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Resistance and Response in Phase 2a
Study of HIV Maturation Inhibitor
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
CROI: PHASE IIA PROOF-OF-CONCEPT TRIAL OF NEXT-GENERATION MATURATION INHIBITOR GSK3640254 - (03/09/21)
Mark Mascolini
Virologic response to 7- to 10-day monotherapy with the investigational HIV maturation inhibitor GSK3640254 (GSK'254) reached 1.5 to 2.0 log10 copies with the highest doses studied, 140 and 200 mg once daily [1]. Resistance mutations emerged in 4 of 6 people taking 200-mg monotherapy for 10 days, which led to a change in dose duration from 10 to 7 days. A phase 2b trial of GSK'254 has begun [2].
Two phase 1 trials testing GSK'254 in healthy adults determined that this antiretroviral has a half-life of about 24 hours [3], a finding supporting development of GSK'254 for once-daily dosing. GSK'254 appears to stymie HIV replication by inhibiting protease cleavage between capsid protein p24 and spacer peptide 1 in Gag late in the viral replication cycle to yield immature, noninfectious virions.
Part 1 of the phase 2a double-blind, placebo-controlled trial randomized 6 antiretroviral-naive adults to receive 200 mg of GSK'254 once daily for 10 days, 6 to receive 10 mg once daily, and 2 to receive placebo. After a planned interim analysis after day 10, the investigators assigned 6 antiretroviral-naive adults each to 140, 80, or 40 mg of GSK'254 once daily for 7 days and 2 to placebo. Participants started combination therapy after the monotherapy phases. The primary endpoint was maximal change in viral load from day 1 during the two parts of the trial.
Across study arms participant age averaged 31.8 years. Two participants (6%) were women, 4 (12%) black, and 6 (18%) of another nonwhite race or ethnicity. Pretreatment viral load averaged about 4.5 log10 copies/mL (about 32,000 copies/mL).
In part 1 of the trial, maximal viral load drops at day 11 were 0.21 log10 with placebo, 0.36 log10 with 10 mg of GSK'254, and 2.01 log10 (about 100-fold) with 200 mg of GSK'254. In part 2 of the trial, maximal viral load declines at day 8 were 0.03 log10 with placebo, 1.18 log10 with 40 mg of GSK'254, 1.02 log10 with 80 mg of GSK'254, and 1.49 log10 (about 30-fold) with 140 mg of GSK'254. Average GSK'254 concentrations lay above the efficacy target of 1.10 ng/mL with the 40-, 80-, 140-, and 200-mg doses.
At day 11 in part 1 of the trial, the maturation inhibitor resistance mutation A364A/V emerged in 4 of 6 participants taking 200 mg of GSK'254 once daily for 10 days. In 1 of 4 people with this emergent mutation, phenotypic testing determined that the mutation made HIV lose susceptibility to GSK'254, indicated by a 132-fold change from baseline in 50% inhibitory concentration. Learning that, the researchers changed the protocol to administer GSK'254 for 7 days instead of 10 to lower chances of emergent resistance mutations. No genotypic or phenotypic resistance emerged in part 2 of the study.
Among the 6 people in each of the 5 GSK'254 groups, 2 each in the 10-, 40-, 80-, and 200-mg arms and 1 in the 140-mg arm had any drug-related adverse event. These events included diarrhea in 3 participants, abdominal pain in 2, and vomiting in 2. No one in the placebo group had a treatment-related adverse event.
A phase 2b trial is testing once-daily GSK'254 doses of 100, 150, and 200 mg combined with 2 nucleoside reverse transcriptase inhibitors in about 240 previously untreated adults with HIV [2]. The trial will compare GSK'254 to dolutegravir, each combined with TAF/FTC or ABC/3TC.
References
1. Spinner C, Felizarta FB, Rizzardini G, et al. Phase IIa proof-of-concept trial of next-generation maturation inhibitor GSK-3640254. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 126.
2. ClinicalTrials.gov. A dose-range finding clinical trial study in human immunodeficiency virus (HIV-1) infected treatment-naive adults. ClinicalTrials.gov identifier NCT04493216. https://clinicaltrials.gov/ct2/show/NCT04493216
3. Joshi SR, Fernando D, Igwe S, et al. Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor. Pharmacol Res Perspect. 2020;8:e00671. doi: 10.1002/prp2.671.
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