Lenacapavir (LEN), a potent first-in-class inhibitor of capsid function, is in development for treatment and prevention of HIV-1. CALIBRATE is an ongoing, open-label, phase 2 study evaluating subcutaneous (SC) and oral LEN, in combination with other antiretrovirals, in treatment-naïve people with HIV-1 (PWH). At Week 28 (W28), LEN + emtricitabine/tenofovir alafenamide (F/TAF) led to high rates of virologic suppression (94%).
Participants were randomized (2:2:2:1) to 1 of 4 treatment groups (TG). TG1 and TG2 both received SC LEN + oral daily (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 bictegravir (B, BIC) (TG2). TG3 received oral QD LEN + F/TAF and TG4 received oral QD B/F/TAF throughout. We report the primary endpoint at W54. The study did not have prespecified formal statistical comparisons between TGs.
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 VL>100,000 c/mL. At W28 (as previously reported), 94%, 92%, 94%, and 100% had VL <50 c/mL by FDA Snapshot algorithm. At W54, 90%, 85%, 85%, and 92% had VL<50 c/mL; in TG1 to TG3 (i.e. those who received LEN), the majority of the remaining participants had discontinued study drug or achieved VL <50 c/mL later. Among those with VL <50 c/mL at W28 when starting the 2-drug maintenance regimen in TG1 and TG2, 94% and 92% had VL <50 c/mL at W54. For participants in TG1 to TG3, CD4 count increased by a median of 219 cells/µL (Q1, Q3: 102, 318) at W54 (vs 177 [30, 290] in TG4). No participant experienced a study drug-related serious adverse event (SAE). Three participants in TG2 discontinued LEN due to AEs of injection site reactions (ISRs) (Grade 1 induration, n=2; Grade 1 erythema/swelling, n=1). In TG1 and TG2 (i.e. those who received SC LEN), LEN-related ISRs included erythema (27%), swelling (23%), and pain (19%), which were mostly mild or moderate. In TG1 to TG3, the most frequent non-ISR AEs were headache and nausea (13% each).
LEN, given subcutaneously or orally in combination with TAF, BIC, or F/TAF, maintained high rates of virologic suppression at one year and was well-tolerated. These results support ongoing evaluation of LEN, as both injectable and oral formulations, in combination with other antiretroviral agents for the treatment of HIV-1 infection in individuals with diverse needs.