Lenacapavir (LEN), a potent first-in-class inhibitor of HIV-1 capsid function, is in development for treatment and prevention of HIV-1 infection. CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced (HTE) people with HIV-1 (PWH) with multidrug-resistance and ongoing viremia (? 400 copies/mL) evaluating LEN in combination with an optimized background regimen (OBR).
In the randomized cohort (Cohort 1), participants were assigned (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 every 6 months; those on placebo started the 2-week oral lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, OBR at D15. In the non-randomized cohort (Cohort 2), participants started OBR concurrent with LEN (oral lead-in ? SC). We report the secondary endpoint of W52 efficacy by FDA-snapshot algorithm in the randomized cohort and additional available efficacy and safety from both cohorts.
72 participants were enrolled: 36 in each cohort. Overall, 25% were female, 38% Black, median age 52 years, 19% had VL > 100k c/mL, 64% had CD4 <200 cells/µL, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI), and 17% did not have any fully active agents in the OBR. In Cohorts 1 and 2 at W26, 81% (29/36) and 81% (29/36) achieved VL<50 c/mL. At W52, in Cohort 1, 83% (30/36) had VL< 50 c/mL; most in Cohort 2 have not reached W52 yet. At W52, CD4 count increased by a median 83 cells/µL (Q1 to Q3: 21 to 142, n=41). Eight participants had emergent LEN resistance (4 in Cohort 1 and 4 in Cohort 2); other than 1 who died at W11 (previously reported), all 7 either had evidence of poor adherence to the OBR (n=4) or did not have any fully active agents in the OBR (n=3).No participant experienced a study drug-related serious adverse event. One participant discontinued LEN at W52 due to an AE of Grade 1 injection site nodule. LEN-related injection site reactions (ISRs) occurred in 63% (45/72) and were mostly mild or moderate (43/45). The most common non-ISR AEs were nausea and diarrhea (13% each) and COVID-19 (11%).
Subcutaneous LEN in combination with OBR led to high rates of virologic suppression and immunologic recovery in HTE PWH at one year and was well tolerated. These results support the ongoing evaluation of LEN for treatment of multi-drug resistant HIV-1 infection.