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

An oral antiviral drug appears to reduce the risk of hospitalization and death from COVID-19 in people newly diagnosed with the infection and at risk of serious illness by about 50%, pharmaceutical company Merck said Friday morning.

The drugmaker and its partner Ridgeback Biotherapeutics have released the first results of a Phase III trial, which the companies terminated earlier based on the positive results. The companies say they will apply for emergency use authorization from the United States Food and Drug Administration as soon as possible.

The trial recruited people who had recently tested positive for SARS-CoV-2 infection and exhibited mild to moderate symptoms of COVID-19 in just the past five days after starting the trial. . Registrants also had to have at least one risk factor for a poor outcome, such as obesity, diabetes, heart disease, or age 60 or older. 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 of the 377 participants who received the placebo were hospitalized with COVID-19, and eight of those participants died. Of those who received the drug, only 28 of 385 were hospitalized and none of those patients died. In other words, 7.3 percent of patients on the drug were hospitalized or died, compared to 14.1 percent in the placebo group.

Merck also pointed out that the trial was global and that the drug appeared to work equally well against various variants of SARS-CoV-2, including delta, gamma and mu. The drugmaker noted that it had viral genetic data to identify variants in 40% of participants.

Safety data was equally promising, with participants reporting a similar number of drug-related adverse events between the placebo group and the drug group (11% and 12%, respectively). About 3.4 percent of people in the placebo group quit the study because of adverse events, while only 1.3 percent quit in the drug group.

Pharmaceutical mythology

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

Molnupiravir is a small molecule that speeds up the work of a viral RNA-dependent RNA polymerase, an enzyme essential for making copies of RNA viruses, such as SARS-CoV-2. The drug had been in the works for years before the emergence of SARS-CoV-2, and as of March 2020, it was set to enter clinical trials for use in influenza. At this point, Ridgeback has teamed up with the nonprofit developers of the drug 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 hit to viral RNA polymerase by presenting itself as a building block of RNA. In the body, molnupiravir is forged into a deceptive ribonucleoside that the polymerase unintentionally incorporates into new strands of viral RNA instead of cytidine. It is essentially fatal. The researchers call the effect a “viral error catastrophe”, in which the rate of genetic mutations or errors exceeds a threshold compatible with the survival of the virus.

These types of nucleoside decoy drugs also raise concerns about creating problems for human enzymes. For this reason, pregnant women were carefully excluded from the trials. However, so far all 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, reduced viral loads, and improved infection-related weight loss. Other early studies have shown that molnupiravir also works to kill cells infecting SARS-CoV-2 in the human respiratory tract.

New clinical data suggests that, when given early, molnupiravir can eliminate the worst case scenarios of COVID-19. Its easy to use oral pill is also a bonus. Remdesivir, another antiviral drug used against COVID-19, must be administered intravenously. If molnupiravir gets clearance from the FDA, it would certainly be another useful tool against COVID-19. However, vaccines will remain the best tool to fight the pandemic, eliminating not only serious illness and hospitalizations, but also infections and transmission.