Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week. (15th October 2021)

• Record Type: Journal Article
• Authors: Schürmann, Dirk; Jackson Rudd, Deanne; Schaeffer, Andrea; De Lepeleire, Inge; Friedman, Evan J.; Robberechts, Martine; Zhang, Saijuan; Liu, Yang; Kandala, Bhargava; Keicher, Christian; Däumer, Martin; Hofmann, Jörg; Grobler, Jay A.; Stoch, S. Aubrey; Iwamoto, Marian; Ankrom, Wendy
• Is Part Of: Journal of acquired immune deficiency syndromes. Volume 89:Number 2(2022)
• Page Start: 191
• Page End: 198
• Publication Date: 2021-10-15
• Subjects: antiretroviral -- HIV-1 infection -- MK-8507 -- pharmacokinetics and pharmacodynamics -- phase 1 -- treatment-naive; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome -- Periodicals; AIDS (Disease); Periodicals; 616.9792005
• DOI: 10.1097/QAI.0000000000002834
• Languages: English
• ISSNs: 1525-4135

Abstract

Abstract : Background: MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor being developed for treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing. Setting: A phase 1, open-label, proof-of-concept study was conducted in treatment-naive adults with HIV-1 infection to assess monotherapy antiviral activity. Methods: In 3 sequential panels, participants aged 18–60 years with baseline plasma HIV-1 RNA ≥10, 000 copies/mL and CD4 + T-cell count >200/mm 3 received a single oral dose of 40, 80, or 600 mg MK-8507 in the fasted state. Participants were assessed for HIV-1 RNA for at least 7 days, PKs for 14 days, and safety and tolerability for 21 days postdose. Results: A total of 18 participants were enrolled (6 per panel). The mean 7-day postdose HIV-1 RNA reduction ranged from ∼1.2 to ∼1.5 log10 copies/mL across the doses assessed. One patient had a viral rebound associated with emergence of an F227C reverse transcriptase variant (per chain-termination method sequencing) 14 days postdose; this variant was found in a second participant by ultra-deep sequencing as an emerging minority variant. MK-8507 PKs were generally dose-proportional and similar to observations in participants without HIV-1 infection in prior studies; mean MK-8507 half life was 56–69 hours in this study. MK-8507 was generally well tolerated at all doses. Conclusions: The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants.