Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254
Por:
Spinner, CD, Felizarta, F, Rizzardini, G, Philibert, P, Mitha, E, Domingo, P, Stephan, CJ, DeGrosky, M, Bainbridge, V, Zhan, J, Dumitrescu, TP, Jeffrey, JL, Xu, JF, Halliday, F, Gan, JJ, Johnson, M, Gartland, M, Joshi, SR, Lataillade, M
Publicada:
14 sep 2022
Ahead of Print:
1 ene 2022
Resumen:
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 log(10) occurred with GSK'254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses >= 40 mg resulted in >= 1-log(10) 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.
Filiaciones:
Spinner, CD:
Tech Univ Munich, Univ Hosp Rechts der Isar, Sch Med, Dept Internal Med 2, Munich, Germany
Rizzardini, G:
ASST Fatebenefratelli Osped Sacco, Infect Dis, Milan, Italy
Univ Witwatersrand, Fac Hlth Sci, Sch Clin Med, Johannesburg, South Africa
Philibert, P:
Hop Europeen Marseille, Infect Dis, Marseille, France
Mitha, E:
Newtown Clin Res, Johannesburg, South Africa
Domingo, P:
Hosp Santa Creu & Sant Pau, Infect Dis Unit, Barcelona, Spain
Stephan, CJ:
Univ Klinikum Frankfurt, Infect Dis Unit, Frankfurt, Germany
DeGrosky, M:
ViiV Healthcare, Branford, CT USA
Bainbridge, V:
GlaxoSmithKline, Stockley Pk, England
Zhan, J:
GlaxoSmithKline, Collegeville, PA USA
Dumitrescu, TP:
GlaxoSmithKline, Collegeville, PA USA
Jeffrey, JL:
ViiV Healthcare, Res Triangle Pk, NC USA
Xu, JF:
GlaxoSmithKline, Upper Providence, PA USA
Halliday, F:
GlaxoSmithKline, Stockley Pk, England
Gan, JJ:
GlaxoSmithKline, Collegeville, PA USA
Johnson, M:
ViiV Healthcare, Res Triangle Pk, NC USA
Gartland, M:
ViiV Healthcare, Res Triangle Pk, NC USA
Joshi, SR:
ViiV Healthcare, Branford, CT USA
Lataillade, M:
ViiV Healthcare, Branford, CT USA
hybrid, Hybrid Gold
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