We first heard about EIDD-2801 in May, 2020. Researchers were trying to develop antiviral drugs against coronaviruses well before COVID-19 arrived. A study in Science Translational Medicine described NHC/EIDD-2801. That was the early name for molnupiravir, one of the first oral drugs with antiviral activity against SARS-CoV-2. This week a panel of experts assembled by the FDA narrowly voted to recommend approval of this compound. These outside advisors voted 13 to 10 to give molnupiravir the green light. Why was the debate so intense? How well will the drug work and what are the risks?
The early findings from a mouse trial were encouraging:
“The potency of NHC/EIDD-2801 against multiple CoVs [coronaviruses] and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.”
Ever since we read that initial study, we have been interested in this drug. The company now has results from human trials, and the FDA is poised to decide whether molnupiravir deserves Emergency Use Authorization (EUA).
Fast Forward to November 30, 2021:
On Tuesday, November 30, 2021, an advisory panel of outside experts debated the future of molnupiravir at the Food and Drug Administration. The interactions were intense and the outcome was not a slam dunk for the developers, Ridgeback Biotherapeutics and Merck.
Originally, the public was told that the drug was 50% effective at reducing severe illness and hospitalizations.
Here is the Merck press release from October 11, 2021:
“The submission is based on positive results from a planned interim analysis from the Phase 3 MOVe-OUT clinical trial, which evaluated molnupiravir in non-hospitalized adult patients with mild-to-moderate COVID-19 who were at risk for progressing to severe COVID-19 and/or hospitalization. At the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 following randomization (28/385), compared with 14.1% of placebo-treated patients (53/377); p=0.0012. Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo.”
That seemed pretty impressive. We discussed the results of the trial on our radio show/podcast on November 22, 2021 with one of the early researchers. The trial of the drug was stopped early because it appeared the positive results were so clear.
What Happened on the Way to the FDA?
By the time the outside panel of experts met at the FDA on November 30, the data on the drug became less compelling.
A new press release from Merck on November 26, 2021 dampened enthusiasm:
“Data are now available from all enrolled participants (n=1433). In this study population, molnupiravir reduced the risk of hospitalization or death from 9.7% in the placebo group (68/699) to 6.8% (48/709) in the molnupiravir group, for an absolute risk reduction of 3.0% and a relative risk reduction of 30%. Nine deaths were reported in the placebo group, and one in the molnupiravir group.”
The revised outcome information was disappointing. Molnupiravir cut the risk for serious COVID-19 infection, hospitalization and death by about 30%. In this clinical trial, unvaccinated people with confirmed cases of COVID-19 took either molnupiravir or a look-alike placebo pill. All of these volunteers had pre-existing conditions putting them at high risk for severe disease. In other words, they were obese or elderly. They started taking the medicine within five days of initial symptoms.
One person taking the drug died. Nine people in the placebo arm did. About 7% of those getting molnupiravir were hospitalized, whereas roughly 10% of those on placebo ended up in the hospital. That’s not nothing, but we were disappointed when we read the final results. So were many of the experts on the FDA’s advisory panel.
What About Risks?
Concerns were raised that the drug might be dangerous for fetal development and could lead to birth defects. Because the drug interferes with the way the virus replicates itself, some experts worry that scrambling the way the virus multiplies might lead to new variants. Critics warned that if patients failed to take the full five-day dose of antiviral medicine, this risk could increase. On the other hand, five days is a relatively short course of treatment.
The drug is supposed to be effective against delta, gamma and mu variants of SARS-CoV-2. We suspect that it will also work to disrupt viral replication of the new omicron variant. It is also unlikely that the virus will be able to develop resistance to this oral antiviral medication.
Some FDA advisory committee members would have been willing to accept the possible risks of molnupiravir if the benefits had been more compelling. Despite reservations, the panel ultimately agreed that the benefits outweighed the risks. It is expected that the FDA will follow British regulators and approve molnupiravir in coming days. It is being sold in the UK as LAGEVRIO.
Emergency Use Authorization (EUA) for Molnupiravir?
It is likely that the Food and Drug Administration will go along with its outside advisory panel. We anticipate that within the next few days the agency will give the drug emergency use authorization (EUA) That is the same process that has been used for vaccines and the monoclonal antibodies. That puts it on an ultra-fast track for patient access.
The drug company has already started making pills. That’s a pretty clear indication that Merck believes the FDA will grant EUA. The US government has already committed billions for the first pills that come off the production line.
If the FDA Grants Molnupiravir Emergency Use, What’s Next?
For one thing, people who are vaccine hesitant might be willing to take molnupiravir. It could also be distributed world wide in relatively short order. Indian drug manufacturers are already gearing up production.
To be maximally effective, most antiviral medications need to be taken at the very first sign of infection. That’s how antiviral drugs like Tamiflu (oseltamivir) work against influenza. Someone exposed to the coronavirus might take molnupiravir to prevent infection. However, research has not yet demonstrated such a tactic is effective.
We have not seen the data about side effects with molnupiravir, so we don’t know how well people will tolerate this new medicine. Nonetheless, an oral drug against COVID-19 that is taken at home could be a real step forward in managing this pandemic.
That is especially true if rapid home testing identifies infection early. At the earliest stage of the illness, a doctor could write an electronic prescription and a patient could pick it up at a local pharmacy within 24 hours, if not sooner. This would give the antiviral drug the best opportunity to halt the COVID infection before it starts causing much damage.
There is another oral antiviral medicine against COVID waiting in the wings. You can learn more about Pfizer’s Paxlovid at this link.
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