Introduction: This first-time-in-human study describes the pharmacokinetics, drug-drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor.

Methods: This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV administered orally as single ascending doses as powder-in-bottle (PiB; part 1) and tablet (part 3) formulations and as multiple ascending doses as PiB formulation dosed once daily for 14 days (part 2). Midazolam was used to evaluate the effect of VH-499 on cytochrome P450 3A (CYP3A) activity (part 2).

Results: Overall, 73 participants were included (VH-499, n = 56; placebo, n = 17). VH-499 plasma exposures were less than dose-proportional, with median time to maximum observed concentration of 8.0-12.0 h for the PiB formulation and 24.0 h for the tablet formulation. Geometric mean terminal half-life was 51.2-66.5 h (2-3 days). The tablet formulation resulted in 45-63% lower exposures compared with PiB. Concomitant midazolam administration after single and multiple VH-499 doses did not lead to clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-499 is not expected to inhibit or induce CYP3A4. VH-499 was well tolerated. Adverse event (AE) frequency was comparable between placebo and VH-499 groups. VH-499-related AEs were predominantly grade 1. No serious AEs across VH-499 groups, AEs leading to withdrawal from drug/study, or deaths occurred. There were no trends in vital signs, electrocardiograms, or laboratory hematology parameters and no clinically relevant changes in chemistry parameters.

Conclusion: First-time-in-human data further characterize the pharmacokinetics of orally administered VH-499 and provide support for development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment and prevention.

Clinical trial registration: ClinicalTrials.gov, NCT05393271.

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.

Background: The HIV-1 capsid inhibitor VH4011499 (VH-499) is currently in development as a long-acting antiretroviral agent for HIV-1. In a proof-ofconcept study, oral VH-499 demonstrated rapid and potent antiviral activity in people with HIV-1 and was well tolerated. Here we present safety and pharmacokinetics (PK) findings from a first-time-in-human study assessing the ultra-long-acting (ULA) potential of an injectable VH-499 formulation. Methods: In this double-blind (sponsor-unblinded) ongoing phase 1 study (NCT06724640), we randomized participants without HIV-1 to receive single ascending intramuscular (IM) or subcutaneous (SC) doses of VH-499 (100, 200, or 400 mg evaluated herein) or placebo. Safety and PK data were collected post-dose. Single-dose PK parameters using available data were evaluated by non-compartmental analyses. Results: Overall, 48 participants received VH-499 or placebo as an IM or SC injection (6 groups total, n=8 each). Median age was 36 years, 94% of participants were male, and 40% identified as non-White. Most adverse events (AEs) had a maximum grade of 1 or 2 in severity across all treatment groups. VH-499–related AEs were primarily injection site reactions (ISRs), most frequently injection site pain (27/36; 75%). Median overall ISR event duration ranged from 1 to 3 days across all groups. Frequency of VH-499–related ISRswas higher in SC vs IM groups (83%-100% vs 33%-83%). No participants withdrew for safety reasons. No serious AEs were reported. Based on preliminary PK analysis, median time to maximum VH-499 concentration (tmax) was approximately 7 to 18 days post-dose for IM; tmax was approximately 112 days post-dose for SC due to slower absorption (Figure). Maximum VH-499 concentrations were lower after SC administration compared with IM at all doses. Given the relatively flat VH-499 PK profile for both IM and SC routes, no terminal half-life could be identified based on available data, and longer-term PK data are required. Conclusions: Both IM and SC single-dose injections of VH-499 were well tolerated and demonstrated slower absorption through SC administration in people without HIV-1. These results suggest that the long-acting injectable VH-499 formulation has the potential to support ULA (ie, ≥4 months) dosing intervals, and either healthcare provider or self-administration could be feasible. Model-informed drug development approaches using emerging PK and safety data from this study will help to optimize the design of the future development of VH-499.