June 3, 2023

Meet molnupiravir, Merck’s Thor-inspired pill that hammers COVID

Meet molnupiravir, Merck’s Thor-inspired pill that hammers COVID
Meet molnupiravir, Merck’s Thor-inspired pill that hammers COVIDMeet molnupiravir, Merck’s Thor-inspired pill that hammers COVID
A Merck sign stands in front of the company's building on October 2, 2013, in Summit, New Jersey.
Enlarge / A Merck sign stands in front of the company’s building on October 2, 2013, in Summit, New Jersey.

An oral antiviral drug appears to cut the risk of hospitalization and death from COVID-19 by roughly 50 percent in people newly diagnosed with the infection and at risk for severe disease, pharmaceutical company Merck announced Friday morning.

The drug-maker and its partner, Ridgeback Biotherapeutics, released top-line results of a Phase III trial, which the companies ended early given the positive results. The companies say they will apply for an Emergency Use Authorization from the US Food and Drug Administration as soon as possible.

The trial enrolled people who had newly tested positive for a SARS-CoV-2 infection and had onset of mild-to-moderate COVID-19 symptoms within just the past five days of starting the trial. The enrollees also had to have at least one risk factor for a poor outcome, such as having obesity, diabetes, heart disease, or being age 60 or above. While some participants received a placebo and standard care, others took an oral dose of the drug every 12 hours for five days.

After 29 days of follow-up, 53 out of 377 participants who received the placebo were hospitalized with COVID-19, and eight of those participants died. Among those who received the drug, only 28 of 385 were hospitalized and none of those patients died. Put another way, 7.3 percent of patients on the drug were either hospitalized or died compared with 14.1 percent in the placebo group.

Merck also highlighted that the trial was global and that the drug appeared to work equally well against varying SARS-CoV-2 variants, including delta, gamma, and mu. The drug-maker noted that it had viral genetic data to identify variants from 40 percent of participants.

The safety data was equally promising, with participants reporting similar numbers of drug-related adverse events between the placebo group than the drug group (11 percent and 12 percent, respectively). About 3.4 percent of people in the placebo group quit the study due to adverse events, while only 1.3 percent quit in the drug group.

Pharmaceutical mythology

The drug at the center of these seemingly smashing results is dubbed molnupiravir—a name inspired by that of Thor’s hammer, Mjölnir. The idea is that the drug will strike down SARS-CoV-2, like a mighty blow from the god of thunder. In an interview with Stat news, Merck’s head of research and development, Dean Li, said that the new data proves the drug’s mythological force. “Our prediction from our in vitro studies and now with this data is that molnupiravir is named after the right [thing]… this is a hammer against SARS-CoV-2 regardless of the variant.”

Molnupiravir is a small molecule that wallops the work of a viral RNA-dependent RNA polymerase, an enzyme critical for making copies of RNA viruses, such as SARS-CoV-2. The drug had been in the works for years before SARS-CoV-2 emerged and, in March of 2020, it was on the verge of entering clinical trials for use against influenza. At that point, Ridgeback partnered with the drug’s non-profit developers at Emory University to turn it against SARS-CoV-2. A few months later, in May, Ridgeback and Merck announced a collaboration to develop the drug, then called EIDD-2801, into a COVID-19 treatment.

Molnupiravir delivers a precise blow to viral RNA polymerase by posing as a building block for RNA. In the body, molnupiravir is forged into a deceptive ribonucleoside that the polymerase unwittingly incorporates into new strands of viral RNA instead of cytidine. This is essentially lethal. Researchers call the effect a “viral error catastrophe,” in which the rate of genetic mutations or errors exceeds a threshold compatible with the virus surviving.

These types of nucleoside decoy drugs raise concerns of creating problems for human enzymes, too. For this reason, pregnant people were carefully excluded from trials. However, so far, all the animal and clinical trials have suggested good safety results.

In early animal studies with other coronaviruses, namely SARS-CoV and MERS-CoV, molnupiravir improved lung function, lowered viral loads, and improved infection-related weight loss. Other early studies showed molnupiravir also worked to kill off SARS-CoV-2 infecting cells from human airways.

The new clinical data suggests that, when given early, molnupiravir can bash out the worst-case scenarios of COVID-19. Its easy-to-use oral pill is also an advantage worth noting. Remdesivir, another antiviral drug used against COVID-19, must be given intravenously. If molnupiravir gains FDA authorization, it would certainly be another useful tool against COVID-19. However, vaccines will remain the best tool for pounding out the pandemic, smashing down not only severe disease and hospitalization but infection and transmission as well.