Once a year, it can be called a “mini” HIV vaccine, right?

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New findings from a phase 1 study investigating two formulations of once-yearly intramuscular (IM) lenacapvir for HIV preoperative prophylaxis (PrEP) were discussed at the 2025 Conference on Retroviruses and Opportunistic Infections. The results, published simultaneously in The Lancet, represent a major advance in the fight against HIV and could open new avenues for long-term prevention.

Comparison of once-yearly and twice-yearly formulations of lenacapvir

In the Phase 1 study, participants received a single dose of 5,000 mg of either the first formulation (containing 5% ethanol) or the second formulation (containing 10% ethanol) by intramuscular injection. Both formulations showed encouraging pharmacokinetic profiles, with lenacapavir concentrations remaining above the threshold associated with efficacy for more than 56 weeks.

Overall, the two formulations compare very well. The pharmacokinetic data showed that the once-yearly lenacapvir formulation lasted for more than 52 weeks, specifically 56 weeks, and consistently maintained above 95% effective concentrations.

Key results from the study included median trough concentrations at Week 52 of 57 ng/mL for the first formulation and 65.6 ng/mL for the second formulation, both exceeding the median trough concentrations of 23.4 ng/mL observed with the previously twice-yearly subcutaneous (SC) formulation at Week 26. These results suggest that the once-yearly formulations not only last longer, but also maintain higher plasma concentrations compared to the twice-yearly SC formulations.

The study confirmed that these high concentrations remained stable over 56 weeks. The median peak plasma concentration was 247 ng/mL for the first formulation, while the second formulation had a higher peak of 336 ng/mL, which is much higher than the highest concentration observed with the twice-yearly SC formulation (67.3 ng/mL).

Injection Site Reactions and Safety Profile

As with many injectable drugs, injection site reactions are a key consideration in any clinical trial. In this study, the most common adverse event reported was injection site pain, which is consistent with results for other long-acting injectable formulations. “Not surprisingly, the most common side effect was injection site pain,” said Das. “In our study, 80% of participants who received the first formulation and 75% of those who received the second formulation reported injection site pain. This pain was mostly mild to moderate and resolved within a few days.”

Das also noted that pre-treatment with ice prior to injection, a strategy that has been shown to be useful in previous studies of the twice-yearly SC formulation, helps reduce pain associated with injections. “Pre-treatment with ice prior to injection, as we used in the PURPOSE trial, was effective in reducing injection site pain, and we continued this approach in this study.”

The safety profile of the once-yearly formulation was consistent with that observed in previous studies of lenacapvir. No serious adverse events or abnormal laboratory test results were reported, indicating that both formulations were well tolerated.

Given the encouraging data from the Phase 1 study, Das outlined the next steps in the development of once-yearly lenacapvir for HIV PrEP. “We continue to monitor plasma concentrations and safety and plan to initiate a Phase 3 trial later this year to determine which formulation we will develop further,” Das explained. “These findings are very promising, and we are hopeful that once-yearly lenacapvir will eventually become a viable option for HIV prevention.”

Das emphasized that the flexibility of lenacapasvir—offering potential daily oral, weekly oral, and long-acting injectable formulations—helps meet the needs of different patients. “Lenacapasvir is a unique molecule with multiple delivery options for HIV prevention, from oral tablets to long-acting injectables,” she said. “We are particularly excited about the potential for a once-yearly injectable formulation because it could address the adherence challenges many people face with daily regimens or more frequent injection options.”

“Many people face challenges with more frequent treatments such as daily pills or even monthly injections,” Das said. “We hope that if a once-yearly formulation is approved, it will improve adherence, help people stay on PrEP, and ultimately reduce new HIV infections worldwide.”

Phase 1 Study Background

This Phase 1, open-label study included 40 healthy adult participants aged 18-55 years. Participants were divided into two groups, one receiving the first formulation (5% ethanol) and the other receiving the second formulation (10% ethanol). Participants were followed up for up to 56 weeks, and plasma concentrations of lenacapavir were measured at multiple time points from baseline to week 56. The pharmacokinetic parameters evaluated included the area under the curve (AUC), peak plasma concentration, and trough concentration (Ctrough).

The study results were compared with data from the Phase 3 PURPOSE 1 and PURPOSE 2 trials, which evaluated twice-yearly subcutaneous nacapasvir for HIV prevention. As previously reported, the once-yearly IM formulation not only maintained higher concentrations for a longer period of time, but also showed a safety and tolerability profile consistent with previous findings.

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Posted to: News

March 17, 2025

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