The first-ever COVID antiviral pill developed by Merck could be available before the end of the year. The drug, molnupiravir, has been shown to reduce the risk of hospitalization and death from COVID-19 by 50 percent, and on Oct. 11, Merck requested the Food and Drug Administration for an emergency authorization of the pill.
To demystify molnupiravir, Cornell professors explain the science behind the COVID pill and its potential risks.
If approved, molnupiravir could be an inexpensive treatment option, with the potential to reach more high-risk populations who tested positive for COVID-19 than injectable antiviral options and antibody treatments currently used.
Compared to antibody treatments, which are currently being used to treat high-risk patients with mild to moderate COVID-19, molnupiravir is less effective. These antibodies have been shown to reduce hospitalizations and death by 85 percent in those patients. Despite the difference in effectiveness, the Merck’s pill may have a larger effect on treating patients with COVID, since its pill form is said to be a more convenient and less expensive option.
Antivirals rely on suppressing a virus’ ability to infect and replicate. The drugs often work by preventing the virus from binding to host cells or disrupting its mechanism of replication.
As a result, antivirals must be taken early in the infection phase, before symptoms appear, so that the first copies of the virus can be halted, according to Prof. Gary Whittaker, microbiology and immunology. Molnupiravir achieves this effect by inducing ambiguous base pairing in the viral genome — in which the viral mutation rate is accelerated, resulting in the production of mutant viruses that are less infectious.
Although the COVID pill can reduce symptoms and shorten time of illness, this mechanism of action raises some concerns about the possibility for mutations within mammalian cell cultures, which may translate into complications for pregnant women, according to Whittaker.
“The antiviral drug is super important, but it’s not important enough for the risk of birth defects in pregnant women … The risk is really high with the developing fetus,” Whittaker said.
Since antivirals that enhance mutations target how viral genes are replicated, this may affect the replication of genes that encode the development of major limbs and organs in the fetus, leading to birth defects.
On the other hand, the risk of inducing mutagenesis — the process of altering genetic information — in human, non-developmental cells is significantly lower than in developing cells, since the antiviral medication only affects the RNA, which hold the virus’ genomic information, according to Prof. Luis Schang, microbiology and immunology.
Two types of nucleic acids are found in mammalian cells — ribonucleic acids, which are nongenomic, and deoxyribonucleic acids which are genomic. Since ribonucleic acid does not incorporate into the DNA well, the risk of the new drug producing mutagenesis is low, according Schang.
Considering these hazards, it is likely that the pill will only be available for unvaccinated people who are not pregnant and considered high risk.
Merck is prepared to produce tens of millions of doses of molnupiravir, if given regulatory approval by the FDA for distribution.
FDA approval of COVID vaccines was within 21 days after submission under emergency authorization, which was significantly shorter than the typical 10-month wait time for a drug review.
However, for molnupiravir, possible risks may delay the approval process. The cost-benefit is noticeably high, especially for pregnant women, since there is a possibility that the drug may cause unwanted mutations in the developing fetus.
“Generating an antiviral drug is actually very easy, but generating one that is not toxic is the hard part,” Whittaker said. “Because the virus is so intertwined in replicating with the cell, it’s very hard to strike that balance. We just gotta make sure these things are safe.”
Molnupiravir is not the only antiviral COVID drug on the way. Pfizer, which has been developing antivirals for SARS-CoV-1, is currently developing a COVID pill using a similar mechanism of action. Currently, it is in phase two out of three trials for treating people who are just recently infected.
Cornellians are also conducting research on developing COVID treatments. Abrrey Monreal, postdoctoral researcher in immunology and microbiology, and Prof. Tirosh Shapira, Ph.D. ’16, microbiology and immunology, Life Sciences Institute at the University of British Columbia, recently wrote a paper describing the potential of a spray containing a small molecule compound that impedes viral entry in host cells. This may provide a localized and safer way to treat COVID-19.
According to Whittaker, who is part of the research collaboration, the good ratio of toxicity to efficacy starting point is in the 10,000 range. The spray treatment, however, is in the millions, meaning the therapeutic benefit greatly outweighs unacceptable side-effects or toxicity.
As for the Merck COVID pill, molnupiravir, the FDA has scheduled a meeting on Nov. 30 with outside experts to evaluate the drug.