Gilead's Once-Yearly Lenacapavir Formulations Show Sustained Efficacy for HIV PrEP in Phase 1 Study
New pharmacokinetic data, shared by Moupali Das, MD, MPH, reveal long-lasting plasma concentrations, surpassing twice-yearly subcutaneous formulation for HIV prevention
At the CROI 2025, Moupali Das, MD, MPH, vice president of HIV prevention and virology pediatrics at Gilead Sciences, discussed new findings from a Phase 1 study investigating two formulations of once-yearly intramuscular (IM) lenacapavir for HIV pre-exposure prophylaxis (PrEP). These results, published simultaneously in The Lancet, present significant progress in the fight against HIV and could pave the way for a new class of long-acting prevention options.
Comparing Once-Yearly and Twice-Yearly Formulations of Lenacapavir
In the Phase 1 study, participants received a single dose of 5000 mg of either formulation 1 (with 5% ethanol) or formulation 2 (with 10% ethanol), administered via intramuscular injection. Both formulations demonstrated promising pharmacokinetic profiles, with concentrations of lenacapavir maintained at levels above the threshold associated with efficacy for over 56 weeks.
Das explained, “The bottom line is, the formulations compare quite well. The pharmacokinetics data show that these once-yearly formulations of lenacapavir last longer than 52 weeks—specifically, 56 weeks—and remain above the 95% effective concentration.”
Key results from the study included median trough concentrations at Week 52 of 57 ng/mL (for formulation 1) and 65.6 ng/mL (for formulation 2), both of which surpassed the median trough concentration observed in the twice-yearly subcutaneous (SC) formulation (23.4 ng/mL at Week 26 from previous PURPOSE trials). These results highlight that the once-yearly formulations not only last longer but also maintain higher plasma concentrations compared to the twice-yearly SC formulation.
The study confirmed that these high concentrations were sustained throughout the 56-week period. The median peak plasma concentration for formulation 1 was 247 ng/mL while formulation 2 had a higher peak at 336 ng/mL, which remained well above the highest concentration observed for the twice-yearly SC formulation (67.3 ng/mL).
Injection Site Reactions and Safety Profile
As with many injectables, injection site reactions are a key consideration in any clinical trial. In this study, the most common adverse event reported was injection-site pain, a result consistent with what has been seen with other long-acting injectable formulations. According to Das, “The most common side effect was injection-site pain, which is not surprising. In our study, 80% of people receiving formulation 1 and 75% with formulation 2 reported some pain at the injection site. It was mostly mild to moderate and resolved within a few days.”
Das also noted that pre-treatment with ice, a strategy proven useful in earlier studies with the twice-yearly SC formulation, helped reduce the pain associated with the injections. “Pre-treatment with ice, as we used in the PURPOSE trials, was effective in reducing injection-site pain, and we continued that in this study.”
The safety profile of the once-yearly formulations was consistent with what has been observed in prior lenacapavir studies. No severe adverse events or abnormal lab findings were reported, indicating that both formulations of lenacapavir were well tolerated.
Given the encouraging data from the Phase 1 study, Das outlined the next steps in the development of once-yearly lenacapavir for HIV PrEP. “We’re continuing to monitor plasma concentrations and safety, and we plan to initiate a Phase 3 trial later this year to determine which formulation we will pursue for further development,” Das explained. “These findings are very promising, and we are hopeful that once-yearly lenacapavir will eventually become a viable option for HIV prevention.”
Das emphasized that lenacapavir’s flexibility—offering potential formulations in daily oral, weekly oral, and long-acting injectable forms—could help address a variety of patient needs. “Lenacapavir is a unique molecule with multiple ways to be used in HIV prevention, from oral tablets to long-acting injectables,” she said. “We’re particularly excited by the potential of the once-yearly injectable, as it could address adherence challenges many individuals face with daily regimens or more frequent injectable options.”
“Many people face challenges when it comes to daily pills or even something more frequent like monthly injections,” Das said. “We’re hopeful that if the once-yearly formulation is approved, it will improve adherence, help people stay on PrEP, and ultimately reduce new HIV infections globally.”
Background of the Phase 1 Study
The Phase 1, open-label study included 40 healthy adult participants aged 18-55 years. Participants were divided into two groups, with one group receiving formulation 1 (5% ethanol) and the other receiving formulation 2 (10% ethanol). The study followed participants for up to 56 weeks, measuring plasma concentrations of lenacapavir at multiple time points, from baseline to Week 56. The pharmacokinetic parameters assessed included the area under the concentration-time curve (AUC), peak plasma concentration, and trough concentration (Ctrough).
The study's results were compared to data from the PURPOSE 1 and PURPOSE 2 Phase 3 trials, which evaluated twice-yearly subcutaneous lenacapavir for HIV prevention. As noted, the once-yearly IM formulations not only sustained higher concentrations for a longer period but also demonstrated safety and tolerability profiles in line with previous findings.
