Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week

  • J Acquir Immune Defic Syndr. 2022 Feb 1;89(2):191-198. doi: 10.1097/QAI.0000000000002834.
Dirk Schürmann  1  2 ,  Deanne Jackson Rudd  3 ,  Andrea Schaeffer  3 ,  Inge De Lepeleire  4 ,  Evan J Friedman  3 ,  Martine Robberechts  4 ,  Saijuan Zhang  3 ,  Yang Liu  3 ,  Bhargava Kandala  3 ,  Christian Keicher  1 ,  Martin Däumer  5 ,  Jörg Hofmann  6 ,  Jay A Grobler  3 ,  S Aubrey Stoch  3 ,  Marian Iwamoto  3 ,  Wendy Ankrom  3
Affiliations
  • 1. Charité Research Organisation GmbH, Berlin, Germany.
  • 2. Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 3. Merck & Co., Inc., Kenilworth, NJ.
  • 4. MSD, Brussels, Belgium.
  • 5. Seq-IT GmbH & Co. KG, Kaiserslautern, Germany; and.
  • 6. Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
PMID: 34654041 DOI: 10.1097/QAI.0000000000002834
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/mm3 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.

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