Pharmacokinetics of a simplified subcutaneous lenacapavir regimen versus Phase 2/3 regimen

BACKGROUND: Lenacapavir (LEN) is a potent, first-in-class, HIV-1 capsid inhibitor currently in clinical development for HIV-1 infection treatment and prevention. The ongoing Phase 2/3 studies in people with HIV-1 uses every 6 months subcutaneous (SC) dosing injection with oral loading/lead-in (oral LEN 600 mg on Days 1 and 2, and oral LEN 300 mg on Day 8 followed by SC LEN 927 mg on Day 15 and every 6 months thereafter). While this Phase 2/3 regimen has been shown to be safe and effective, a more simplified regimen (oral LEN 600 mg on Days 1 and 2, with SC LEN 927 mg on Day 1 and every 6 months thereafter) can be more convenient. Our objective was to compare the pharmacokinetics (PK) of the simplified regimen with that of the Phase 2/3 regimen.
METHODS: 31 and 14 healthy participants received the Phase 2/3 regimen (Cohort 1) and the simplified regimen (Cohort 2), respectively, in a Phase 1 single subcutaneous dose study. Intensive LEN PK and safety through Day 196 were summarized. PK was evaluated using noncompartmental analysis.
RESULTS: LEN C_max (within ±8%) and AUC_{0-196 days} (within ±15%) were comparable between regimens. Mean LEN concentrations achieved the efficacy target (inhibitory quotient of 4 [IQ4] =15.5 ng/mL) rapidly and were maintained above IQ4 through the dosing interval. LEN was well tolerated with no Grade 3 or 4 adverse events (AEs), serious AEs or deaths reported. Most common AEs were injection site reactions.

CONCLUSIONS: LEN concentrations of the simplified regimen were generally comparable to those of the Phase 2/3 regimen. LEN concentrations reached efficacious target rapidly and were maintained through the dosing interval. These results suggest that the simplified regimen provides similar exposures to the Phase 2/3 regimen and can be utilized as a potential clinical regimen for treatment and prevention of HIV-1 infection.

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