GS-6207, a potent, selective, first-in-class, multi-stage inhibitor of HIV-1 capsid function that inhibits HIV at picomolar concentrations and is in development as a long-acting agent for treatment of HIV-1 infection. The safety, antiviral activity and pharmacokinetics (PK) of GS-6207 were evaluated in people living with HIV (PLWH) in this Phase 1b study.
This is an ongoing, Phase 1b, randomized, double-blinded, placebo-controlled dose-ranging study of GS-6207 in HIV capsid-inhibitor naive PLWH who are not taking antiretroviral therapy. A single subcutaneous (SC) dose of GS-6207 (20, 50, 150, 450, or 750 mg; N=6/cohort) or placebo (N=2/cohort) was administered. The primary endpoint was maximum reduction of plasma HIV-1 RNA through post dose day 10 (D10). Safety was assessed using laboratory tests and adverse event (AE) reporting. We present antiviral activity, blinded safety, and dose-response relationship for the 20 to 450 mg dose cohorts; enrollment of the 750 mg cohort is ongoing.
Demographics and baseline characteristics were similar across groups (N=32, n=8 per group). All PLWH who received active drug had significantly greater reductions in HIV-1 RNA by D10 than the placebo (all p<0.0001). The 50 to 450 mg groups had a numerically greater mean reductions in HIV-1 RNA through D10 (range: 1.8 to 2.2 log10copies/mL) than the 20 mg group (1.4 log10copies/mL). At these doses, the inhibitory quotients (mean GS-6207 concentrations for each group/protein adjusted 95% maximal effective concentration in MT-4 cells for wild type HIV-1) on D10 ranged from 0.7 to 9.9. Using a maximum effect (Emax) model for GS-6207 (SC 20 to 450 mg) and antiviral activity, Emax was ~2.1 log10copies/mL decline in HIV-1 RNA, and a dose inhibiting viral replication by 50% (ED50) was ~10 mg. One participant experienced a serious AE (Grade 3) of atrial fibrillation after using methamphetamine; no other SAEs, Grade 3 or 4 AEs, AEs leading to discontinuation, or clinically relevant Grade 3 or 4 laboratory abnormalities were reported. The most common AEs were injection site reactions that were mostly mild and transient (50%).
In PLWH, GS-6207 demonstrated potent antiviral activity, with up to a 2.2 log10 copies/mL decline at Day 10, and was generally safe and well tolerated. These results support further clinical evaluation of GS-6207 as a long-acting antiretroviral agent.