Long-Acting Injectable VH-499 Shows Favorable Safety and PK Profile in Early Study

VH4011499 (VH-499) is a next-generation HIV-1 capsid inhibitor being developed as a long-acting antiretroviral therapy, building on prior proof-of-concept data showing rapid and potent antiviral activity with oral dosing. New findings from an ongoing first-in-human phase 1 trial now evaluate the safety and pharmacokinetics of an injectable formulation designed to support long-acting (LA) dosing. In this randomized, double-blind (sponsor-unblinded) study, participants without HIV received single ascending doses of VH-499 administered either intramuscularly (IM) or subcutaneously (SC), with the goal of assessing tolerability and drug exposure over time.

Across six treatment groups, 65 participants received VH-499 or placebo, with a median age of 36 years and a demographically diverse cohort. Overall, VH-499 was well tolerated, with no serious adverse events or study withdrawals due to safety concerns. Most adverse events were mild to moderate, and treatment-related events were primarily injection site reactions, most commonly pain, which resolved within one to three days. Injection site reactions occurred more frequently with SC administration than IM, but remained transient and low grade across all dose levels.

Pharmacokinetic analyses revealed slower absorption following SC injection compared with IM, reflected by a longer time to maximum concentration and lower peak drug levels. Both routes showed relatively flat PK profiles, and a terminal half-life could not yet be determined, underscoring the need for longer-term follow-up. Importantly, the observed exposure patterns support the potential for dosing intervals of 6 months. Together, these results suggest that injectable VH-499 could offer a flexible, ultra-long-acting treatment option, with future development guided by model-informed approaches to optimize dosing and administration strategies.

Contagion spoke to Paul Benn, MB, ChB, FRCP, MFPM, HIV physician and early development lead for VH499, ViiV Healthcare, about the early, investigational compound.

Contagion: What do the safety and tolerability results from this study tell us about developing VH-499 as a long-acting injectable for HIV treatment?

Benn: We already know that VH-499 is highly potent and has been well tolerated in previous studies, both in people with HIV and in people without HIV. In this phase 1 study, we are evaluating a long-acting injectable formulation of VH-499 administered either subcutaneously (under the skin) or intramuscularly into the gluteal muscle.

From a systemic safety perspective, the results continue to show that VH-499 is very well tolerated, with no significant safety concerns observed across any of the individuals dosed to date. Because this is an injectable formulation, a key focus of the study has been local tolerability, specifically injection-site reactions.

Participants received single injections ranging from 100 to 1,200 mg across multiple cohorts, and local tolerability has been very encouraging. While injection-site reactions are expected with injectable therapies, about nine in ten participants experienced reactions that were predominantly mild (Grade 1) local pain. These reactions were generally short-lived, with a median duration of one to four days across cohorts. Overall, this favorable local tolerability profile supports continued development of VH-499 in future studies.

Contagion: As VH-499 is being developed long-acting injectable, What are the dosing intervals being studied?

Benn: Our aspiration is to develop a long-acting, 2-drug regimen that can be administered twice yearly. Based on the data we will present tomorrow from this study, the pharmacokinetic (PK) profile supports dosing intervals of up to, and including, 6 months.

These conclusions are primarily based on the intramuscular data, which show a half-life of approximately 11 weeks. The PK profile following subcutaneous administration appears flatter, with an expected longer half-life. While we do not yet have sufficient long-term data to fully characterize the subcutaneous half-life, the data available so far—together with the safety findings—support a six-month dosing interval.

We will continue the study to further evaluate whether dosing intervals beyond six months are feasible, but at this stage, we are confident that six-monthly administration is achievable.

Contagion: Can you talk about the therapy’s mechanism of action?

Benn: VH-499 is a novel HIV-1 capsid inhibitor with a mechanism of action similar to that of the approved capsid inhibitor lenacapavir. It has activity at both early and late stages of the HIV life cycle.

Its most potent effects occur early, where it inhibits pre-integration steps by blocking transport of the viral particle into the nucleus and preventing uncoating of the capsid core. In the later stage of the life cycle, VH-499 also disrupts capsid assembly, interfering with the formation of new viral particles and preventing them from infecting additional CD4 T cells.

Contagion: Are there any other takeaways or important points that you wanted to make about this therapy?

Benn: We’ve already discussed its high potency, but another important point to emphasize is that, based on the data available so far, VH-499 is predicted to cause few drug-drug interactions. It does not induce or inhibit CYP3A4, and therefore is unlikely to be associated with significant interaction risk.

As the population of people living with HIV continues to age and develop comorbidities that require multiple medications, having a long-acting regimen with a low potential for drug–drug interactions will be critically important for effective long-term management. This is a key additional attribute that we think is important for readers to understand.

The responses have been edited for clarity.