Background:
Lenacapavir (LEN) is a potent first-in-class capsid inhibitor in development for the treatment and prevention of HIV-1 infection. Current data indicates that LEN exhibits near maximal antiviral activity when the lower bound of the 90% confidence interval (CI) of mean Ctrough is maintained above inhibitory quotient 4 (IQ4) (at least 4-fold greater than the in vitro protein adjusted 95% effective concentration). In ongoing Phase 2/3 studies, people with HIV-1 (PWH) received 2 weeks of oral LEN loading prior to starting every 6 month (q6m) subcutaneous (SC) dosing on Day 15. The objective of this analysis was to simulate scenarios to assess the impact of potential shifts (advancement or delays) in q6m dosing on Ctrough to allow flexibility in dosing window for LEN SC injection.
Methods:
A previously developed 2-compartment LEN PopPK model with first-order absorption and linear elimination based on data from Phase 1-3 studies was utilized to simulate LEN concentrations. Various scenarios for second SC dose were simulated to evaluate the forgiveness window.
Results:
Following oral lead-in and SC maintenance, simulated LEN concentrations at 26 weeks after last SC injection were 29.2 ng/mL corresponding to a mean IQ of 7.5 with 90% CI of IQ 6.3-8.4. Similarly, at 24 weeks after last SC dose LEN concentrations were 34.6 ng/mL (mean IQ of 8.9 with 90% CI 7.5-9.9) and at 28 weeks after last SC dose, LEN concentrations were 24.5 ng/mL (mean IQ of 6.3 with 90% CI 5.2-7.0) as shown in Figure 1. If the maintenance SC dose is administered 2 weeks earlier than the planned 26-week dosing interval (i.e., Week 24), LEN concentrations (upper bound of 90% CI was 38.5 ng/mL) are predicted to remain within a range that can be supported with existing safety data. If SC dose is administered 2 weeks later (i.e., Week 28), LEN concentration (lower bound 90% CI was 20.4 ng/mL) were above IQ 5.2, providing a dosing window of ±2 weeks after last SC dose. For participants who cannot receive SC LEN within this window, i.e., participants whose dosing falls beyond the 28-week window, restart of oral LEN loading followed by SC LEN is recommended.
Conclusions:
In administering SC LEN every 6 months, a 4-week dosing window (±2 weeks around the scheduled injection) is adequate to maintain safe and efficacious exposure.
Simulated Lenacapavir Ctrough on Weeks 24 to 32 in Adult People With HIV Who Received the Phase 2/3 Dosing Regimen 