Why should males use contraception for longer after taking molnupiravir for COVID?

Question

Molnupiravir (brand name Lagevrio) is a small-molecule antiviral prodrug active against SARS-Cov-2 and in one trial was found to reduce risk of hospitalization or death from COVID by 52% (Jayk Bernal et al 2022. PMID 34914868).

According to the New York Times:

Molnupiravir cannot be used during pregnancy because of the potential harm to the fetus. For this reason, doctors may also recommend that sexually active men and women of childbearing age use contraception during treatment and for a period afterward (three months for men and four days for women).

The package insert confirms these recommendations and there is a black box warning:

Based on findings from animal reproduction studies, LAGEVRIO may cause fetal harm when administered to pregnant individuals.

It also mentions:

While the risk is regarded as low, nonclinical studies to fully assess the potential for LAGEVRIO to affect offspring of treated males have not been completed. Advise sexually active individuals with partners of childbearing potential to use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose of LAGEVRIO.The risk beyond three months after the last dose of LAGEVRIO is unknown. Studies to understand the risk beyond three months are ongoing.

As an article from Forbes notes:

Reporters have asked the manufacturers about potential mutagenic effects, which Merck has answered by saying that, “the drug will be safe if used as intended and at the concentrations where we have looked and in the concentrations which we are achieving in patients.”

What is the hypothesized mechanism underlying the recommendation that males use contraception for three months after taking molnupiravir while females should only use contraception for four days?

Answer 1

The mechanism of action of molnupiravir is "lethal mutagenesis" (see Malone and Campbell, 2021) - it interferes with the viral RNA polymerase by introducing copying errors severe enough that the resulting RNA cannot code anything functional.

The mechanism is selective to viral RNA polymerase, but Zhou et al, 2021 have found DNA mutagenesis induced in cell culture:

(active metabolite of molnupiravir) also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate

Three months is a rough approximation to the timeline of spermatogenesis. DNA replication during oogenesis occurs much earlier.

Biologically, these guidelines are consistent with preventing presence of the drug during DNA replication in gametes, zygote, and embryo. Because DNA replication is occurring in sperm but not eggs within the immediate months before conception, there is a longer pre-conception window for males versus females.

The FDA's discussion about these research findings is revealed in the Emergency Use Authorization for Molnupiravir:

Uncertainty about genotoxicity was cited as a cause for concern by Committee members... A particular concern raised was the potential effect on male germ cells that could result in birth defects. As the in vivo mutagenicity assays performed to date use somatic cells ... and not germ cells (eggs and sperm), the ability for [molnupiravir] (MOV) to induce mutations in germ cells has not been directly assessed. Somatic cell assays may represent a worst-case, as male germ cells, while reproductively active in adults, appear to be relatively protected from mutagenic DNA damage, including having more efficient DNA repair mechanisms than do somatic cells (Olsen et al. 2001). However, the capacity for DNA repair appears to wane as spermatogonia mature to sperm (Marchetti and Wyrobek 2008) in a process that takes 74 days in humans.

Repair mechanisms such as mismatch repair and homologous recombination that are active in the earliest phases of spermatogenesis give way to the more error-prone nonhomologous end joining process in spermatids (Garcia-Rodriguez et al. 2018). ... Male germ cell (sperm) maturation starts in early puberty and the sperm maturation process takes 74 days; a period covered by the use of contraception for 90 days in males of reproductive potential who are exposed to MOV. The carcinogenicity study and the testicular germ cell mutation assay will provide data regarding the risk to male patients, and their offspring, beyond 90 days.

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Malone, B., & Campbell, E. A. (2021). Molnupiravir: Coding for catastrophe. Nature Structural & Molecular Biology, 28(9), 706-708.

Zhou, S., Hill, C. S., Sarkar, S., Tse, L. V., Woodburn, B. M., Schinazi, R. F., ... & Swanstrom, R. (2021). β-d-N 4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells. The Journal of infectious diseases, 224(3), 415-419.