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How Molnupiravir Moved to the Head of the 'COVID Pill' Pack

— Work on the broad-spectrum antiviral started over a decade ago at Emory

MedpageToday
The chemical structure of molnupiravir over a photo of a woman in a sari and the rooftops of Delhi, India

As coronavirus cases rage in India, Merck that it has entered into non-exclusive voluntary licensing agreements with five manufacturers of generic drugs in that country to speed and expand access to molnupiravir, an antiviral that is currently being studied in the phase II/III clinical trial of outpatients with COVID-19.

"This isn't just India's problem. This is the world's problem. We live in a very interconnected world, and we're all in this together," George Painter, PhD, said at a Tuesday press conference at Emory University about the Merck announcement. "We're quite pleased with Merck's announcement this morning. This certainly is in line with the mission that DRIVE was conceived to meet."

Painter is the CEO of , a nonprofit biotech company affiliated with Emory University in Atlanta. At DRIVE, the focus is on developing treatments for emerging and re-emerging infectious diseases, particularly those that affect underserved and underdeveloped countries.

DRIVE is also credited with the invention of molnupiravir, formerly called EIDD-2801.

Molnupiravir is a small molecule drug being investigated as an oral antiviral with broad spectrum activity against RNA viruses such as SARS-CoV-2. The drug acts as a ribonucleoside analog for an enzyme called RNA-dependent RNA-polymerase, which SARS-CoV-2 uses to replicate. Essentially, molnupiravir insinuates itself into the RNA of the virus, which increases the viral mutation rate to the point that the virus can no longer replicate and dies -- a process called .

Early Development of Molnupiravir

on molnupiravir goes back to 2003, when researchers at Emory were studying a related compound called EIDD-1931/NHC. Laboratory studies in human cell lines and mice suggested that EIDD-1931/NHC was active against a range of RNA viruses including the hepatitis C virus, seasonal and pandemic flu viruses, and coronaviruses such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). But EIDD-1931/NHC was not well absorbed orally, and that earlier work also suggested it could possibly induce mutations in host cells. So it was set aside, Painter said at the briefing.

In 2013, the Defense Threat Reduction Agency requested proposals to find treatments for , an RNA virus that is endemic to the Americas and causes potentially deadly encephalitis. Researchers at DRIVE screened drug libraries of known antiviral compounds with broad activity against RNA viruses, and found EIDD-1931/NHC. By changing the they made it into a (an inactive drug that is converted into an active drug after absorption) that had better oral absorption, which they called EIDD-2801, later renamed molnupiravir.

"As we began investigating the drug candidate, we found that it had broad spectrum activity against a number of respiratory viruses, including avian influenza, which can be fatal, and the pathologic coronaviruses including SARS-MERS and ultimately SARS-CoV-2," Painter said during the press conference.

EIDD-2801 also appeared to have qualities that would make it useful in a public health emergency, Painter explained. It has a specific target on RNA viruses. It is orally available and can be self-administered, making it useful for diseases that are widespread and have an acute onset. It crosses the blood-brain barrier, which is important for treating viruses that can infect the central nervous system. It is robustly and quickly distributed to the lungs, making it useful for treating respiratory infections. And its onset of activity is quick, making it useful for treating viruses that have a narrow window of opportunity for treatment, such as early in infection, he said.

Additionally, in ferrets and human airway cells infected with influenza suggested the drug may create a barrier to antiviral drug resistance, an increasing problem that is occurring with flu antivirals.

Those earlier studies lead to a research grant from the National Institute of Allergy and Infectious Diseases (NIAID) to study the drug in phase I and II studies in healthy humans made experimentally sick with the flu.

Later Development: Partnering with Ridgeback BioTherapeutics and Merck

In late 2019, researchers at DRIVE were in the process of filing an investigational new drug (IND) application for EIDD-2801 for the treatment of influenza. But when the pandemic hit, human trials of the drug in influenza were put on hold and "all resources were directed toward COVID-19," Painter told ľֱ by email.

DRIVE formed a partnership and transferred their IND to Ridgeback BioTherapeutics in January 2020. Ridgeback quickly started a phase I study that looked at pharmacokinetics, safety, and tolerability of EIDD-2801 in humans.

Within 9 weeks, results from the phase I study showed that the drug had "good oral bioavailability, was well tolerated, and had a good safety profile," Painter said at the press conference.

The randomized double-blind controlled study included 130 healthy participants who were given different doses of molnupiravir or placebo. Results helped to establish dosage and showed that the drug was rapidly absorbed within less than 2 hours. Less than half of participants reported adverse events, and 93.3% of reported adverse events were mild. No serious adverse events were reported.

In partnership with Merck, Ridgeback next started a phase II trial, results of which were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in March 2021. The trial included 175 participants with confirmed COVID-19, including non-hospitalized individuals, who were randomized to twice daily molnupiravir or placebo.

At 5 days follow-up, no infectious virus could be grown from nose swabs taken from participants who received molnupiravir. In comparison, 24% of participants who received placebo still had infectious virus on nose swabs at day 5 (P=0.001).

"The hope is that the drug impacts transmission and early stage of disease, and lowers the burden on an already burdened healthcare system," Painter said during the press conference.

So far, animal studies seem to support the idea that molnupiravir could block transmission of the virus. A in ferrets infected with SARS-CoV-2 has shown that treatment with molnupiravir stopped spread of the virus from infected animals to cage-mates.

"Like any direct-acting antiviral, molnupiravir will be more successful the earlier that it's given, to either eliminate the viral burden or significantly lower it to where clinical manifestations of disease and viral shedding are minimized. So that you both impact the need for advanced medical treatment and you arrest the spread of disease," Painter added.

Since presentation of the phase II results, Merck has that the phase III trial of molnupiravir will proceed in outpatients only. Based on interim analyses, Merck has said that "molnupiravir is unlikely to demonstrate a clinical benefit in hospitalized patients."

Following recommendations of an external data monitoring committee, the MOVe-OUT outpatient trial will focus on patients at high risk for severe illness and early treatment within 5 days of symptom onset, based on subgroup analysis suggesting potential benefit in these groups.

Merck has said that molnupiravir has gone through comprehensive , which have suggested that the compound does not induce mutations in mammalian cells.

In the development of molnupiravir, DRIVE also worked with collaborators at the Georgia Research Alliance Venture, Georgia State University, University of North Carolina at Chapel Hill, Vanderbilt University, Utah State University, and Colorado State University.

All for the post-licensing development of EIDD-2801/molnupiravir have been provided by Ridgeback Biotherapeutics and Merck. Emory University holds the patents and retains royalties to molnupiravir, according to Painter.