In the search for effective COVID-19 treatments, many drugs failed to live up to their early promise. The antiviral molnupiravir performed well in trials, reducing hospitalizations and deaths among those at high risk. Medical News Today has revisited the evidence and looked at new findings to see whether molnupiravir has realized its potential.

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The experimental drug molnupiravir has brought fresh hope in the fight against COVID-19. But what do we know about it so far? Image credit: Jordan Lye/Getty Images

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In October 2021, a global trial investigated an experimental viral drug called molnupiravir, which is branded Lagevrio outside the United States.

The research was led by the pharmaceutical company Merck — known as MSD outside the U.S. and Canada — and Ridgeback Therapeutics.

The scientists found that the drug reduced the risk of hospital admission or death from COVID-19 by approximately 50%.

The World Health Organization (WHO) has now conditionally recommended its use for some people with COVID-19 who have the highest risk of hospital admission.

In the initial 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 daily 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.

These overwhelmingly positive results brought recruitment into the study to a halt. In December 2021, the Food and Drug Administration (FDA) granted the manufacturer, Merck, emergency use authorization.

The United Kingdom government has signed up for more than 2.2 million courses of the antiviral. The European Union has not yet authorized molnupiravir for use but recently completed a review of the treatment with a view to possible authorization.

“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

The study results gave rise to optimism. Prof. Tim Spector, a professor of genetic epidemiology at King’s College London, told Medical News Today, “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.”

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.

The advantage of molnupiravir is that, unlike most other treatments so far, it is an oral tablet that a person can take outside a clinical setting.

In trials, the monoclonal antibody treatment sotrovimab was more effective, reducing hospitalizations and deaths to below 1%, compared with almost 7% for molnupiravir. However, a person must receive it intravenously, meaning directly into a vein, which limits its use outside hospital settings.

“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

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-19.”

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 told MNT: “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 it 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%.

A randomized controlled phase 3 trial, published in February 2022, confirmed that molnupiravir had reduced the likelihood of hospitalization or death in those at high risk of COVID-19.

Of the 1,433 participants, 6.8% of the treatment group and 9.7% of the placebo group were hospitalized or died by day 29 of the trial. The researchers reported one death in the molnupiravir group and nine in the placebo group.

However, molnupiravir did not perform as well as Paxlovid, produced by rival drug company Pfizer. In a trial involving 2,246 participants at high risk, 0.7% of those taking Paxlovid were hospitalized and none died, and 6.5% of those receiving placebo were hospitalized or died.

Both drugs are orally administered tablets. Molnupiravir is taken as 4 tablets twice per day, and Paxlovid as 3 tablets twice daily. Molnupiravir is more expensive, at $712 for a 5-day course, compared with $530 for Paxlovid. Both antivirals must be taken within 5 days of first symptoms.

“Here, in the U.S., we have both molnupiravir and Paxlovid. The general sense is, frankly, that Paxlovid is more effective.”

– Prof. William Schaffner

The WHO bases its conditional recommendation on results from six randomized controlled trials with a total of 4,796 participants.

However, it states that, because of the lack of safety information, doctors should prescribe molnupiravir only to patients with “non-severe” COVID-19 at the highest risk of hospitalization. These individuals include:

  • older adults
  • people who have not received a COVID-19 vaccination
  • those with immunodeficiencies
  • those living with chronic conditions

A healthcare professional would need to give treatment to a person within 5 days of symptom onset.

Dr. Peter English, a retired consultant in communicable disease and a former chair of the British Medical Association Public Health Medicine Committee, 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.

Some experts did raise 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 [brith control]. 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

The WHO states that healthcare professionals should not prescribe molnupiravir to children and pregnant and nursing individuals, as there is insufficient safety data about the drug’s effects.

Anyone who has received a molnupiravir prescription should be using birth control to avoid pregnancy. Animal studies have suggested that molnupiravir may cause fetal harm when administered to pregnant individuals.

None of the studies published so far have reported any serious adverse events.

In this trial, molnupiravir was effective against all variants, including the Delta variant, which a study showed to have a 235% increased risk of intensive care unit admission, compared with the original variant.

An in vitro study has found that both molnupiravir and Paxlovid are effective against the Omicron variant.

The positive results applied to people who received molnupiravir soon after the onset of mild to moderate symptoms.

A previous trial shows no benefit in giving the drug to people already in the hospital with COVID-19. The WHO is not recommending molnupiravir for individuals who have already been hospitalized.

“I was always a little bit tempered in my optimism [about molnupiravir], but I think that for people who are older, frail, particularly immunocompromised, if molnupiravir were the only drug available, I would tell them to run, not walk. Get the drug in you as quickly as possible, because it has been shown to reduce your risk of serious disease.”

– Prof. William Schaffner

Prof. Spector was 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.”

However, when asked for an update following more trials, he was less convinced, “Having seen the latest results, the drug appears less impressive, and even if reserved for high-risk patients, there may well be better antiviral options available.”

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