A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency Virus Type 1 Infection.

Abstract

BACKGROUND:

GSK2838232 is a second-generation, potent, small-molecule, oral human immunodeficiency virus type 1 (HIV-1) maturation inhibitor for once-daily administration boosted with a pharmacoenhancer.

METHODS:

The phase 2a, proof-of-concept study was an open-label, adaptive dose-ranging design. Safety, pharmacokinetics, and efficacy of GSK2838232 boosted by cobicistat were evaluated in individuals with HIV-1 infection. The study participants (N = 33) received GSK2838232 once daily across a range of doses (20-200 mg) with cobicistat 150 mg for 10 days.

RESULTS:

GSK2838232 was safe and well tolerated with no clinically meaningful changes in safety parameters or adverse events. Exposure (maximum concentration and area under the concentration-time curve from time zero to the concentration at 24 hours postdose) increased 2- to 3-fold with repeated dosing in an approximately dose-proportional manner, reaching steady-state by day 8 with a half-life (t½) from 16.3 to 19.2 hours. Clearance and t½ values were not dependent on dose. Viral load declined from baseline with all GSK2838232 doses. Mean maximum declines from baseline to day 11 in HIV-1 RNA log10 copies/mL with the 20-mg, 50-mg, 100-mg, and 200-mg cohorts were -0.67, -1.56, -1.32, and -1.70, respectively. CD4+ cell counts increased at doses ≥50 mg.

CONCLUSIONS:

GSK2838232 with cobicistat was well tolerated and exhibited efficacy as a short-term monotherapy in participants with HIV-1. This positive proof-of-concept study supports the continued development of GSK2838232 for the treatment of HIV as part of combination antiretroviral therapy.

CLINICAL TRIALS REGISTRATION:

NCT03045861.

• Authors: Edwin DeJesus, Sara Harward, Roxanne C Jewell, Mark Johnson, Etienne Dumont, Viviana Wilches, Fiona Halliday, Christine L Talarico, Jerry Jeffrey, Jianjun Gan, Jianfeng Xu, Franco Felizarta, Anita Scribner, Moti Ramgopal, Paul Benson, Brian A Johns
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 71 Issue 5 Pg. 1255-1262 (08 22 2020) ISSN: 1537-6591 [Electronic] United States
• PMID: 31769793 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Anti-HIV Agents
• Pentacyclic Triterpenes
• GSK-2838232

Topics

• Anti-HIV Agents (adverse effects)
• HIV Infections (drug therapy)
• HIV-1
• Humans
• Pentacyclic Triterpenes
• Viral Load