Background:
Lenacapavir (LEN), a potent first-in-class long-acting HIV-1 capsid inhibitor, is in development for treatment and prevention of HIV-1. CALIBRATE is an ongoing Phase 2 open-label active-controlled study evaluating subcutaneous (SC) and oral LEN, in combination with other antiretrovirals, in people with HIV-1 (PWH) who are initiating treatment. At the Week 54 (W54) primary endpoint, SC LEN every 6 months or oral LEN daily (QD) in combination with tenofovir alafenamide (TAF), bictegravir (BIC; B), or emtricitabine (F)/TAF, maintained high rates of virologic suppression (90%, 85%, 85%, respectively) and was generally well tolerated.
Methods:
Participants were randomized (2:2:2:1) to 1 of 4 treatment groups (TG). TG1 and TG2 both received SC LEN + oral QD F/TAF for 28 weeks, after which virologically suppressed participants continued a 2-drug maintenance regimen: SC LEN with QD TAF (TG1) or QD BIC (TG2). TG3 received oral QD LEN + F/TAF, and TG4 received oral QD B/F/TAF throughout. We report the secondary efficacy endpoint by FDA Snapshot algorithm and safety at W80. The study did not have prespecified formal statistical comparisons between TGs.
Results:
182 participants (7% female, 52% Black) were randomized and dosed (n=52, 53, 52, 25 in TG1 to TG4). Median age was 29 years; 15% had viral load (VL) >100,000 c/mL. At W28, 94%, 92%, 94%, and 100% had VL < 50 c/mL. At W80, 87%, 76%, 87%, and 92% had VL < 50 c/mL; most remaining participants had discontinued study drug for reasons other than efficacy or safety (e.g. lost to follow up, participant decision, investigator decision: TG1 [n=6, 11%], TG2 [n=9, 17%], TG3 [n=6, 11%]). By missing=excluded analysis, 98%, 100%, 98% and 96% had VL < 50 c/mL. For participants in TG1 to TG3, CD4 count increased by a median of 249 cells/µL (IQR 122, 384) at W80 (223 [92, 350] in TG4). No participant experienced a study drug-related serious adverse event (SAE). No participants discontinued LEN due to AEs after W54. In TG1 to TG3, the most frequent non-injection site reaction (ISR) AEs were headache (16%) and nausea (13%). LEN-related ISRs were mostly mild to moderate.
Conclusions:
LEN, given SC or orally in combination with TAF, BIC, or F/TAF, maintained high rates of virologic suppression through W80 and was well tolerated. These results support ongoing evaluation and further development of LEN in combination with other long-acting partner agents for the treatment of HIV-1 infection and support Gilead’s long-acting oral and injectable development program.