Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254

Abstract

Background: GSK3640254 (GSK'254) is a next-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy.

Methods: This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK'254 monotherapy administered with food (moderate-fat meal) in HIV-1-positive, treatment-naive adults. In part 1, participants received GSK'254 10 or 200 mg for 10 days. In part 2, participants received GSK'254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA.

Results: Maximum changes in HIV-1 RNA of -0.4, -1.2, -1.0, -1.5, and -2.0 log10 occurred with GSK'254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on day 11 in part 1, 1 with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n = 4). Two non-drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non-drug-related AEs in 1 participant.

Conclusions: This monotherapy study established a dose-antiviral response relationship for GSK'254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216).

Clinical trials registration: NCT03784079.

Keywords: HIV infection; HIV-1 RNA; pharmacodynamics; tolerability; treatment-naive.

Conflict of interest statement

Potential conflicts of interest. C. D. S. has received grants, personal fees, and/or nonfinancial support from ViiV Healthcare/GlaxoSmithKline, Janssen-Cilag, Gilead, Merck Sharp & Dohme, AbbVie, Apeiron, Formycon, Eli Lilly, and B. Braun Melsungen. F. F. has received grants and personal fees from ViiV Healthcare, AbbVie, and Gilead. G. R. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead, ViiV Healthcare, Janssen, Merck Sharp & Dohme, Angelini Pharma, and AbbVie; has received travel/meeting attendance support from AbbVie; and has participated on a data safety monitory board or advisory board for Rotapharm, outside the submitted work. C. J. S. has received research grants and/or honoraria for scientific advisory board participation from Gilead and Janssen. M. D., J. L. J., M. J., M. G., S. R. J., and M. L. are employees of ViiV Healthcare and may own stock in GlaxoSmithKline. V. B., J. Z., F. H., and J. G. are employees of and may own stock in GlaxoSmithKline. T. P. D. and J. X. were employees of GlaxoSmithKline during the conduct of the study and may own stock in GlaxoSmithKline. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Mean (SD) change from baseline in log10 plasma HIV-1 RNA by treatment in (A) part 1 and (B) part 2. Abbreviations: GSK’254, GSK3640254; HIV-1, human immunodeficiency virus type 1; SD, standard deviation.

Figure 2.

Change from baseline in log10 plasma HIV-1 RNA and HIV-1 Gag genotyping results from day 8 to end of study in the 200-mg group. Abbreviations: GSK’254, GSK3640254; HIV-1, human immunodeficiency virus type 1.

Figure 3.

Plasma GSK’254 PK parameters after (A) single-dose administration on day 1 and (B) repeat-dose administration at steady state. Dashed line indicates the clinical efficacy target value for which ≥95% of participants in a phase IIb study are projected to exceed target trough concentrations (110 ng/mL). Abbreviations: GSK’254, GSK3640254; PK, pharmacokinetics. aOne participant in the 10-mg group had a predose concentration that was inconsistent with the expected PK profile. One participant in the 200-mg group was excluded from PK analysis due to vomiting postdose ≤1 × time to maximum observed concentration. bSteady state was measured on day 8, 9, or 10 in part 1 and day 7 in part 2.

Figure 4.

Maximum change from baseline to day 8 in log10 plasma HIV-1 RNA vs (A) GSK’254 dose and (B) Cτ fitted to an Emax nonlinear model. Solid and dashed lines represent the fitted value from the Emax model and 95% confidence interval, respectively. Abbreviations: Cτ, concentration at the end of the dosing interval; Emax, maximum effect; GSK’254, GSK3640254; HIV-1, human immunodeficiency virus type 1.