Highlights

An Advisory Committee of the U.S. Food and Drug Administration (FDA) has voted to approve the experimental drug molnupiravir for the outpatient treatment of COVID-19 infection.

The positive verdict, however, was pronounced practically on the verge: 13 specialists voted for it and 10 voted against it.

Apparently, in the very near future, the FDA will turn on the “green light” for molnupiravir for its use in the treatment of moderate-to-severe COVID-19 in adult patients who are at high risk of progression of the disease to a severe form. It is possible that the spectrum of eligible patients will be limited to unvaccinated ones.

Molnupiravir, developed by Merck & Co. and Ridgeback Biotherapeutics, will be approved under the Emergency Use Authorization (EUA) policy.

Molnupiravir, if it arrives on the planet’s main pharmaceutical market, will be the first anti-COVID-19 drug that is implemented in an oral formulation (capsules) and that can be administered in an outpatient setting. Until now, treatment of COVID-19 has involved the inpatient use of injectable drugs: Veklury (remdesivir) or monoclonal antibodies — bamlanivimab with etesevimab, casirivimab with imdevimab, sotrovimab.

We cannot say that the therapeutic efficacy of molnupiravir has been excellent. Nevertheless, its appearance is a significant achievement of pharmaceutical science. First, now it will be possible to treat COVID-19 at home, second, it will reduce the burden on the health care system which is dying from the flow of patients, and third, molnupiravir will somehow help those who oppose vaccination or cannot be vaccinated for medical reasons.

Molnupiravir is a multibillion-dollar revenue stream for Merck & Co.: in developed economies, a five-day course of treatment would cost about $700.

A number of countries, including the U.K., have already approved the use of molnupiravir, known by the brand name Lagevrio.

Paxlovid, an oral antiviral drug from Pfizer that has demonstrated significantly better efficacy in treating COVID-19, is awaiting regulatory approval.

 

Details

The key message of the panel discussion is that the expert debates about molnupiravir were organized primarily because of its unimpressive efficacy, with no way to call its oral formulation as therapeutic progression, rather than its intravenous formulation.

Still, according to FDA experts, molnupiravir should be approved because the COVID-19 pandemic is still an emergency situation, and an oral drug would organically complement the existing (but still scarce) arsenal against SARS-CoV-2. Again, molnupiravir would be a definite lifesaver for those unwilling or unable to be vaccinated and would act as an alternative to monoclonal antibodies, which may not be effective in the face of the threat of the Omicron variant of the coronavirus.

However, patients should be cautioned that the use of molnupiravir in pregnant or lactating women and children is unlikely to be justified because of the potential toxicity of the drug.

Other experts who have spoken out against molnupiravir pointed to the fact that there are difficult to explain differences between the interim and final results of COVID-19 treatment efficacy. Why did the first analysis show that molnupiravir reduced the risk of hospitalization and/or death by 48%, while the second found that the risk was reduced by 30%? Neither Merck & Co. nor the FDA could give a specific reason.

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Yes, according to a subgroup analysis of patients, molnupiravir did better with the coronavirus variants Gamma and Mu than with the Delta variant, but that does not explain the dramatic drop in efficacy in any way. Merck & Co. itself was quite surprised: some regression to the mean was expected after all the data had been collected, but not as impressive. Among the likely reasons: the overwhelming dominance of the Delta strain of SARS-CoV-2; more female participants in the clinical trial, who are less likely than men to be hospitalized or die from COVID-19; more elderly and diabetic patients (their risks are higher); and subjects from Europe (possible problems in following the trial protocol) in the final data analysis.

Another issue for the Committee was how molnupiravir works, which stimulates SARS-COV-2 mutagenesis to make it incapable of replication. There were concerns that, in theory, this would increase the likelihood that new variants of the coronavirus would emerge that were resistant to treatment or vaccination. Of course, a variety of strains are born in abundance on their own, but a multi-million army of patients taking molnupiravir could well accelerate the process dramatically. Meanwhile, the FDA has assured that there is no evidence that the emergence of SARS-CoV-2 spike protein amino acid sequence changes has affected patients’ virological or clinical outcomes.

Merck & Co. has indicated that it will strongly encourage people to complete 5-day courses of treatment to avoid the emergence of SARS-CoV-2 variants with drug resistance. At any rate, the information so far is that no cases of infection with the coronavirus have been identified on day 5 by completing the full course of treatment. In addition, molnupiravir suppresses the replication of the virus, preventing it from evolving or being transmitted to other people.

If we talk about the effectiveness of molnupiravir in counteracting the Omicron variant, around which there is a lot of research now, there are no unequivocal data on this yet. Although the peculiarities of the mechanism of action of molnupiravir suggest that it is independent of the characteristics of any SARS-CoV-2 strain, circulating or future. Merck & Co. are going to organize the appropriate testing: it will take a relatively long time, since they will have to collect an extensive set of data relevant to the entire genome of the Omicron variant, rather than its individual fragments.

Julia Mardi

BioPharma Media’s Scientific Editor.

Julia strives to recognize in advance in which direction the pharmaceutical industry is moving. Her professional interests include gene therapy, immune checkpoint inhibitors, molecular biology, and drug repurposing.

For more information about Julia and her contact data, see Our Team.

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