CROI 2025: Potential for once-yearly lenacapavir injections

An oral presentation by Renu Singh from Gilead Sciences included pharmacokinetic results using two new intramuscular (IM) formulations of lenacapavir designed to be given once-yearly. [1]

The IM formulations used higher concentrations of lenacapavir which is released more slowly from the drug depot formed near the site of the injection.

This was a phase 1 study using two 5 mL doses of each formulation, given once, in 20 HIV negative participants. Each group included 20 participants, with intensive PK drugs levels monitored over the first 36 hours and then with less frequent sampling out to week 56.

Both formulations produced significantly higher Cmax, Ctrough and AUC compared to the 6-monthly twice-yearly subcutaneous (SC) injections used in the PURPOSE studies. For example, median (IQR) observed Ctrough after 56 weeks was 50.7 ng/mL (36.6 to 73.7) and 55.9 ng/mL (43.2 to 83.3) with formulations 1 and 2, respectively, compared with 23.4 ng/mL (15.7 to 34.3) in PURPOSE 1 and 2 at week 26.

Both IM formulations took about 12 weeks to reach the highest plasma concentrations (Tmax) and although higher than achieved with the 6-monthly SC formulation, this remained three-fold lower than well-tolerated levels in early studies.

Safety and tolerability results were generally good with no grade 4 events and most side effects being grade 1 or 2. This included injection site reactions which were commonly reported and reduced using ice packs. There were no long-term injection site nodules.

There were eight discontinuations before week 56 (n=7 in Arm 1) but none were related to the study medication. However, as the study design only included one set of injections there are no data on whether participants would continue with annual dosing. However, the presenter also commented that a lower dose might be used for future studies.

The PURPOSE 1 and 2 studies already reported 100% and 96% efficacy as PrEP respectively, using 6-monthly SC injections.

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These exciting results show the potential for an annual formulation which will need to be studied in larger studies. This will also enable results based on more diverse participant characteristics including for inter-participant differences.

We also need to understand the pharmacokinetic tail, including after multiple injections, which might extend to several years, and was not discussed in the presentation or the published paper.

Many of the practical concerns about a very long half-life might relate to background prevalence of undiagnosed HIV in the populations where this is being used. This will in turn be affected by access to earlier versions of injectable PrEP.