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GSK3640254 is a next‐generation maturation inhibitor with demonstrated potency across HIV‐1 subtypes and a high barrier to emergent resistance. This phase I, 2‐part, randomized, open‐label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate‐fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3‐ to 4‐fold under high‐ and moderate‐fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high‐fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV‐1. [ABSTRACT FROM AUTHOR]

Aims: GSK3640254 is a next‐generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV‐positive women. Methods: This phase I, open‐label, 1‐way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate‐fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration–time curve to the end of the dosing interval (AUC0‐t), maximum observed concentration (Cmax) and plasma concentration at the end of the dosing interval (Cτ) for ethinyl oestradiol and levonorgestrel. Serum follicle‐stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. Results: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0‐t, Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle‐stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver‐stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. Conclusion: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady‐state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel. [ABSTRACT FROM AUTHOR]

Aims: GSK3640254, a novel, next‐generation maturation inhibitor effective against a range of HIV polymorphisms with no cross‐resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2‐drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. Methods: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1–5 in period 1, GSK3640254 200 mg QD on Days 1–7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1–7 in period 3. All treatments were administered with a moderate‐fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. Results: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration–time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118–1.233), 1.09 (1.044–1.138) and 1.24 (1.160–1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992–1.094), 0.99 (0.923–1.065) and 0.10 (0.939–1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady‐state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. Conclusion: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated. [ABSTRACT FROM AUTHOR]

GSK3532795 (formerly known as BMS-955176) is a second-generation maturation inhibitor targeting a specific Gag cleavage site between capsid p24 and spacer peptide 1 of HIV-1. Study 205891 (previously AI468038) investigated the efficacy, safety, and dose response of GSK3532795 in treatment-naive, HIV-1-infected participants. Study 205891 (NCT02415595) was a Phase IIb, randomized, active-controlled, double-blind, international trial. Participants were randomized 1:1:1:1 to one of three GSK3532795 arms at doses 60 mg, 120 mg or 180 mg once daily (QD), or to efavirenz (EFV) at 600 mg QD, each in combination with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (300/200 mg QD). Primary endpoint was proportion of participants with plasma HIV-1 RNA <40 copies/mL at Week 24. Between May 2015 and May 2016, 206 participants received treatment. At Week 24, 76–83% participants receiving GSK3532795 and 77% receiving EFV achieved HIV-1 RNA <40 copies/mL. Fifteen participants receiving GSK3532795 and one receiving EFV met resistance testing criteria; 10/15 receiving GSK3532795 had emergent substitutions at reverse transcriptase positions M184, and one at position K65, while the participant receiving EFV did not have any nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI mutations. EFV, relative to GSK3532795, had more serious adverse events (9% versus 5%) and adverse events leading to discontinuation (17% versus 5%). However, 3–4-fold higher rates of gastrointestinal adverse events were observed with GSK3532795 relative to EFV. GSK3532795 combined with TDF/FTC is efficacious with 24 weeks of therapy. However, GSK3532795 showed a higher rate of gastrointestinal intolerability and treatment-emergent resistance to the NRTI backbone relative to EFV. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]