Lenacapavir (LEN, GS-6207), the long-acting first-in-class HIV capsid inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. With its novel mechanism of action, LEN is fully active in vitro against HIV-1 strains resistant to the major antiretroviral (ARV) classes.
We conducted a Phase 2/3, randomized, double-blind, placebo (PBO)-controlled study in heavily treatment-experienced (HTE) people with HIV (PWH) failing their current regimen with HIV-1 RNA (VL) ? 400 c/mL and documented resistance to ? 2 agents from ? 3 of the 4 major ARV classes. Participants were randomized (2:1) to add LEN or PBO to their failing regimen for 2 weeks. During this functional monotherapy period, LEN or PBO was given orally (600 mg on Day [D] 1 and 2 and 300 mg on D8). The primary efficacy endpoint was the proportion of participants with at least 0.5 log10 c/mL decline in VL by D15. At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg (q6month), while those on PBO started the LEN 2-week oral lead-in, followed by q6month SC. All participants initiated an investigator-selected, optimized background regimen (OBR) at D15. Here we report complete data for the functional monotherapy period and preliminary data for the LEN+OBR period.
36 participants were randomized: 28% were female and 46% Black. Median age was 54 years. Mean baseline VL was 4.27 log10 c/mL. At D15, 88% of participants on LEN (21 of 24) had at least 0.5 log10 c/mL decline compared to 17% on PBO (2 of 12) (difference: 71%, 95% CI 35 to 90%, p<0.0001). The median (range) change in VL (log10 c/mL) was -2.00 (-3.29 to -0.29) vs -0.08 (-1.93 to 0.31). During the LEN + OBR period at 4 weeks after SC dosing, 58% (21 of 36) had VL <50 c/mL. One participant with no fully active agent in OBR had emergent resistance to LEN but later re-suppressed while on LEN after adding TAF. The median (range) duration of follow up on LEN was 26 (7-46) weeks. There were no serious adverse events (AEs) related to study drug, discontinuations due to AEs, or deaths. The most frequent AEs (any grade) were injection site swelling (28%) and nodule (25%). Injection site reactions related to LEN (50%) were all mild or moderate. Longer term data will be reported.
LEN led to a rapid and clinically relevant decline in VL when added to a failing regimen in HTE PWH. LEN was generally safe and well-tolerated. These results support the ongoing evaluation of LEN for the treatment and prevention of HIV-1 infection.