January 2022 Editor's Choice Article

The January 2022 EMM Editor's Choice article is Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir" (https://onlinelibrary.wiley.com/doi/ftr/10.1002/em.22471) by Michael D. Waters, Stafford Warren, Claude Hughes, Philip Lewis, Fengyu Zhang.

In this review, the authors propose that the genotoxicity of molnupiravir (MOV), an antiviral with emergency use authorization for COVID-19 treatment, should be further investigated using human-centric methods before final FDA approval. This is based on MOV being considered for a more widespread use for other known and future RNA viral infections as well as base substitution mutagenicity of its active metabolite, β-d-N4-hydroxycytidine (NHC), which is not detected in the usual in vivo assays that mostly reveal clastogenic effects. This is because both MOV and NHC are apparently unique gene mutagens like 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), an antiviral drug which was developed for treatment of herpes simplex infections. [See below --Table 3 from the article]. They support this argument by describing known mechanisms of action observed for other congener nucleoside analogs (NAs) and for NHC reported in the literature.

MOV induces genome catastrophe by lethal mutagenesis in viral genomes and is 100 times more potent than its congener drugs, ribavirin (RBV) and favipiravir (FAV or FPV). Because it’s designed effect is RNA mutagenesis, more work is required to answer whether it is mutagenic to human DNA. To date, there is no satisfactory answer to this because in vivo genotoxicity assays (which are more sensitive to clastogenic compounds) range from negative to equivocal, while a number of in vitro studies signal that MOV and its metabolite, NHC, can cause host DNA mutation.

The authors cover some history of the research on MOV and NHC, as well as congener drugs RBV and FPV. NHC has exhibited DNA mutagenic activity in eukaryotic systems, as have the congeners. While RBV and FPV are mutagenic, they have targeted use in chronic viral diseases such as HIV-AIDS and hepatitis C, where the benefit of this compound outweighs the risk when used under physician care. However, the risk to benefit analysis is altered when considering such drugs for non-chronic viral infections and outpatient use before symptoms develop in a large patient population. The authors describe a study called “MOVe-AHEAD” studying the efficacy of MOV in at-risk nonhospitalized (outpatient) adults and discovered that ≥90% of the people treated had no benefit yet were exposed to the risk of the drug. Quality preclinical safety evaluations, tolerability, and pharmacokinetics should be conducted and perhaps augmented with human error-corrected next generation sequencing (ec-NGS) and the human PIG-A assay before full approval due to the greater patient population targeted and the equivocal genotoxicity results in the body of MOV and NHC research results. The authors conclude that incorporation of ec-NGS studies and PIG-A could provide an unequivocal answer to whether MOV is mutagenic to humans when used as prescribed, thereby aiding the evaluation of this drug for regulatory decisions.

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