The roll-out of COVID-19 vaccines at the beginning of 2021 marked a key turning point in the fight against the global pandemic. Another major milestone arrived at the end of the year, with the approval of two oral antiviral treatments — molnupiravir and Paxlovid — that promise to reduce the number of COVID-19 hospitalizations and deaths. But as these pills slowly make their way into pharmacies worldwide, researchers are already looking ahead to the drugs that could supersede them.
“These are our first-generation antivirals against coronaviruses,” says Sara Cherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Our experience with antivirals against other diseases, like hepatitis C and HIV, proves that “we can do better and better over time”, she adds.
Clinical-trial data showed that molnupiravir, developed by the pharmaceutical firm Merck, based in Kenilworth, New Jersey, and the biotechnology company Ridgeback Biotherapeutics in Miami, Florida, cut hospitalizations and deaths by 30%, compared with people who took placebos. Meanwhile, Paxlovid (nirmatrelvir and ritonavir), made by Pfizer, based in New York City, cut hospitalizations and deaths by 89%. UK regulators approved molnupiravir in November and Paxlovid in December, and US regulators granted emergency authorizations for both drugs in December. Other countries have followed suit with their own approvals, and many are negotiating with the drug makers to buy courses of the drugs or to manufacture their own generic versions.
For now, the pills are in short supply. Drug makers are still scaling up production of the antivirals, which are in huge demand to treat the highly transmissible Omicron variant. But when they become more widely available — and if their clinical-trial data is borne out in the real world — the pills will become vital tools to prevent people from becoming seriously ill with COVID-19, says Cherry.
It’s too soon to tell whether SARS-CoV-2 is likely to develop any resistance to these first-generation antivirals, says Tim Sheahan, a coronavirologist at the University of North Carolina at Chapel Hill. Although its sky-high rate of replication is a breeding ground for mutations, he says, the virus also causes acute infections that offer relatively little time for resistance-causing mutations to accumulate.
But the threat of resistance is particularly severe for ‘monotherapies’ such as molnupiravir and Paxlovid that each target only one part of the virus. That’s why it’s imperative to develop new antivirals aimed at different targets, or ones that can be combined into a single treatment to attack the virus on multiple fronts, says Sheahan.
A race against resistance
Successful antivirals have typically targeted two key pieces of a virus’s biological machinery, a polymerase and a protease, both of which are essential for viral replication. The current COVID pills are no exception: Paxlovid inhibits SARS-CoV-2’s main protease, whereas molnupiravir tricks its RNA polymerase into incorporating part of the drug into the virus’s RNA, creating so many errors that it cannot survive. A third drug — remdesivir, developed by Gilead, based in Foster City, California — inhibits RNA polymerase, but treatment is expensive and currently requires intravenous infusions over three consecutive days, making it inaccessible to many people.
Unfortunately, molnupiravir’s mode of attack means that it might not be wise to include it in a combination therapy, says Luis Schang, a virologist at Cornell University in Ithaca, New York. If the treatment does not completely wipe out the virus in a patient, some of the RNA errors it creates might inadvertently give the virus resistance against the other drug in the combination. That’s why it’s a key priority for researchers to find an accessible drug that effectively blocks the virus’s RNA polymerase, he says, which could be used in partnership with a protease inhibitor such as Paxlovid. One option may be an oral version of remdesivir, which Gilead is currently testing.
Other antiviral drug candidates are slowly working their way through the clinical-trial pipeline, says Carl Dieffenbach, director of the division of AIDS at the US National Institute of Allergy and Infectious Diseases (NIAID). He says that one promising candidate is a protease inhibitor, developed by Shionogi & Company, based in Osaka, Japan, and Hokkaido University in Japan, that is currently in phase II/III clinical trials in Asia. The candidate targets the same protease as Paxlovid but would only require patients to take a single pill each day.
That simpler regimen could help to avert the rise of resistance, Cherry says. Unfinished treatments can hasten drug resistance by allowing the virus to develop defences against the drug while it continues multiplying and wreaking havoc in the body. Both molnupiravir and Paxlovid consist of several pills that must be taken twice a day for five consecutive days. “The second you have people taking something multiple times a day when they’re sick is when you have issues with compliance,” Cherry says.
Researchers should also develop treatments that target other parts of the virus, Schang says. “This time we got lucky with a virus that encodes both a polymerase and a protease, and here we are two years later with only a suboptimal arsenal,” he says. “We really have to identify and validate new targets for antivirals so that when the next [pandemic] happens, we have a much broader pipeline to choose from.”
Other potential targets include a different protease in SARS-CoV-2 called PLpro, and an enzyme called methyltransferase that stabilizes the virus’s RNA, says Matt Hall, the director of the early translation branch at the US National Center for Advancing Translational Sciences (NCATS). Clear Creek Bio, a biotechnology firm based in Cambridge, Massachusetts, announced on 6 January that it will collaborate with NCATS to develop an oral drug targeting the PLpro enzyme.
Dieffenbach says that researchers would ideally like to identify targets that are common to entire families of viruses and inhibit them with a single drug. That would potentially allow public-health officials to rapidly deploy an effective antiviral the next time a novel virus with pandemic potential emerges.
Developing such broad-spectrum drugs will take significant public and private investment, and the cooperation of pharmaceutical companies, says Hall. Calls for such efforts were not heeded in the wake of the 2003 SARS-CoV outbreak, he adds, but the latest pandemic has underlined the need for action. Last year, the United States appropriated US$1.2 billion to NIAID to launch the Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern, which will fund basic research on developing antivirals for seven virus families. Hall says this gives him hope that antiviral research will continue even as the COVID-19 pandemic wanes.
But all antivirals face an inherent limitation, says Dieffenbach: they must be taken within days of infection to stop a virus from proliferating. Antivirals are only effective if people acknowledge that they might be ill, and can access tests that provide a timely diagnosis. “We can build the best drugs in the world, but if people don’t understand that they have to get on board quickly, they’re not going to do any good,” says Dieffenbach. “Pills do not take themselves.”