Study results support clinical evaluation of GS-6207 as a long-acting ARV agent

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A phase Ib study of Gilead Sciences‘ long-acting HIV-1 capsid inhibitor GS-6207 in people living with HIV demonstrated the drug’s potent antiviral activity, as well as its safety, according to results presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2020), by Dr Eric Daar from the Harbour-UCLA Medical Centre in California.

GS-6207 is the first-in-class capsid inhibitor that interferes with the assembly and disassembly of the HIV-1 capsid, which encloses the genetic blueprint of the virus. This dose-ranging study looked at the dose-response relationship of subcutaneous injections of GS-6207 in both treatment-naive and -experienced patients.

The study primary endpoint was a maximum reduction of plasma HIV-1 RNA through day 10, while the secondary endpoint was the safety and tolerability of the drug. Daar concluded that single subcutaneous doses of GS-6207 resulted in potent antiretroviral activity, with HIV-1 RNA declining over 10 days by a mean 1.4 to 2.3 log10copies/ml, and that the mean GS-6207 concentrations obtained were predictors of a maximal antiviral activity. Also, GS-6207 and the placebo were generally safe and well tolerated, with self-limiting, mild to moderate injection site reactions, although the safety review was blinded.

These results support further evaluation of GS-6207 as a long-acting antiretroviral agent in two ongoing phase II clinical trials (CALIBRATE and CAPELLA) in treatment-naive or -experienced people living with HIV, with a six-month dosing interval of the drug.

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.

Eric Daar, Cheryl McDonald, Gordon Crofoot, Peter Ruane, Gary Sinclair, Edwin DeJesus, Mezgebe Berhe, Moti Ramgopal, Heena Patel, Ya-Pei Liu

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CROI 2020 abstract

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