Background
Long-acting antiretrovirals for HIV-1 treatment may help address suboptimal adherence, stigma, and treatment fatigue. GS-3242 is an integrase strand transfer inhibitor (INTSI) with potent anti-HIV-1 activity and physiochemical properties well-suited for a long-acting formulation. Antiviral activity, safety and pharmacokinetics (PK) of GS-3242 were evaluated in Phase (Ph)1a and Ph1b studies.
Methods
In a Ph1a study, participants without HIV were randomized (3:1 ratio) to receive a single dose of GS-3242 (400, 800, or 1200 mg) or placebo intramuscularly (IM) in the thigh. Primary endpoints were incidence of adverse events (AEs), laboratory abnormalities, and plasma PK parameters. In a Ph1b study, people with HIV-1 who were treatment-naïve or treatment experienced but naive to the INSTI class and off antiretroviral therapy for ≥12 weeks were administered GS-3242 450 mg orally on Day (D)1 and D2. Primary endpoint was change in plasma HIV-1 RNA from baseline to D11. Secondary endpoints included safety.
Results
In Ph1a, a total of 26 participants were randomized and received GS-3242 IM 400 mg or Placebo (n=9), 800 mg or Placebo (n=8), or 1200 mg or Placebo (n=9). Treatment-related AEs were Grade £2 and included injection site pain (n=7 [58%] Grade 1; n=5 [42%] Grade 2), headache (n=2), nausea (n=1), and malaise (n=1). There were no clinically significant laboratory abnormalities. In the Ph1b GS-3242 450 mg oral cohort (n=6), mean reduction in HIV-1 RNA from baseline to Day 11 was -2.31 (95% CI -2.87, -1.75) log10 copies/mL. There were no treatment-related AEs, Grade ≥3 AEs, or clinically significant laboratory abnormalities.
For Ph1a participants with complete D1 injections of 400, 800, or 1200 mg, mean (coefficient of variation, %) Cmax was 5062 (31%), 9640 (52%), 14,580 (36%) μg/mL, and median (range) time to Cmax was 34 (27–41), 21.5 (13–27), and 27 (6–27) days. Terminal half-life (t1/2) ranged from 47–56 days. Dose proportionality was observed across the dose levels of 400–1200 mg.
Conclusions
GS-3242 demonstrated a favorable safety profile, potent antiviral activity, and PK supporting a possible dosing interval of Q3 months or longer. The Ph1b study is ongoing to evaluate a range of doses. The combination of GS-3242 with another long-acting agent has the potential to form a complete long-acting HIV-1 treatment regimen.