Background
Long-acting injectables may address barriers to HIV pre-exposure prophylaxis (PrEP), such as stigma and pill burden. In a Phase 3 trial in cisgender women, twice-yearly (Q6M) subcutaneous (SC) lenacapavir (LEN) (927 mg, in two 1.5 mL injections) was safe and 100% efficacious as PrEP, with high adherence among participants. We assessed the pharmacokinetics (PK) and safety of two once-yearly (Q12M) LEN formulations.
Methods
This ongoing, open-label study in healthy participants (n=20/cohort) evaluated the PK, safety, and tolerability of two intramuscular (IM) single-dose 500 mg/mL LEN free acid formulations: formulations 1 and 2. Intensive PK sampling occurred from Days 1–15, and single anytime PK samples were collected at prespecified times through Day 449. LEN plasma concentrations were quantified using a validated liquid chromatography–tandem mass spectrometry method. LEN PK parameters (maximum observed concentration [Cmax], trough concentration [Ctrough]) were estimated using non-compartmental analysis. Safety and tolerability, including participant-reported pain scores, were assessed throughout.
Results
Peak concentrations of LEN formulation 1 were achieved ~12 weeks (W) post dose with mean (coefficient of variation [CV]) Cmax of 290 ng/mL (61.4%) (Fig). After 12 months (M) (52W, n=13), mean (CV) Ctrough was 62.2 ng/mL (42.8%), and its lower bound 90% CI was 49.1 ng/mL, which were above the target concentration (mean Ctrough following Q6M SC LEN: 21.1 ng/mL [Jogiraju et al, AIDS 2022]). Preliminary PK data for LEN formulation 2 (40W) showed similar LEN concentrations; mean Ctrough and the lower bound 90% CI are expected to remain above target concentration after 12M. Adverse events (AEs), including injection-site reactions (ISRs), were similar between the two cohorts; most were mild or moderate in severity. The most common ISR was pain (75%); pain scores were similar between cohorts. Most reported mild pain, which resolved within 1 week of injection. Pretreatment for approximately 3-5 minutes with an ice pack substantially reduced pain.
Conclusions
Following administration of IM LEN formulation 1, mean Ctrough after 12M was above mean SC LEN Q6M Ctrough, confirming the potential of Q12M dosing. Comparison with LEN Q6M Phase 3 PrEP will be conducted as PK data become available. Both formulations of Q12M LEN were safe and well tolerated. These data support future development of IM Q12M LEN for HIV PrEP, which has the potential to significantly improve PrEP uptake and persistence.
Table or Figure
