Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial

PLoS One. 2018 Oct 23;13(10):e0205368. doi: 10.1371/journal.pone.0205368. eCollection 2018.

Abstract

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 NCT02415595.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkynes
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / therapeutic use*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / therapeutic use
  • Cyclopropanes
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Resistance, Viral
  • Drug Therapy, Combination
  • Emtricitabine / pharmacokinetics
  • Emtricitabine / therapeutic use*
  • Female
  • HIV Infections / drug therapy*
  • HIV-1 / genetics
  • HIV-1 / isolation & purification
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • RNA, Viral / blood
  • Tenofovir / pharmacokinetics
  • Tenofovir / therapeutic use*
  • Treatment Outcome
  • Triterpenes / pharmacokinetics
  • Triterpenes / therapeutic use*

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • RNA, Viral
  • Triterpenes
  • BMS-955176
  • Tenofovir
  • Emtricitabine
  • efavirenz

Associated data

  • ClinicalTrials.gov/NCT02415595

Grant support

Funding was provided by Bristol-Myers Squibb, original sponsor (and through the Week 24 analysis) of 205891. ViiV Healthcare UK Limited subsequently acquired the GSK3532795 compound and now supports the study.