A GROUNDBREAKING Phase 1 study suggests that once-yearly intramuscular lenacapavir could be a promising option for HIV pre-exposure prophylaxis (PrEP), with sustained drug levels exceeding those seen with the approved twice-yearly subcutaneous formulation.
The open-label study enrolled 40 HIV-negative adults aged 18–55 years to assess the pharmacokinetics, safety, and tolerability of two intramuscular lenacapavir free acid formulations. Participants received a single 5,000 mg ventrogluteal injection of formulation 1 (5% ethanol) or formulation 2 (10% ethanol), and plasma concentrations were measured at prespecified time points over 56 weeks. Key pharmacokinetic parameters, including peak concentration, time to peak concentration, and drug exposure over one year, were compared with data from the Phase 3 PURPOSE 1 and PURPOSE 2 trials of twice-yearly subcutaneous lenacapavir. Safety and tolerability, including pain scores, were also assessed.
Both formulations achieved rapid absorption, with median time to peak concentration at 84.1 days (interquartile range [IQR]: 56.1–112.0) for formulation 1 and 69.9 days (IQR: 55.3–105.5) for formulation 2. The highest median drug concentrations reached 247.0 ng/mL (IQR: 184.0–346.0) for formulation 1 and 336.0 ng/mL (IQR: 233.5–474.3) for formulation 2—well above the 67.3 ng/mL (IQR: 46.8–91.4) observed with the twice-yearly subcutaneous formulation. At 52 weeks, median trough concentrations remained high at 57.0 ng/mL (IQR: 49.9–72.4) for formulation 1 and 65.6 ng/mL (IQR: 41.8–87.1) for formulation 2, exceeding the median 23.4 ng/mL (IQR: 15.7–34.3) for twice-yearly dosing at 26 weeks. Total drug exposure over one year was also higher for the intramuscular formulations.
The most common adverse event was mild injection-site pain, affecting 80% of formulation 1 recipients and 75% of formulation 2 recipients, typically resolving within a week and alleviated by pretreatment with ice.
These findings highlight the potential of once-yearly intramuscular lenacapavir for PrEP, offering a long-acting alternative that could improve adherence and reduce barriers to HIV prevention. Further studies will be needed to confirm its efficacy in larger populations.
Reference
Jogiraju V et al. Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study. Lancet. 2025; DOI:10.1016/S0140-6736(25)00405-2.
