If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.


Global Health


Two COVID-19 antiviral pills advance to late-stage trials

Merck’s and Ridgeback’s molnupiravir and Pfizer’s PF-07321332 could stop infection early enough to prevent hospitalization

by Megha Satyanarayana
September 7, 2021


Two COVID-19 antivirals in pill form are now in Phase 3 trials, raising hopes that a proven oral treatment will soon be available to quell SARS-CoV-2 infection.

The structure of molnupiravir.

Merck & Co. with partner Ridgeback Biotherapeutics are well into a Phase 3 trial of molnupiravir as a treatment for people who are in early infection. The firms announced this week that they are enrolling uninfected people who live with someone who is COVID-19 positive in a new Phase 3 trial to test the small molecule’s ability to prevent SARS-CoV-2 infection.

The structure of PF-07321332.

Pfizer’s PF-07321332, in combination with the HIV antiviral ritonavir, has begun Phase 2/3 testing as a treatment for people who are infected with SARS-CoV-2 but who are less likely to be hospitalized with COVID-19.

Support nonprofit science journalism
C&EN has made this story and all of its coverage of the coronavirus epidemic freely available during the outbreak to keep the public informed. To support us:
Donate Join Subscribe

As the pandemic reaches the 18-month mark, there is still only one antiviral approved for use by the US Food and Drug Administration to treat COVID-19. Remdesivir, from Gilead Sciences, is an injectable drug that must be given in a hospital setting. COVID-19 starts off as a viral infection that can be mild, but it progresses in many people to an inflammatory disease that can kill. Some clinicians have said that by the time someone is hospitalized and eligible to receive remdesivir, the inflammatory symptoms have taken over, thwarting the antiviral’s effect.

Having an antiviral in pill form would take the burden off hospitals, says Daria Hazuda, an antiviral expert and vice president of infectious disease discovery at Merck. A pill would also be easier to disseminate to patients and be easier to take, bolstering compliance.

“There’s a lot of excitement for the potential of oral agents, not just for treatment,” Hazuda says. “The other huge advantage is the use of oral therapies for prevention.”

Molnupiravir works by confusing SARS-CoV-2’s polymerase, the enzyme that builds the viral genome during replication. The drug looks enough like some of the natural building blocks that the enzyme incorporates it into the replicating virus, creating mutations in its genetic code, Hazuda says. The virus can copy itself, she says, but with the drug in its genome, it’s weak or non-infectious.

In earlier treatment trials, molnupiravir was not effective in curbing disease in people who were hospitalized. The drug somewhat reduced hospitalization and death in early trials and did appear to reduce viral load in people who were infected.

Pfizer’s molecule curbs the main protease of SARS-CoV-2, preventing the virus from copying itself. Its companion, ritonavir, is also a protease inhibitor and is often used as part of combination HIV therapies. The company unveiled the structure of PF-07321332 at the 2021 American Chemical Society Spring Meeting.

A trial of people who are infected and at risk of hospitalization is underway. The trial is randomized and double-blind—so neither the volunteer or the clinician knows what the volunteer is getting—and placebo-controlled. It has just begun, and the company wants to enroll about 1,110 people.

Merck’s trials are also randomized, double-blind, and placebo-controlled. The company expects to enroll more than 1,300 people in the new prevention trial and hopes to have data after the end of the year. It hopes to have data from its Phase 3 treatment trial by the end of the year, Hazuda says.

The arc of COVID-19 has been somewhat unpredictable, with the emergence of new variants, and this might affect enrollment, she says. But one thing the company will do is a genetic analysis of each participant to see what variant of SARS-CoV-2 they have. Delta is surging right now, but it’s not the only possibility.

Aaron Weinberg, who runs clinical research for Carbon Health, which is participating in the Merck trials, says his firm is recruiting unvaccinated volunteers from different parts of California for the treatment and prevention trials. For the treatment trial it is working with people who have decided to forego antibody treatments, which are part of the standard of care in early infection. Participants are being monitored for infection and progression of disease. If they get sick or worsen, they will be offered standard treatment.

Weinberg says an oral treatment for COVID-19 would be a game changer in how doctors manage the disease. “A doctor could call in a prescription to someone’s pharmacy, they can even get it delivered to their home and they can immediately take it as soon as they have onset of symptoms,” he says.

Molnupiravir has a possible extra benefit, Hazuda says: in preclinical testing it can work on other coronaviruses, making it a potential tool for preparedness for future pandemics. Many companies started developing antivirals during the SARS epidemic, but once the virus fizzled out, the funding fizzled too.

When asked if continued funding of antiviral development might mean we would have had an antiviral ready when SARS-CoV-2 emerged, she says, “I think we probably would have.”



This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.