COVID-19 antiviral drugs
SciLine reaches out to our network of scientific experts and poses commonly asked questions about newsworthy topics. Reporters can use the video clips, audio, and comments below in news stories, with attribution to the scientist who made them.
What are Quotes from Experts?
December 1, 2021
How do the new antiviral pills from Merck and Pfizer fit into the framework of existing COVID-19 therapies?
David N. Frick, Ph.D.
“I would say these are really to help people who don’t respond to the vaccine or people who aren’t protected by the vaccine. And so in America we probably have almost a hundred million people like that. Right, either they’ve chosen not to get the vaccine, they can’t get it because they’re allergic, or they’re people like me who are immunosuppressed, and they just don’t respond to the vaccine. So a lot of people who’ve had a liver transplant—I had a liver transplant, that’s why I say that—a lot of people who are immunosuppressed don’t make antibodies to protect themselves after they get the vaccine. So these drugs are really designed to help them.” (Posted December 1, 2021 | Download Video)
David N. Frick, Ph.D.
Professor of chemistry and biochemistry, University of Wisconsin-Milwaukee
Katherine Seley-Radtke, Ph.D.
“Well, as you know, the vaccines protect us from the virus, but they don’t cure or kill the virus. And so we need pills to actually accomplish that. The pills would actually stop the virus from growing and treat the patient, where the vaccine just protects us.” (Posted December 1, 2021 | Download Video)
Katherine Seley-Radtke, Ph.D.
Professor of chemistry & biochemistry, University of Maryland, Baltimore County
“The Merck and Pfizer antiviral pills can be taken orally. Efficacy trials show that they have the most effect when taken early on in disease. Oral administration makes this possible, as the antiviral pills can be prescribed and taken on an outpatient basis (assuming Food and Drug Administration approval). The other direct acting antiviral therapeutics must be administered intravenously, such as remdesivir or the various monoclonal antibody treatments.” (Posted December 1, 2021)
Benhur Lee, M.D.
Professor of microbiology, Icahn School of Medicine at Mount Sinai
“So far we have three different vaccines to help combat COVID-19. However, vaccines are only preventative. They cannot be used to treat COVID patients. So, with that being said, antiviral drugs are critical, important complements of vaccines, and the drugs Pfizer and Merck are working on are the oral COVID-19 drugs. So if successful, they can be prescribed directly to patients to let them take it at home. So, with that being said, this will drastically reduce the burden of hospitals and is going to be a game changer.” (Posted December 1, 2021 | Download Video)
Jun Wang, Ph.D.
Associate professor of pharmacology and toxicology, University of Arizona
How do Merck’s molnupiravir and Pfizer’s Paxlovid differ from each other? Is one better than the other?
David N. Frick, Ph.D.
“Both of these drugs are what we call direct-acting antivirals, and those are drugs that essentially mess up the machines that a virus makes inside your cells so that the virus can replicate. The virus makes a lot of different little machines in your cell, and each of those drugs inhibit a different machine. The Merck drug inhibits the machine that the virus uses to make its genome, which is made out of RNA. The Pfizer drug inhibits an enzyme called protease, and that’s an enzyme that the virus makes to cleave up its own little proteins so it can make it a functional machine. So they have different targets; they work differently. The Pfizer—the data I’ve seen suggest that the Pfizer drug is more potent, so you take a lot less of it, and it might be less toxic, so it might have fewer side effects.” (Posted December 1, 2021 | Download Video)
David N. Frick, Ph.D.
Professor of chemistry and biochemistry, University of Wisconsin-Milwaukee
Katherine Seley-Radtke, Ph.D.
“Molnupiravir and Paxlovid work by inhibiting the virus from replicating at different points in that virus life cycle. Molnupiravir basically causes a series of mutations that keep mutating more and more, and they accumulate until the virus is no longer viable. In the case of Paxlovid, it actually inhibits the protease, which is really important for the virus to form new virus particles. It causes cutting of the long chain of genetic material into short pieces that then become the new virus particles.
“And in terms of which one is better, according to the FDA’s reports yesterday, molnupiravir is only about 30% effective against high-risk, unvaccinated patients, where Paxlovid has been shown to have 89% efficacy against unvaccinated, high-risk patients. So clearly, it looks like Paxlovid is much better.” (Posted December 1, 2021 | Download Video)
Katherine Seley-Radtke, Ph.D.
Professor of chemistry & biochemistry, University of Maryland, Baltimore County
“Merck’s molnupiravir is a nucleoside analog that acts to disrupt the action of viral polymerase enzyme, which is responsible for making more copies of the viral genome. Molnupiravir tricks the viral polymerase into making mistakes as the virus attempts to replicate its genomes, leading to many mutations that eventually result in a virus that can no longer replicate. Pfizer’s Paxlovid is a protease inhibitor that inhibits one of the main viral enzymes that is required to process large pieces of viral proteins into smaller active ones. Paxlovid prevents the virus from making many of the critical proteins required to complete its life cycle.
“In on-going clinical trials, Paxlovid appears to be more effective (about 89%) than Molnupiravir (30-50%) in preventing hospitalization and deaths if started within 3-5 days of a positive test or symptomatic onset. The trials are designed differently, so direct efficacy comparison might be difficult. As is true in all things in medicine, some people may be able to tolerate one drug better than the other in terms of side effects. Although the side effects reported so far are all relatively mild. In the case of Pfizer’s Paxlovid, the actual SARS-CoV-2 directed antiviral needs to be taken with ritonavir, which is an old HIV drug that helps to slow down the metabolism of the Pfizer drug, so that more of the drug stays active in the patient.” (Posted December 1, 2021)
Benhur Lee, M.D.
Professor of microbiology, Icahn School of Medicine at Mount Sinai
“Both of them are so-called direct-acting antivirals. They target particular viral proteins. As a result, they inhibit viral replication. Molnupiravir targets the viral polymerase and by doing so increases the mutation rate during viral replication. And the Pfizer drug works by inhibiting the viral main protease and, as a result, inhibits viral replication. Both of them are highly effective in inhibiting viral replication in cell culture, animal models, and both of them have shown really promising results in clinical trials. We could not have the full set of data from the clinical trials yet. But as for now, the Merck drug molnupiravir shows about 30% effective in reducing hospitalization and death. For the Pfizer drug we’re still waiting to get the full set of data.” (Posted December 1, 2021 | Download Video)
Jun Wang, Ph.D.
Associate professor of pharmacology and toxicology, University of Arizona
Might antiviral pills such as these not only treat disease but also slow the spread of COVID-19?
David N. Frick, Ph.D.
“That’s really unlikely. These are really to prevent the virus from replicating inside your cell. So once you’re tested you’re probably not going to go out and infect a lot of people once you know you’re infected. The vaccine, that prevents the spread, but these things don’t really prevent spread, they just will hopefully keep you out of the hospital if the vaccine doesn’t protect you.” (Posted December 1, 2021 | Download Video)
David N. Frick, Ph.D.
Professor of chemistry and biochemistry, University of Wisconsin-Milwaukee
Katherine Seley-Radtke, Ph.D.
“Absolutely, because the more that people we can treat early, the less chance we have of this spreading. And in particular, we have a lot of people that are unvaccinated, and so we need to shut this down as fast as possible. And the pills are easy to take, and that would do it.” (Posted December 1, 2021 | Download Video)
Katherine Seley-Radtke, Ph.D.
Professor of chemistry & biochemistry, University of Maryland, Baltimore County
“Possibly, although the clinical trials have not been designed to show that. If the antiviral pills decreased the amount of virus in the nose and airway (which it does), then it stands to reason that these drugs will also shorten the time interval in which the infected person will be infectious. Lower viral load, lower spread.” (Posted December 1, 2021)
Benhur Lee, M.D.
Professor of microbiology, Icahn School of Medicine at Mount Sinai
“Theoretically, yes. If the antiviral drugs can inhibit the viral replication it’s not only going to be able to treat the disease but also reduce the transmission. But practically you have to think about that the major issue with COVID-19 is basically the asymptomatic transmission. So the patients have to know that they’re getting infected before they can take the pill. So, with that being said, to effectively reduce transmission, antiviral drugs have to be coupled with fast and early detection.” (Posted December 1, 2021 | Download Video)
Jun Wang, Ph.D.
Associate professor of pharmacology and toxicology, University of Arizona
How might patients’ experiences taking these new COVID-19 pills differ from the experience of current COVID-19 therapies?
David N. Frick, Ph.D.
“Well, the therapy that’s most like this is the monoclonal therapy that you would take. A difference is that these are just pills. You take a pill; you can take it at home; you don’t have to go to the hospital. Monoclonal antibodies and even remdesivir, all those drugs have to be injected either in a hospital or some sort of setting where you can to be hooked up to an IV. So this can change things a lot, because it’s just a single pill that you take a couple times a day for a week.” (Posted December 1, 2021 | Download Video)
David N. Frick, Ph.D.
Professor of chemistry and biochemistry, University of Wisconsin-Milwaukee
Katherine Seley-Radtke, Ph.D.
“Well, obviously you can take pills at home. You don’t need to go to the hospital, you don’t need to undergo transfusions, which is what you have to do with monoclonal antibodies and remdesivir. And so this is definitely going to increase patient compliance, which in turn means we’re more likely going to shut this down faster, and—in addition—80% percent of the people don’t need to go to the hospital.” (Posted December 1, 2021 | Download Video)
Katherine Seley-Radtke, Ph.D.
Professor of chemistry & biochemistry, University of Maryland, Baltimore County
“The biggest difference is that these antiviral pills can be taken orally at home (on an outpatient basis). There is no need for the patient to come into the hospital (or infusion center) to receive the drug intravenously. This is the biggest advantage.” (Posted December 1, 2021)
Benhur Lee, M.D.
Professor of microbiology, Icahn School of Medicine at Mount Sinai
“Currently we do not have an oral pill for COVID-19. The only drug we have is remdesivir, which is an IV drug reserved for hospitalized patients, patients that are in critical care. So if we can have oral pills, so people—whoever tests positive, they can take this drug back at home, this will drastically reduce the burden of hospitals.” (Posted December 1, 2021 | Download Video)
Jun Wang, Ph.D.
Associate professor of pharmacology and toxicology, University of Arizona
Given the mechanisms of action of these two drugs, what can we infer about their likely effectiveness in treating new variants such as Omicron?
David N. Frick, Ph.D.
“These direct-acting antivirals are designed to target parts of the virus that can’t vary. So if the virus mutates or changes to change the drug binding site, it’s going to die. So they’re not going to survive. So it’s very unlikely that the virus is going to evolve to be resistant to these therapies, and it’s very unlikely that we’re going to see a lot of new viruses that don’t respond to the drugs. And what’s even cooler is that if you put these two drugs together, it’s even less likely that you’ll get a mutation. So these’ll probably be good for all the variants of the COVID virus, but also similar viruses like the ones that cause the common cold and similar coronaviruses. So it’s really exciting.” (Posted December 1, 2021 | Download Video)
David N. Frick, Ph.D.
Professor of chemistry & biochemistry, University of Wisconsin-Milwaukee
Katherine Seley-Radtke, Ph.D.
“Well, unfortunately, I think that still has to be studied. I think there’s a lot left to learn about this new variant, and so it’s unclear what will happen. But I think what we really need are combination therapies, where we have multiple drugs in a drug cocktail that can be used, and that in turn is much, much more effective in shutting down viral replication as well as the spread of resistance and new variants.” (Posted December 1, 2021 | Download Video)
Katherine Seley-Radtke, Ph.D.
Professor of chemistry & biochemistry, University of Maryland, Baltimore County
“In the first instance, these antivirals will likely work against all variants as they target viral enzymes that are not under selective pressure to mutate (unlike the spike protein which has to mutate to evade antibody responses).
“In vitro experiments have shown that the ‘barrier to resistance’ is high. That means it is difficult for the virus to become resistant to the drug without a corresponding cost in fitness. That doesn’t mean the virus cannot become resistant – it can. And in vitro experiments have already identified resistant mutations. (This is true for almost any antiviral, including all the highly effective anti-HIV drugs). What it does mean is that resistant viruses are less fit. That is, resistance comes at a cost – the resistant virus cannot replicate as well as the parental virus.
“Now viruses will always find a way. In the early days of the HIV epidemic, HIV developed resistance to every new drug – when the drug was used as a monotherapy. It is only when drug combination cocktails came on the scene that we turned the tide.
“SARS-CoV-2 is very different. While HIV replicates forever, SARS-CoV-2 only replicates for a week or so before the immune system takes care of it. So treatment needs to only work for 5-7 days, and there is less time for resistance to develop. Just as in HIV drug treatment, I suspect combination drug therapy that inhibits SARS-CoV-2 at multiple points will be highly effective. If the lawyers ever allow Pfizer and Merck to put their drugs into one pill, I am almost sure that combination will work much better and slow the development of any resistance.” (Posted December 1, 2021)
Benhur Lee, M.D.
Professor of microbiology, Icahn School of Medicine at Mount Sinai
“This is basically the major advantage of antiviral—small-molecule antiviral drugs, compared with monoclonal antibody therapies. So monoclonal antibody therapies target spike proteins, which we now know that are prone to become drug resistant, because of the mutation in the spike proteins. The small molecules, both the Merck drug and the Pfizer drug, they target the essential viral proteins, like the viral polymerase and protease, those are so-called highly conserved drug targets that do not change much between the alpha, delta and omicron variants. So, with that being said, those drugs—both drugs are expected to be highly effective or remain highly effective against those variants.” (Posted December 1, 2021 | Download Video)
Jun Wang, Ph.D.
Associate professor of pharmacology and toxicology, University of Arizona
David N. Frick, Ph.D., professor of chemistry and biochemistry, University of Wisconsin-Milwaukee
No conflicts of interest
Benhur Lee, M.D., professor of microbiology, Icahn School of Medicine at Mount Sinai
Dr. Lee is a virologist who conducts research into emerging zoonotic viruses. He serves on the Novel and Exceptional Technology Research Advisory Committee for the National Institutes of Health (an NIH director appointed position) and is a scientific consultant for Sana Biotechnology.
Katherine Seley-Radtke, Ph.D., professor of chemistry & biochemistry, University of Maryland, Baltimore County
Dr. Seley-Radtke is currently the President-elect of the International Society for Antiviral Research, a former president and current Secretary for the International Society for Nucleosides, Nucleotides and Nucleic Acids, and on the Scientific and Clinical Advisory Board of Antios Therapeutics (all volunteer positions).
Jun Wang, Ph.D., associate professor of pharmacology and toxicology, University of Arizona
No conflicts of interest
