New COVID-19 Antiviral Pills: How Do They Work?
17:33 minutes
Late last year, two new drugs joined the lineup of options for high-risk patients who may need extra help fighting COVID-19: Merck’s pill molnupiravir, and Pfizer’s pill Paxlovid.
The two pills join remdesivir, an infusion-only drug, as antiviral compounds that attack the SARS-CoV2 virus in different ways. But how exactly do they work, how well do they work, and what makes them complicated to use in real life?
Ira talks to virologists Ron Swanstrom and Adam Lauring about the fundamentals of antiviral drugs, concerns about molnupiravir’s method of mutating the virus to death, and the long drug interaction list for Paxlovid. Plus, why timing is a critical issue for getting drugs to patients.
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Ronald Swanstrom is a virologist and Director of the Center for AIDS Research at the University of North Carolina in Chapel Hill, North Carolina.
Adam Lauring is a virologist and an associate professor of Microbiology and Immunology at the University of Michigan in Ann Arbor, Michigan.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. Communities reeling from the Omicron wave of COVID-19 this winter received a last-minute Christmas gift from the FDA in December, emergency use authorizations for two antiviral pills that patients might be prescribed to help them fight the virus. One is molnupiravir, made by Merck. Another, Paxlovid from Pfizer. The two drugs join remdesivir, an infusion-only antiviral that’s been around since the early days of the pandemic.
We wondered how these new pills work to fight the virus. We wondered about possible side effects, drug resistance, or even new variants. And why, two years into the pandemic, do we still have so few treatment options? To get some answers, we’re turning to our guests, Dr. Ron Swanstrom, a virologist and director of the University of North Carolina Center for AIDS Research in Chapel Hill, and Dr. Adam Lauring, a virologist and infectious disease physician at the University of Michigan in Ann Arbor. Welcome to Science Friday.
RON SWANSTROM: Glad to be here.
ADAM LAURING: Great to be here. Thank you.
IRA FLATOW: You’re welcome. Nice to have you. You know, I think we all need a little bit of virus science 101 here. So let’s go through each of these three drugs, shall we? We currently have molnupiravir, Paxlovid, and remdesivir. Adam, how do they work?
ADAM LAURING: Sure. So they target different proteins in the virus. Paxlovid targets what’s called a protease in SARS-CoV-2, which is a protein that the virus makes that cleaves other proteins. And so it’s like a scissors, and then Paxlovid essentially functions as if you stick a big stick in the middle of the scissors and it can’t cut anymore.
Remdesivir targets the viral polymerase. So the polymerase of the virus is what copies the genome, so it’s the virus’s photocopy machine. And remdesivir essentially induces a paper jam. So it gets into the polymerase, and it stops the polymerase from working well.
What’s different about molnupiravir and how it works is the virus takes that drug and thinks it’s a normal base. So the A’s, C’s, G’s, or U’s, in the case of RNA, the bases of the virus’s genome, and it incorporates that. And then that causes a mutation in the virus’s genome. So it actually makes the virus make more mutations as it copies itself. And so it’s a unique mechanism of action for an antiviral drug.
IRA FLATOW: One of the criticisms about antiviral drugs is that they have to be taken at just the right time. Adam, how important is that timing?
ADAM LAURING: It’s actually proven to be pretty important. And I think that’s, in my view, one of the reasons why sometimes people feel disappointed in how well antivirals work, particularly for short-term infections like SARS-CoV-2 or influenza, infections that are come and gone in one to two weeks in most cases, as opposed to HIV or hepatitis C, which are much more chronic infections.
IRA FLATOW: For SARS-CoV-2, then, what is the critical stage where you need to take it?
ADAM LAURING: It’s generally pretty early, within a couple days of having symptoms. And the reason why is not that the drug doesn’t work at later stages. It’s just you don’t get as much benefit from it. And that’s because in many people, their immune responses kick in after a few days, and so your body starts clearing it.
We’ve seen with the trials for the monoclonal antibody drugs as well as for molnupiravir, remdesivir, even Paxlovid, that the people who get the most bang for the buck on the drug are the ones who get the drug early, because later on, it’s not that the drug doesn’t work, it’s just that your body is already doing its job. And I think that was probably one of the issues with remdesivir. It was pretty unimpressive early on in the pandemic when we were giving it, often, to people a week into their disease course. But the latest studies, which really try to get it into people very quickly for just a three-day course, really showed remarkable benefits.
IRA FLATOW: Ron, is there anything about how the antivirals work that may be more concerning to you than, let’s say, an antibiotic?
RON SWANSTROM: For any drug, there are potential for side effects, there are dose issues, and sort of this ratio of benefit to risk. And so these risks are different for every drug. I don’t know of risks for remdesivir. Paxlovid, because it has this booster second inhibitor in there, the ritonavir, that actually causes a lot of drug-drug interactions. The EUA notice includes 100 drugs in the list of drugs that you have to worry about if you want to take Paxlovid, including two I’m taking. So there’s going to be some management involved there.
It’s the molnupiravir that’s different, though. It’s a very different mechanism of action. It’s a mutagen, as Adam pointed out. And we want it to go into the cell and get metabolized and get into viral RNA and cause mutations.
The potential problem with molnupiravir is that when it’s going into viral RNA, there’s a pathway in the cell for it to get into cellular DNA. That’s host DNA. And it is designed to be a mutagen. We want it to be a mutagen. But when it gets into DNA, then there’s the potential for it to cause mutations in our DNA. And we just don’t know what that risk is.
The FDA did– in the toxicity studies, there were some concerns about reproductive health. There were no acute toxicities. The drug is safe to take, between taking it today and being fine in a month. But there were some developmental toxicities in animal models that were recognized.
So there are some restrictions around reproductive health issues. So definitely not pregnant women. The idea of conceiving and participating in conception event is discouraged until the drug is cleared. But these long-term events were not considered as part of the evaluation, as far as I can tell, by the FDA. Or at least they were viewed to be of small enough risk to not worry about them in terms of approving the drug.
IRA FLATOW: Ron, you were concerned enough, though, about this drug that you wrote about those concerns in the journal Science. Tell us what those– specifically what the concerns are.
RON SWANSTROM: There’s kind of a disconnect. I’m a virologist. I’m not a toxicologist. And so I’m on a big learning curve here. But I think there’s a disconnect.
For most drugs that get developed, we don’t think they’re mutagens. And so there are a series of tests that the genotoxicity field has agreed on. And they do those tests, and they’re negative. And so you look at the drug and you say, well, it shouldn’t be a mutagen, and it wasn’t a mutagen in my tests, so let’s go forward.
This one’s different. This is a mutagen. And we don’t have data on mutagens in these animal tests and a correlation with long-term outcomes in people. As far as I know, that just doesn’t exist.
So when you have an assay that has been negative for other drugs that have been safe, but you put a mutagen in it, and the assay is negative, you haven’t changed the drug. It’s still a mutagen. So to me, it says your assay isn’t sensitive enough to detect it. In either case, it doesn’t answer the question of, will this mutagen cause a long-term risk or not?
To be balanced in this discussion, we get exposed to mutagens every day. A good example is you go get an X-ray from the dentist. You’ve now sent X-rays through your head. And lots of DNA has been damaged, and nothing bad happens. We go through our lives getting X-rays at the dentist.
So there are levels of exposures to mutations and carcinogens that we live with. And many of those exposures are inconsequential. I just don’t know where molnupiravir is going to fall on this scale.
IRA FLATOW: Yeah. Other virologists have also raised concerns that mutating the virus could lead to new variants, as you did in your piece, Ron. Adam, are you as concerned about that?
ADAM LAURING: I think Ron’s piece, I must say, I think was nice and balanced. We know that mutations, of course, are random. And viruses are very sensitive to mutation. That’s the whole logic behind molnupiravir. We know that just increasing the mutations a small amount will really limit the virus.
And so the chances of a virus hitting upon a right combination of mutations that are beneficial to it while avoiding all the mutations that it would make that hurt the virus, I think it seems unlikely. The analogy I give, which is, it’s a bit like monkeys on a typewriter and them coming out with Shakespeare in the end. It could happen. It’s unlikely.
Maybe molnupiravir is– maybe generating new variants is a little bit more likely than the monkeys on a typewriter, but I still think it’s probably low. We know that new variants can arise without molnupiravir. I’m not sure that the molnupiravir usage is going to substantially increase that risk. At least, that’s how I look at it.
IRA FLATOW: And Ron, how do we balance those concerns overall with its ability to help high-risk people?
RON SWANSTROM: For me, there’s a pretty simple idea. The concerns about reproductive health or the long-term risk of cancer, those are the places where I think you worry about a mutagen the most. And if we were just to use the drug in older people, like me, and having that risk later in life reduces the chance that it’ll come into play. And older in life, we’re past our reproductive years for the most part. Focusing the use of this drug in older people where it’s already a risk– age is a risk factor for COVID progression anyway– to me makes the most sense.
And one thing I’ll point out is that both the concerns for variants in the virus population and concerns for mutating DNA, it’s really the same thing in that we’re taking this drug that is designed to be a mutagen, and we’re putting it into genetic systems, whether it’s the virus or the host. And this is really a new experiment. Intentionally increasing diversity, either in the host or the viral population, is a new idea in biology. And I think we should be humble and proceed cautiously.
IRA FLATOW: Adam, that would seem to be some good advice.
ADAM LAURING: I always think we should proceed with caution, especially, yeah, it’s a new mechanism. And I’m not of the camp of going so far as to say, oh, we shouldn’t use it, or we should restrict it. And I don’t think that’s what Ron is saying. It is novel, and more study is needed. And I’m confident that there will be. I think it’s appropriate.
You know, proceed with caution. But I think we do know a lot about how increasing viral genetic diversity works. This has been an idea that’s been around for 20, 30 years. This is not something that’s come out of blue. There is a body of work there.
But yeah, I think we need to follow this closely and follow these patients closely moving forward, because there’s always things that we don’t know. And that’s what science is all about.
IRA FLATOW: Molnupiravir, with these concerns in mind, only reduces the likelihood of hospitalization and death by 30%. Paxlovid does seem much more effective, despite having so many drug interactions. Is there something harder about creating antivirals that work decisively for most people? Ron?
RON SWANSTROM: A fair question to ask about molnupiravir. Its interim analysis was 50% effective, which sounded better. Its end analysis was 30%, which was definitely less. And I think it depends a lot on when you get patients. As Adam pointed out earlier, the earlier you take it, the better. I think for any of these antivirals, the later you take it, they’ll look worse.
So no one’s done a head-to-head comparison of Paxlovid and molnupiravir to find out if it really is that much better when you identify patients in the same way. I think molnupiravir has the potential to be more active than we saw in the trial. Again, no head-to-head comparison has been made.
The other thing about molnupiravir to keep in mind is it is a broadly-acting antiviral. It will work against essentially any RNA virus. We don’t need to have a targeted drug. Because it’s attacking the genetic mechanism of the virus, it’ll be ready to go on day one the next time a new virus shows up. So that’s one of its advantages that we should keep in mind. But right now it does look like Paxlovid is the big winner in terms of an orally available drug that I would certainly want to take if I was SARS-CoV-2 positive, on day one.
IRA FLATOW: Just a quick reminder, this is Science Friday from WNYC Studios. In case you’re just joining us, we’re talking to virologists Ron Swanstrom and Adam Lauring about the challenge of developing antiviral treatments for COVID-19. People listening to this show are all prospective patients who might receive these drugs at some point if COVID is indeed not going away. How should we be listening to this conversation and making choices about what to ask for if we end up needing treatment?
ADAM LAURING: Unfortunately, right now, most people are not going to have a choice. These drugs are in very short supply through the Omicron surge. There are Byzantine pathways to getting them to people that differ across localities, because they’re just not widely available, and there’s so much need. There are elaborate criteria that different health systems and states have over who gets which drug. So it’s often, right now, just not a choice.
As we move forward in the future, there are going to be, just like with other drugs, that there are certain patients who you want to use one drug in versus the other, depending on what other meds they take, what other conditions they have, where we learn that these drugs can be used best. I think there’s been a lot of talk about, well, this one is 30% effective at preventing hospitalization and death, and one is 90%, so why would I want this terrible drug that’s only 30%? Well, that’s actually pretty good as a drug.
And you know, I think we saw with remdesivir that the early trials were pretty disappointing, but now we do more work and learn more about the drug and how best to use it, and we get better results. And so I think in the future, as we emerge from this surge, we’ll learn which ones are best for which patients. Some people might even get combinations of these drugs.
IRA FLATOW: Now, I know you two have worked with HIV and influenza. Do you think– and they’re still around, right? We don’t have a cure for either one of them. Does COVID look like it’s heading in that direction? It’s going to be around for a long time, and we just better get used to dealing with it? Ron, what do you think?
RON SWANSTROM: Yes, It’s probably here to stay. There are many people who aren’t vaccinated, many people who will be very slow to get access to treatment. So the virus will keep circulating. We need to have some understanding of how much pre-infection, or previous infection, protects against the virus coming back. That will determine how much it can continue to circulate.
But then also, the thing that we seem to be incapable of predicting right now is the appearance of new variants. And so if there’s a next Omicron, or something that has the properties of Omicron that allows infection in people who have been previously infected and even people who have been vaccinated, then we’ll be in this cycle. But if Omicron was just a rare thing, if we don’t see any more Omicron equivalents, then I think we’ll be in a good spot.
IRA FLATOW: Adam, your thoughts?
ADAM LAURING: Yeah, I think I largely agree. My sense, and I’ll preface by saying I’ve been wrong many times over the past two years, is that as we build up immunity, we certainly won’t have the disruptions that we’ve been having for the past two years. My hope is that that will move us much closer to I think what many of us consider normal moving forward.
And we’re going to have to see what that means in terms of getting vaccinated again, and then these drugs and how we’re going to use them. And can they be used to prevent infection? Can they be used as prophylaxis? There’s a lot to learn in the next year or two in terms of what the future holds for SARS-CoV-2.
IRA FLATOW: Dr. Ron Swanstrom, a virologist and director, University of North Carolina Center for AIDS Research in Chapel Hill. Dr. Adam Lauring, a virologist and infectious disease physician at the University of Michigan in Ann Arbor. Thank you both for joining us.
RON SWANSTROM: You’re welcome.
ADAM LAURING: It’s been great. Thank you.
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