Molnupiravir is one of the antiviral drugs that has caused excitement over the past few months. Preliminary clinical-trial results have shown that it can significantly reduce COVID-19 hospitalizations and deaths. However, the US Food and Drug Administration (FDA) has not yet issued an emergency authorization for Molnupiravir. A FDA advisory committee met in November and narrowly voted to approve the drug candidate for emergency approval.
Long-running discussions by the agency could indicate uncertainties about the antiviral’s safety and efficacy. Full trial data submitted to FDA show that molnupiravir may be less effective than initially thought. This dampens scientists’ hopes that this relatively inexpensive and easy-to administer treatment will change the course and end the pandemic.
The advisory committee met to discuss the results. They found that the antiviral, which was created by Merck Pharmaceuticals, Kenilworth, New Jersey and Ridgeback Biotherapeutics, Miami, Florida, reduced the risk of COVID-19 hospitalization by 30%. This is a decrease of 50% from the initial trial. Katherine Seley-Radtke is a medicinal chemist at the University of Maryland in Baltimore County who developed antiviral drugs. “That’s not all of that good.” “It’s pretty poor.” Eliav Bar, senior vice president for global medical and scientific affairs at Merck says that it would still be beneficial to reduce hospitalizations, particularly in areas where there is a rise in infections.
Monoclonal antibodies treatments reduce severe COVID-19 risk by as much as 85%. However, they can be expensive and must be administered intravenously. Therefore, finding an oral antiviral treatment for severe COVID-19 has been a top priority for scientists all over the world.
Expectations are lower
Merck’s first study group consisted of 762 people who were given 4 pills each of the antiviral and a placebo for five consecutive days between May and August. The same treatment was also given to 646 others in a second group that took place between August and October. Nearly 80% of participants were from Europe or Latin America and started the regimen within five working days of developing COVID-19 symptoms. Researchers tracked participants in each group and determined how many were hospitalized or died from COVID-19 complications. Participants’ rates of death or hospitalization dropped by half in the first group if they were given molnupiravir instead of a placebo. The outcome of the antiviral group was nearly identical to that of the placebo.
On 30 November, Nicholas Kartsonis (Senior Vice-President of Clinical Research at Merck) told FDA advisory that Merck couldn’t explain the strikingly different results. These results have not been peer reviewed. Some committee members noted that the highly transmissible Delta version of the SARS/CoV-2 coronavirus was not yet dominant in the first half of this trial, but it had by half-way. This could indicate that molnupiravir doesn’t work as well against Delta virus as it does for other variants.
Sankar Swaminathan is the University of Utah Health’s division chief for infectious disease. He believes that it is possible that the trials’ locations or demographics might have had an impact on which participants were admitted or what quality of care they received. Swaminathan was a member the FDA advisory committee that reviewed Molnupiravir.
13-10 votes were taken by the committee to approve the emergency use authorization. This is far from the unanimous approval that was expected after Merck released its preliminary trial results. The panel members struggled to decide whether molnupiravir’s many benefits outweigh the largely unknown risks.
Assessing the risks
Merck reported the same side effects rates for the trial participants as for those who took the placebo. However, some researchers worry that the novel mechanism of molnupiravir’s action could pose long-term safety concerns. The antiviral is incorporated into virus RNA and causes errors that can impede SARS-CoV-2 from reproducing.
Critics say that intentionally introducing mutations in viral RNA could lead to a more dangerous form of SARS-CoV-2. This scenario could lead to mutations in the virus’s spike protein. The virus uses this protein to gain access to human cells. It can make the virus more transmissible and able to evade vaccines. Swaminathan, who voted against molnupiravir authorization, said that this will be the main concern if people don’t complete the full 5-day, forty-pill treatment. Because some of the mutated viruses might survive and be passed on to others.
Researchers argue that it is unlikely that a perfectly mutated SARS-CoV-2 will survive the antiviral, but this is not impossible. Kartsonis pointed out that Merck failed to detect any virus among trial participants during the five-day course. However, the company didn’t test the drug on immunocompromised patients, as they might not be able to fully clear the virus from their bodies even with the antiviral.
The FDA advisory committee discussed the potential risks that could be posed to individuals in addition to those for the larger community. Although tests on laboratory dishes indicated that there was a possibility of molnupiravir causing mutations in the human genome, particularly in rapidly reproducing cells like blood cells and spermatozoas, animal tests showed that this risk is very low. Many members of the advisory panel recommended that the agency place warnings about molnupiravir and prevent pregnant women from being given it until more data is available.
Janet Cragan (a medical officer at the US Centers for Disease Control and Prevention, Atlanta, Georgia) voted against the recommendation. She said, however, that it was not possible to tell a pregnant woman with COVID-19 that she cannot have the drug, if she decides that that’s what she needs.
There is still hope
Public-health officials hope that antivirals like molnupiravir can be quickly deployed worldwide to save lives, especially since the Omicron variant is rapidly spreading.
Omicron’s effects on COVID-19 vaccine efficacy and vaccine effectiveness are still being understood by scientists. Swaminathan states that Omicron was an issue that was prominently discussed during the meeting. Although molnupiravir is able to work against all versions of SARS-CoV-2, he says it theoretically should be effective regardless of which one it encounters. However, the trial data showing its effectiveness against Delta suggests that this may not be true. A single antiviral that can be used against all forms of SARS-CoV-2 is a boon. This is especially true if current monoclonal antibodies treatments are ineffective against Omicron and future variants. He said that in such a situation, there would be very limited options for preventing hospitalizations.
The United States isn’t the only country that has considered authorizing this antiviral. The United Kingdom approved molnupiravir on 4 November. In mid-November, Bangladesh’s Beximco Pharmaceuticals based in Dhaka began selling a generic version in the country.
Public-health officials are eager to find alternative solutions due to questions about molnupiravir’s effectiveness and possible risks. Pfizer, New York City-based, released initial results that showed its COVID-19 antiviral Paxlovid reduced hospitalizations and deaths by 89%. However, the full data were not yet available or peer reviewed. The mechanism of action of Paxlovid is different from that of Molnupiravir.
Seley-Radtke believes that, despite the lower quality of the results for Molnupiravir’s research, it is possible that Paxlovid and its research could still yield effective drug cocktails that combine antivirals that kill SARS-CoV-2. She says that multi-prong attacks not only stop the virus’ growth but also slow down the development of resistance. Multi-drug combinations are more resistant than single drugs. She says that a combination of drugs is ultimately better than a single drug.
