Written by Katharine Lang
In October 2021, a global trial, led by the pharmaceutical company Merck — known as MSD outside the United States and Canada — and Ridgeback Therapeutics, has found that the companies’ experimental antiviral drug molnupiravir reduces the risk of hospital admission or death from COVID-19 by approximately 50%.
The initial positive results have led to countries rushing to sign up for supplies of the drug.
In the randomized, phase 3 trial, scientists gave molnupiravir or a placebo to 775 people. All the participants had tested positive for SARS-CoV-2 and experienced mild to moderate COVID-19 symptoms that had begun no more than 5 days earlier.
Every participant had at least one risk factor for severe COVID-19 but had not been admitted to the hospital. Risk factors included obesity, an age of over 60 years, diabetes, and heart disease.
The scientists allocated each of the 775 participants randomly to one of two groups. One group received molnupiravir and the other a placebo. The participants took the capsules twice per day for 5 days.
Of the 385 patients taking molnupiravir, 28 were admitted to the hospital, compared with 53 of those in the placebo group. Eight of the placebo group participants died, while all those receiving the antiviral were alive at the end of the 29-day study period.
Recruitment into the study has now been halted because of these overwhelmingly positive results. The manufacturer, Merck, applied for emergency use authorization from the Food and Drug Administration (FDA).
The Singapore health ministry has signed a purchase agreement for molnupiravir, and the European Medicines Agency is considering a rolling review of the drug.
“With these compelling results, we are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”
– Robert M. Davis, chief executive officer and president of Merck
Merck plans to produce 10 million courses of the treatment in 2021 and more in 2022.
The study results have been greeted with optimism. Prof. Tim Spector, a professor of genetic epidemiology at King’s College London, told MNT, “This is an exciting result from a randomized study of 775 patients, showing major effects in reducing severity and death from a simple pill given at the onset of infection.”
What is molnupiravir?
Molnupiravir belongs to a class of antivirals called mutagenic ribonucleosides. These change the viral genetic material and introduce errors to prevent replication and transcription of the viral genome.
Inside the host cell, molnupiravir is converted to molnupiravir triphosphate. When the virus tries to replicate, molnupiravir triphosphate is incorporated into the viral RNA instead of the nucleoside cytidine, causing a mutation.
The mutation stops the virus from replicating. This keeps numbers of the virus in the body low and should reduce the severity of the disease.
Other drugs that interfere with viral RNA have shown potential as COVID-19 treatments. Remdesivir, an intravenously administered drug that interferes with an enzyme essential for replicating viral RNA, showed early promise.
Although the FDA has granted approval to remdesivir, the World Health Organization (WHO) no longer recommends it as a COVID-19 treatment, due to insufficient evidence to support its use.
The advantage of molnupiravir is that, unlike all the other potential treatments so far, it is an oral tablet that a person can take outside a clinical setting. At a projected cost of around $700 per person for a 5-day course, it is also more affordable than other drugs. However, this cost is still likely to limit its use.
“Antiviral treatments that can be taken at home to keep people with COVID-19 out of the hospital are critically needed. We are very encouraged by the results from the interim analysis and hope molnupiravir, if authorized for use, can make a profound impact in controlling the pandemic.”
– Wendy Holman, chief executive officer of Ridgeback Biotherapeutics
‘Not a magic pill’
Prof. Sir Peter Horby, a professor of emerging infectious diseases and global health at the University of Oxford, is largely optimistic, “A safe, affordable, and effective antiviral would be a huge advance in the fight against COVID.”
However, he retained a note of caution: “It is important to remember that the absolute risks were 14% reduced to 7%, so quite a lot of people need to be treated to prevent one hospitalization or death. This means the drug needs to be very safe and affordable.”
This caution was echoed by Prof. William Schaffner, a professor of infectious diseases at the Vanderbilt University School of Medicine, who said: “In the studies in very high risk patients, it reduced the level of serious disease by only half. It’s not a magic pill.”
He added: “In research settings, you can ensure that people take the pill as directed. In practice, there is usually a lower success rate than in clinical trials.”
Indeed, since the publication of the original trial results in October, Merck has published an update, which was based on more complete data from all the participants enrolled in the Merck study — 1,433 people in total. The new data analysis brought the relative risk reduction of hospitalization with COVID-19 down to 30% from the initial 50%.
Dr. Peter English, a retired consultant in communicable disease and a past chair of the British Medical Association Public Health Medicine Committee, has also expressed doubts, “The problem for antivirals like Merck’s molnupiravir is that they would have to be used before people are (usually) deemed ill enough to need anything other than symptomatic self-care treatment.”
“Unless an antiviral medication could be made so cheap and so safe that it can be used ‘on spec’ by people who might have COVID-19, [it is] unlikely to be widely useful,” he adds.
Despite widespread optimism following the study results, some experts have raised concerns about the safety of a drug that works by causing mutations.
As molnupiravir causes viral RNA to mutate, there are concerns that it might cause mutations in host cells, as well. One study in animal cell cultures found mutations in cells treated with molnupiravir.
This has led to worries that the drug might cause cancers or birth abnormalities. The authors of the animal cell study recommend that this mutagenic potential be assessed in vivo, focusing on rapidly dividing cells. Additionally, they recommend monitoring to assess potential genotoxic side effects.
“It’s worth noting that people involved in the trial were instructed to abstain from heterosexual sex or use contraception. While this is routine practice with some other medicines, such as cancer chemotherapy, it suggests that the drug has the potential to cause birth defects should someone become pregnant.”
– Dr. Simon Clarke, associate professor of cellular microbiology at the University of Reading
Prof. Schaffner was less concerned about the possible genetic implications: “The FDA would certainly not have permitted clinical trials in humans if they thought there were any reasonable danger. […] Animal studies showed no adverse effects.”
In this trial, molnupiravir was effective against all variants, including the Delta variant, which was shown in a recent study to have a 235% increased risk of intensive care unit admission, compared with the original variant.
These positive results applied to people who had received molnupiravir soon after the onset of mild to moderate symptoms. A previous trial showed no benefit in giving the drug to patients already in the hospital with COVID-19.
As an early treatment, molnupiravir could, Prof. Schaffner agrees, “offer another opportunity to prevent serious disease.”
“Although [this trial] had relatively small numbers analyzed (fewer than 400 per group), it had much better results than the study done in hospitalized patients. It approximately halved the rate of hospitalization and notably reduced the number of deaths. Preventing the virus from replicating at an early stage seems very beneficial.”
– Prof. Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine
So, is molnupiravir the drug we have been waiting for to bring COVID-19 under control? Perhaps, but the evidence is not yet conclusive.
Prof. Spector is among those keen to see more trial results. “We are told there were few side effects, but it would be good to know more details and see a full peer-reviewed publication,” he said. “But if this pans out, it will be a major game changer for [COVID-19] treatment and possibly other viruses.”