. Geometric least squares mean ratios (90% CI) with vs. without VH-184 of Cmax and AUC₀-τ were 1.041 (0.974–1.112) and 1.107 (1.062–1.153) for EE, respectively, and 1.210 (1.133–1.293) and 1.234 (1.194–1.274) for NEA, respectively. Steady-state VH-184 concentrations were achieved in ~10 days, consistent with prior studies. Overall, 12 (46%) participants reported 16 treatment-emergent adverse events (TEAEs). The only TEAEs reported by >1 participant were headache (n = 3), abdominal pain (n = 2), fatigue (n = 2) and positive SARS-CoV-2 test (n = 2). All TEAEs had a maximum intensity of Grade 1. Five (19%) participants reported six drug-related TEAEs, none of which were reported by >1 participant. The four drug-related TEAEs reported during treatment period 2 were labelled events for EE/NEA and/or INSTIs. No TEAEs led to discontinuation during either treatment period. No serious AEs or deaths were reported. Five participants experienced asymptomatic Grade 1 or 2 transaminase elevations after treatment period 2 (Day 21). There were no clinically relevant changes in other laboratory parameters, electrocardiograms or vital signs.

Conclusions: VH-184 had no effect on the steady-state PK of EE after repeat oral administration with a common COC containing EE/NEA. A slight increase in NEA exposure was observed with VH-184 coadministration, which was not considered clinically significant. EE/NEA did not meaningfully affect the steady-state PK of VH-184. VH-184 combined with EE/NEA was well tolerated in female participants without HIV. These results indicate that VH-184 can be administered with COCs containing EE/NEA without impacting the efficacy of COCs or the PK of VH-184.

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