A drug that creates mutant Covid? This Stanford researcher tells us why he’s worried about Merck’s molnupiravir

Business of Business: So I'm curious after reading — Recently, the Washington Post published your op ed in which you kind of describe this nightmare-like scenario that could come out from this drug from Merck, molnupiravir, in which essentially, because from what I gather, it encourages mutations of the virus, it could actually turn patients into petri dishes. And make much more destructive and dangerous variants. So first of all, am I getting that right? And second of all, what kind of response have you gotten to this assertion?

Oh, yes, you have that correct. And you have my concerns, correct. Oh, the drug is, is by design a mutagen and creates mutations in the sequence of the virus, it has to do that in order to work, the idea is to mutate the virus to death. 

The concern is basically that before the virus is mutated, to an extent that it no longer replicates, [there is] a time in which it has picked up mutations, but it's still alive and still viable. In that time, if the virus is transmitted to somebody else, then you will have transmitted a mutant virus. Most of the time, those viruses will be worse.

Your second question was, “what was the response?” 

Yeah, it sounds like you have a very strong opinion. And this has also led to some discussion on Twitter. So how would you characterize the way people have reacted?

I would say, first of all, I'm not the first person to have raised this concern. It's already a somewhat well publicized concern. I added my voice because I didn't think that we had discussed the risks involved. To the extent that the public needs to know, the response has been overwhelmingly supportive. 

Of course, there have been some people who have taken issue against my warnings. But overall, among my colleagues, I've received overwhelming support. I will say what I've discussed, the risks are recognized by everyone, even people who support the emergency use authorization.

That's good. So you don't see there being much of a professional risk coming out with this stand?

Oh, there's definitely a professional risk. And that's probably why I, and not somebody else, wrote this opinion piece. 

People who work on antiviral medications or work on SARS-CoV-2 [the pathogen which causes Covid-19], usually they receive funding to do that research. And that funding is decided by a group of peers of other scientists. This particular drug molnupiravir is sort of a favorite among many academics, because it came out of academic research, and the initial preclinical studies were done in academic labs. And so it's, it's certainly a risk for somebody to come out against this drug. Because you might encounter somebody working on the drug at a conference, or that person might be reviewing a paper of yours or a grant application of yours. 

So typically, academics don't like to rock the boat. They don't know when they might annoy somebody who has power over your purse strings. So there's definitely a risk there. 

I'm, in my case, my lab, we work on viruses, and we actually work on SARS-CoV-2 antiviral medications, but we actually received the bulk of our funding for other work that we started before the epidemic. You know, the epidemic took many of us by surprise. Those people who happen to be working in viruses, of course, then turned their attention to SARS-CoV-2. We work on viruses, but it's actually only a fraction of our work. And so maybe that gives me a little bit more freedom and more confidence in raising these issues compared to other people.

Why do you think the FDA went ahead and approved this? What sort of pressures were they facing? Even though, you know, you raise all of these points? And you point to this evidence that maybe it's not very effective? 

What's interesting is we know that the FDA is aware of these risks. First of all, they were discussed [an official meeting]. Then there is the Antimicrobial Drugs Advisory Committee. This, this committee met right after Thanksgiving, Nov. 30, to consider the drug. It's voted on the question whether sufficient benefit versus risk existed for the drug, with a vote of 13 to 10. Many of those 10 have raised this possibility for escaped mutant viruses as one of their concerns, even though wasn't wasn't asked directly. 

The FDA also in their approval notice that patients taking the drug be isolated and be sure to take the entire course of drug in order to prevent the escape of, of mutated viruses. So they're aware of that. So they know that the drug has potential to create evasive variants of the virus. But they wrote in their approval notice that the consequences of these mutations are unknown. 

Now, I believe that's a big mistake. The consequences are known. And they've been discussed. But their conclusion, apparently, is that emergency approval was still an acceptable risk. So what went into that calculation? I'm not sure. But, you know, people have noted that the White House, the administration, has already purchased $1.2 billion worth of that drug. And so there could be a little bit of pressure to eventually approve the drug so that the money would be spent in some useful way.

---

“If it weren't for Omicron, I would guess that we would have a better public discussion of the risks of this drug, but its approval basically occurred in a very rapid fashion within a month, with basically nobody paying attention."

---

Plus, it seems like everyone wants some new pill or something to help us get out of this pandemic, in some way.

There's definitely public pressure for it. But I would say that most of that public pressure is not completely informed. And this goes to doctors as well. You know, doctors don't typically study the mechanisms of a drug and come to their own conclusions about whether it should be approved or not. They basically trust that the FDA has done a good job. I would say the FDA in this case, did not do the best possible job. 

Another thing to consider is that the FDA is staffed by people and these people do read the news. So there is an element of public pressure in FDA approvals. In this particular case, the final drug results, which were rather poor at 30% efficacy and preventing hospitalizations, came out right before Thanksgiving, right before Omicron. All the decision-making on this case occurred during the Omicron wave or the during the lead-up to the Omicron wave.

And so, all the news was obsessed with Omicron. If it weren't for Omicron, I would guess that we would have a better public discussion of the risks of this drug, but its approval basically occurred in a very rapid fashion within a month, with basically nobody paying attention.

The issue that you have, though, with this Merck drug, it's not true of all antivirals that are being used against COVID. Is that right? How does it differ?

That's correct. This is the only time that's ever been made or approved, a drug that works deliberately by mutating virus sequences. The other drug [Pfizer’s Paxlovid] that was approved for Covid-19 works by a completely different mechanism. It doesn't mutate the virus RNA. It inhibits a viral enzyme for the protease. And that’s a safer drug. It is also a more effective drug. It prevents hospitalizations by 88% or 89%, compared to 30%.

That happens to be the mechanism of action that we’re making as well in my own lab. So in a sense, Pfizer is a competitor of ours. People could say Merck is a competitor of ours, too, but in terms of what we’re trying to accomplish, Pfizer is a more direct competitor.

So, Merck, Merck’s drug is unique. I believe it’s the only intervention for Covid-19 with an efficacy lower than 50% that’s been approved now. And on top of that, it has this rather concerning, potentially dangerous mechanism of action that we’ve not seen in any approved antiviral.

What do you think is the risk of a worst-case scenario that the use of this drug would lead to Super Coronavirus or something like that?

Yeah, I mean, this is the trillion dollar question. We don't really know. It hasn't been tried before in any humans. I mean, this is basically an experiment. So the FDA is imposing a gamble on society. We don't really know what the risks are. It’s really just a matter of statistics and chances. It could be it’ll take a year. It could be two years before we see one. It all depends on how many people are taking the drug. The drug increases the mutation rate of the virus five to 10-fold. It’s a low-probability event per patient, but eventually over millions of patients, it becomes more and more likely.

---

“[T]he FDA is imposing a gamble on society. We don't really know what the risks are. It's really just a matter of statistics and chance."

---

But now that this drug can be used, what can we do to limit that risk?

So the FDA guidelines are that patients should isolate for five days and make sure they take all of their pills. In other antimicrobial drugs with a high probability of resistance, such as drugs for tuberculosis, there's often a policy of directly observed therapy where patients have to be seen taking the pill by a healthcare provider. That's to assure that they don't skip any doses and then lead to resistant strains rising.

In this case, we're concerned not about resistance to the drug, but the creation of intense variants.  But again, we would want the patients to take every pill, not to skip any and not to not to stop one or two days in, which would be the worst possible time to stop.

I'm of the opinion that only people who can fully isolate, people living alone, or maybe people living in assisted nursing facilities where the nurses can make sure they take their drugs and the nurses can be wearing protective gear to prevent transmission, that only these people should get the drug. That is my opinion.

And slightly off topic. But as long as you're here and you're a researcher in this space, I am curious: what do you think it will take for us to get past this pandemic? Or return to something that looks like normal? Or is that even possible?

It's possible if we avoid creating new strains that create more waves of disease, I would say, you know, before the approval of molnupiravir, I was quite optimistic. We have reached 70% to 80% vaccination in most Western countries. Now after this Omicron wave, pretty much everybody who was not vaccinated or already infected is going to get infected. We will reach that level of immunity where additional waves won’t be so deadly, as long as we’re not creating new variants. 

So there is this potential endpoint, but we have to be careful about it. I think the worst possible thing would be to extend the epidemic due to a drug. That’s one of the reasons I’m speaking out about this because it would distress me both as a scientist and as a person if something we do as humans, especially as researchers, makes this pandemic worse.