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  Conference on Retroviruses
and Opportunistic Infections
Will be Virtual
Boston USA
March 6-10, 2021
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NNRTI MK-8507 Selects V106 Mutations,
Active Against Common NNRTI Mutations
  CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
MK-8507, an investigational nonnucleoside (NNRTI) antiretroviral, retains activity against common NNRTI-resistant variants, while displaying a resistance profile similar to doravirine [1], the licensed Merck NNRTI available in a single tablet with tenofovir disoproxil and lamivudine (TDF/3TC). MK-8507, which selects mutations at the V106 site, holds the potential for once-weekly oral dosing.
This novel NNRTI has a 50% inhibitory concentration (IC50) of 51.3 nM in vitro and a mean plasma half-life of about 70 hours in humans. In antiretroviral-naive people with HIV, a single MK-8507 oral dose of 40 mg lowered viral load more than 10-fold for up to 7 days. Merck plans a double-blind phase 2 dose-ranging switch study combining MK-8507 with the nucleoside reverse transcriptase translocation inhibitor islatravir as a once-weekly combination for adults with an undetectable viral load while taking bictegravir/FTC/TAF [2].
The phenotypic PhenoSense assay indicates that MK-8507 has activity across common HIV-1 subtypes. Its potency changes less than 5-fold against HIV bearing the common NNRTI resistance mutations K103N, Y181C, or G190A. When tested against clinical NNRTI resistance variants, MK-8507 shows a resistance profile similar to doravirine [3] and is superior to efavirenz against those variants.
In classic resistance selection experiments, MK-8507 selected the V106A mutation in HIV-1 subtype B virus and V106M in subtypes A and C. Other mutations that emerged in these experiments were V106I, E138K, H221Y, P225H, F227C/L, M230L, L234I, P236L, and Y318C/F.
Against a panel of 10 mutations that emerged in MK-8507 selection studies (V106A, V106I, Y188L, P225H, F227C, F227L, F2227V, M230L, L234I, Y318F), fold-change in susceptibility versus wild-type (nonmutant) virus remained below 5-fold for 5 of them, below 10-fold for 7, and below 40-fold for 9. This pattern looked similar to the doravirine fold-change resistance profile. The 10 mutations selected in these experiments are rare in the clinic, appearing in 0.01% to 2.87% of all people with HIV and in 0.08% to 4.66% of NNRTI-experienced people. Islatravir, the reverse transcriptase translocation inhibitor to be partnered with MK-8507 in a phase 2 trial [2], retains activity against resistance variants selected by MK-8507.
MK-8507 has additive activity with islatravir as well as with two entry inhibitors, three integrase inhibitors, four NNRTIs, four nucleoside/nucleotide reverse transcriptase inhibitors, and two protease inhibitors. The MK-8507/islatravir trial is not yet recruiting participants [2].
1. Diamond TL, Lai MT, Feng M, et al. Resistance profile of MK-8507, a novel NNRTI suitable for weekly oral HIV treatment. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 129.
2. ClinicalTrials.gov. Dose ranging, switch study of islatravir (ISL) and MK-8507 once-weekly in virologically-suppressed adults with human immunodeficiency virus type 1 (HIV-1) [MK-8591-013]. ClinicalTrials.gov identifier NCT04564547. https://clinicaltrials.gov/ct2/show/NCT04564547
3. Talwani R, Temesgen Z. Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. Drugs Today (Barc). 2020 Feb;56(2):113-124.doi: 10.1358/dot.2020.56.2.3109966.