GS-9722 is an effector-enhanced, broadly neutralizing antibody (bNAb) targeting a V3 glycan motif of the HIV envelope protein which is being developed for use in a HIV cure regimen. GS-9722 is a derivative of the bNAb PGT121 which has demonstrated immune cell-mediated killing of HIV-infected cells in vitro and efficacy in SHIV-infected monkeys. The safety, tolerability and pharmacokinetics (PK) of GS-9722 administered intravenously (IV; 30’ infusion) were evaluated in a first-in-human study in HIV-negative participants (Study 1) and in virally suppressed people with HIV (VS-PWH; Study 2).
Two randomized, blinded, placebo-controlled, staggered dose escalation studies were conducted. In Study 1, HIV-negative participants received single dose (SD; 150, 500, or 1500 mg) or multiple doses (MD; 150, 500, or 1000 mg every other week [QOW] for three doses) of GS‑9722 (n=6/cohort) or placebo (n=2/cohort). In Study 2, VS-PWH received SD or MD (QOW for five doses) GS-9722 150 or 500 mg (n=6/cohort) or placebo (n=2/cohort). Study 1 has completed; Study 2 is ongoing. Safety and PK are assessed throughout each study.
In Studies 1 and 2, 45 of 49 and 32 of 32 participants completed treatment, respectively. In Study 1, dose-proportional increases in GS-9722 AUC and Cmax were observed (Table). GS-9722 t1/2 was ~26 days, supportive of at least QOW dosing. Preliminary SD PK data in VS-PWH are similar to HIV-negative participants (Table); PK analysis in MD VS-PWH cohorts is ongoing.
Most AEs were grade 1 or 2. In Study 1, two participants discontinued study drug due to AEs (1000 mg; MD), both of which were considered related to study drug; one participant had a grade 3 SAE of thrombocytopenia and the other had a grade 2 AE of infusion related-reaction. In Study 2, one participant had a grade 3 unrelated SAE of small intestinal obstruction (150 mg; SD). No other SAEs or AEs leading to study drug discontinuation were reported to date.
These studies demonstrate that GS-9722 is generally safe and well tolerated in HIV-negative participants and VS-PWH, with similar single dose PK in the two populations. These data support ongoing evaluation of GS-9722 as part of a combination therapy for HIV cure.