On November 30, the world's first oral COVID-19 drug, Molnupiravir, was granted emergency use authorization from the U.S. Food and Drug Administration (FDA), but only in high-risk populations. Two weeks after the emergency approval, the FDA is still weighing Merck's application.
This pending consideration may indicate uncertainty about the effectiveness and safety of the antiviral drug. The full trial data submitted by the company suggests that the effectiveness of monubiravir in treating patients with COVID-19 is only 30 percent, down from 50 percent of earlier studies. On the other hand, the possibility that the drug, in the process of destroying viral genes, may lead to the production of new variants of the virus, or even cause mutations in human DNA, has raised concerns among scientists. In addition, the drug may also bring certain risks to pregnant women and developing fetuses.
Lower-than-expected efficacy: "little difference" between late trials and placebo
As the world's first oral COVID-19 drug, monupiravir is seen as expected to change the way COVID-19 is treated. Last month, the United Kingdom and the United States approved the emergency use authorization of monubiravir, and Canada is also recently in the process of approving applications for the drug. However, the full clinical trial data showed that the efficacy was lower than expected.
Infographic. On November 30, monumpilavi was granted emergency use authorization by the FDA, but only for high-risk groups.
"It's not that good." Catherine Selry-Radek, an antiviral drug expert at the University of Maryland at Baltimore, said. According to data from early trials released by Merck, monumiravir reduces the risk of hospitalization or death for people infected with COVID-19 by about half. But the company later admitted that their eventual analysis found that the drug-related effectiveness was only 30 percent, down from 50 percent observed earlier in the trial.
Merck reportedly found that patients taking the drug had a 50% lower hospitalization rate and mortality rate than those who took a placebo after conducting the first set of trials from May to early August. However, in the second set of trials conducted from August to October, there was little difference in efficacy between taking the drug and taking a placebo. At the NOV.30 meeting of the FDA's advisory board, Katonis, senior vice president of clinical research at Merck, said it was "impossible to explain" the very different results of the two trials.
FDA experts point out that this may mean that this oral drug is not as effective as the Delta variant. The Delta variant has not yet dominated the global outbreak during the first trial, but has become dominant during the second trial.
Infographic. In the second set of trials conducted in August to October, there was little difference in efficacy between taking the drug and taking a placebo.
Merck remains underlining that its COVID-19 oral medications remain beneficial in reducing hospitalizations, especially in areas where infection rates are surging. Ultimately, the FDA Advisory Committee voted 13-10 to recommend the emergency use of the authorization. But experts say it is difficult to decide "whether the benefits of monupipvir outweigh its largely unknown risks."
There are risks in the mechanism of action: drugs may create "more dangerous variants"
At the Nov. 30 meeting, Merck reported that monubiravir was well tolerated by trial participants with few potential side effects. But some researchers worry that the antiviral drug's novel mechanism of action of "introducing mutations into the viral genome" could pose long-term safety risks.
"The principle of action of monumpilavi is to disguise itself and spread the error throughout the genome of the virus." Campbell, an antiviral drug expert at Rockefeller University, said the metabolites produced by monubiravir entering the body resemble one of the RNA building blocks inside the virus. Once the coronavirus enters the host cell and begins to replicate, the metabolite is absorbed by the RNA-dependent RNA polymerase (RdRp) and integrated into the virus's genome, eventually making it impossible for the virus to survive by "inserting" enough errors.
The mechanism of action of monupiravir
Committee experts voting against said the deliberate introduction of mutations into viral RNA by monupiravir could produce a "more dangerous version of the coronavirus." In this case, the spike protein of the virus may mutate, potentially making it more contagious or able to evade vaccine immunity. If people do not complete a complete course of taking 40 tablets of monubiravir for 5 consecutive days, some mutated viruses may survive in the human body and be transmitted to others.
In response, Katonis stressed that after a 5-day course of treatment, the company did not detect any remaining viruses among trial participants. While some researchers believe that most genetic mutations are either harmful viruses or do not affect their function, it is not impossible for a completely mutated version of the new coronavirus to survive the action of antiviral drugs and "become powerful."
Or causes a mutation in human DNA? Experts: It is never recommended for pregnant women
In addition, the committee discussed the potential risks of the drug to individuals. Some laboratory tests have shown that monubiravir can cause mutations in DNA, especially in rapidly reproducing cells such as blood cells. The same metabolites produced by the drug that interfere with the replication of viral genetic material can also be converted into compounds that resemble DNA building blocks, theoretically creating birth defects.
"Do we want to reduce the risk of infection (hospitalization or death) in pregnant women by 30 percent, while exposing embryos or fetuses to greater risk of drug harm?" Dr Hildreth, dean of Mehari Medical School, said at the conference, "My answer is no, and under no circumstances would I recommend this medication to pregnant women." ”
Although tests conducted on animals have shown that there is a lower risk of causing DNA mutations or causing birth defects. But many members of the FDA's advisory board advised the agency to "proceed with caution," especially when treating pregnant women. Either a serious warning of monupipil is raised or children under 18 years of age and pregnant women are prevented from receiving treatment with the drug, unless there are more data indicating the safety of the drug in treating such populations.
Given the questioning of the efficacy and potential risks of monubiravir, efforts to find an effective antiviral oral administration are continuing. In contrast, monoclonal antibody therapy can reduce the risk of severe COVID-19 by 85%, but such drugs are expensive, especially in the case of the rapid spread of the new variant of Omikeron, and are not suitable for relatively poor and under-resourced countries and regions.
In early November, Pfizer announced that preliminary results showed that its antiviral drug Paxlovid reduced hospitalizations and deaths by 89 percent, but the full data has not been released or peer-reviewed. Medicinal chemist Catherine Sely-Radek said that despite the decline in the effectiveness of the monumpiravir trial, it is still hoped that research on the drug and Paxlovid could lead to effective "mixed drug therapies" to kill the new coronavirus.
"It is more difficult for viruses to develop resistance to multiple drug combinations than to a single drug." Sairey-Radek said cocktail therapy with eventual antiviral drugs in combination "could be a better answer."
Red Star News reporter Wang Yalin Intern reporter Hu Yiling
Edited by Zhang Xun
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