Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir

Abstract Molnupiravir is registered or authorized in several countries as a 5-day oral COVID-19 treatment for adults. Molnupiravir is a prodrug of the antiviral ribonucleoside β-D-N4-hydroxycytidine (NHC) that distributes into cells, where it is phosphorylated to its pharmacologically active ribonucleoside triphosphate (NHC-TP) form. NHC-TP incorporates into SARS-CoV-2 RNA by the viral RNA-dependent RNA polymerase, resulting in an accumulation of errors in the viral genome, leading to inhibition of viral replication and loss of infectivity. The potential of molnupiravir to induce genomic mutations and DNA damage was comprehensively assessed in several in vitro and in vivo genotoxicity assays and a carcinogenicity study, in accordance with international guideline recommendations and expert opinion. Molnupiravir and NHC induced mutations in vitro in bacteria and mammalian cells but did not induce chromosome damage in in vitro or in vivo assays. The in vivo mutagenic and carcinogenic potential of molnupiravir was tested in a series of in vivo mutagenicity studies in somatic and germ cells (Pig-a Assay and Big Blue® TGR Mutation Assay) and in a carcinogenicity study (transgenic rasH2-Tg mouse), using durations of exposure and doses exceeding those used in clinical therapy. In vitro genotoxicity results are superseded by robustly conducted in vivo studies. Molnupiravir did not increase mutations in somatic or germ cells in the in vivo animal studies and was negative in the carcinogenicity study. The interpretation criteria for each study followed established regulatory guidelines. Taken together, these data indicate that molnupiravir use does not present a genotoxicity or carcinogenicity risk for patients.