Background: GS-9137 (JTK-303) is a potent (in vitro protein binding-adjusted
IC₅₀ < 30 nM) inhibitor of HIV-1 integrase (strand transfer) with favorable human pharmacokinetics (PK), including QD dosing with ritonavir 100 mg (RTV).

Methods:  The antiviral activity, safety, pharmacokinetics and pharmacodynamics of GS-9137 were evaluated in a prospective, randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1-infected treatment-naïve and -experienced patients. Eligible patients were not currently receiving ART and had a screening HIV-1 RNA between 10,000 and 300,000 copies/mL and CD₄ count ≥200 cells/µL. GS-9137 was administered with food for 10 days in dosage cohorts of 200, 400, or 800 mg twice daily, 800 mg once daily, or 50 mg boosted with 100 mg of ritonavir (RTV) once daily (6 active + 2 placebo/cohort). Clinical chemistries, HIV-1 RNA, and CD₄ cell counts were evaluated throughout the study with intensive pharmacokinetic sampling on days 1 and 10. The primary efficacy endpoint was the maximum reduction in log₁₀ HIV-1 RNA from baseline.

Results:  We enrolled 40 patients (30 active, of whom 15 were experienced and 15 naïve, and 10 placebo) and completed study with a mean baseline viral load of 4.75 log₁₀ copies/mL and a CD₄ count of 442 cells/µL. All GS-9137 dose cohorts exhibited substantial antiviral activity vs placebo (p <0.0001, ANOVA); median (minimum, maximum) results are shown below. An E_max dose-response model demonstrated that antiviral activity was associated with GS-9137 steady state C_min concentrations. All GS-9137 dosage regimens were well tolerated with no study drug discontinuations or serious adverse events. All adverse events related to study drug were grade 1 or 2 in severity, resolved on treatment, and were not associated with GS-9137 dose.

Conclusions:  GS-9137 monotherapy demonstrated substantial antiviral activity. Once-daily dosing of GS‑9137 + RTV will be evaluated in a dose-ranging phase 2 study in treatment-experienced patients.