Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (Capella study)


BACKGROUND: Lenacapavir (LEN), a long-acting first-in-class HIV capsid inhibitor with full activity against multidrug-resistant mutants, is in clinical development. The ongoing Phase 2/3 Capella study in heavily treatment-experienced (HTE) people with HIV (PWH) failing their current regimen with multidrug-resistance achieved the primary endpoint demonstrating short term potent antiviral activity of LEN vs placebo during the 14-day functional monotherapy period.
METHODS: In the randomized cohort, participants were randomized (2:1) to add oral LEN or placebo to their failing regimen (600 mg on Day 1[D] and 2 and 300 mg on D8). At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg (Q6M); those on placebo started the oral lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, optimized background regimen (OBR) at D15. In the non-randomized cohort, participants started OBR concurrent with LEN (oral lead-in à SC). We report the secondary endpoint of Week 26 (W26) efficacy in the randomized cohort, and additional available efficacy and safety from both cohorts.
RESULTS: 72 participants enrolled: 36 in each cohort. Overall, 25% were female; 38% Black. Median age was 52 years; median CD4 count was 150 cells/"µL; mean HIV-1 RNA (VL) was 4.17 log10 c/mL. Resistance to '¥ 2 ARVs in each class was 99%(NRTIs), 97%(NNRTIs), 81%(PIs) and 69%(INSTIs). At W26 in the randomized cohort, 81%(29/36) had VL<50 c/mL via FDA-Snapshot algorithm. In participants with data through W26 from both cohorts, 79%(33/42) had VL<50 c/mL via missing=failure. Median CD4 count increased by 82 cells/"µL. Four randomized participants had emergent LEN resistance; 3 suppressed afterwards, one with OBR change and two without. Resistance analysis in non-randomized participants is ongoing. There were no study drug-related serious adverse events (AEs) or AEs leading to discontinuations. LEN-related ISRs occurred in 56% (40/72) and were mostly mild or moderate (38/40). Most common ISRs (>20%) were swelling (26%) and erythema (24%); both resolved within days.
CONCLUSIONS: Subcutaneous LEN in combination with OBR led to sustained virologic suppression in 81% of HTE PWH at W26. LEN was safe and well tolerated. These results support the ongoing evaluation of LEN for treatment and prevention of HIV-1 infection.