Edwin DeJesus1, Sara Harward2, Roxanne C Jewell3, Mark Johnson4, Etienne Dumont5, Viviana Wilches5, Fiona Halliday6, Christine L Talarico7, Jerry Jeffrey8, Jianjun Gan9, Jianfeng Xu10, Franco Felizarta11, Anita Scribner12, Moti Ramgopal13, Paul Benson14, Brian A Johns8. 1. Orlando Immunology Center, Orlando, Florida, USA. 2. Clinical Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. 3. Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. 4. Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. 5. Clinical Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA. 6. Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Stockley Park, United Kingdom. 7. Clinical Virology, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. 8. Human Immunodeficiency Virus Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. 9. Biostatistics, GlaxoSmithKline, Collegeville, Pennsylvania, USA. 10. Global Clinical Sciences and Delivery, GlaxoSmithKline, Collegeville, Pennsylvania, USA. 11. Bakersfield Family Medical Center, Bakersfield, California, USA. 12. Diagnostic Clinic of Longview, Center for Clinical Research, Longview, Texas, USA. 13. Midway Immunology and Research Center, Fort Pierce, Florida, USA. 14. Well Medical Center, Berkeley, Michigan, USA.
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.
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: Christoph D Spinner; Franco Felizarta; Giuliano Rizzardini; Patrick Philibert; Essack Mitha; Pere Domingo; Christoph J Stephan; Michelle DeGrosky; Veronica Bainbridge; Joyce Zhan; Teodora Pene Dumitrescu; Jerry L Jeffrey; Jianfeng Xu; Fiona Halliday; Jianjun Gan; Mark Johnson; Martin Gartland; Samit R Joshi; Max Lataillade Journal: Clin Infect Dis Date: 2022-09-14 Impact factor: 20.999