COVID Transmissions for 10-4-2021

Molnupiravir can keep COVID-19 patients out of the hospital—and the grave

Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.

It has been 687 days since the first documented human case of COVID-19. In approximately 687, construction of the Dome of the Rock, a truly magnificent work of Arabic architecture, was begun among the ruins of the Jewish Temple on the Temple Mount in Jerusalem

Today we’ll discuss a new drug success against COVID-19 from Merck, a legendary company in the infectious disease business.

Also, we’re back on the normal Monday-Wednesday-Friday schedule.

Bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

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Merck changes the game for antiviral treatments for COVID-19

Last week, Merck announced interim analysis¹ findings from a Phase 3 trial, MOVe-OUT, looking at the use of the drug molnupiravir, co-developed with another company called Ridgeback, in COVID-19. The trial specifically looked at the use of molnupiravir in COVID-19 patients with at least one risk factor for hospitalization or death due to COVID-19, and was interested in the ability of this drug to reduce hospitalizations or deaths in this population relative to placebo treatment.

Interim analysis results are very good: https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/

The reduction in hospitalization or death, relative to placebo, was 50%. This was statistically significant with a p-value of 0.0012, meaning that there is a 99.98% chance that the results are not due to random chance. For an interim analysis this is extremely impressive. Often, pharmaceutical trials that are designed to look at risk reduction aim for being able to successfully detect, at their final analysis, a statistically significant risk reduction of about 20%, because that’s about what people expect to see from a typical drug. 50%, at an interim analysis, is way above and beyond that expectation.

That’s sort of just a rule of thumb, though. Every trial is different, and each trial sets stopping rules for their interim analyses. There is usually a stopping rule for situations where the drug appears to be actively harmful compared to placebo, after which the drug will never be pursued further for the specific condition being explored. There is also often a stopping rule for obviously superior efficacy. This type of stopping rule is put in place because it is unfair to have a drug that obviously works but to keep studying it without making it, at least potentially, available to the public for use in treatment of the condition it’s supposed to target.

MOVe-OUT hit its stopping rule for superior efficacy. The trial will stop enrolling new patients at this time and will continue only for the purposes of monitoring drug safety, finishing out the efficacy follow-up of existing patients if applicable, and pursuing any unresolved secondary endpoints in the existing population. This is as good a result as anyone can hope for from an interim analysis.

What’s more, this efficacy was apparently consistent regardless of the virus variant that a given patient might have had. There is a mechanistic reason to expect this that I will come to in a moment, because this drug is scientifically clever and really pretty neat.

Efficacy is not the only thing that clinical trials are supposed to tell us about, however. Safety is also very important. At this point, it looks like there will not be any adverse reactions identified for molnupiravir based on this interim analysis—a situation so unusual that I don’t believe I’ve ever encountered it before. The rate of adverse events was 40% in the molnupiravir population, and 35% in the placebo population. Often, adverse reactions are only reported in product labeling if they happen more than 1-10% of a treatment population and at greater frequency than placebo, so I’m not sure what the safety section of this product’s label would potentially look like. The FDA may require that safety monitoring be expanded and performed for all patients under an Emergency Use Authorization for this drug, so maybe we will flesh out the safety profile further when the drug is out in the field saving people from hospitalization or death. There is some concern over how it might affect pregnant people, and since they were excluded from this trial, that’s still an open question. Still, outside that population this drug seems to be pretty favorable for short term use in terms of its risk-benefit profile. There is probably a mechanistic reason for the relative safety, too. Again, we will come to that.

In terms of the impact on fighting COVID-19, I think that there is a clear use case for this drug, even though we have vaccines. We know that vaccines are not perfect—nothing is perfect. Masks aren’t perfect, vaccines aren’t perfect, even staying in your home all the time wouldn’t ever be perfect. Each of these reduces but does not eliminate risk. This drug, likewise, reduces but does not eliminate risk. However, if you take a series of steps that reduce risk, they have geometrically increasing effects. By setting a series of obstacles to the undesirable outcome, you reduce the odds of that outcome each time. I like to use coin-flipping examples for this—imagine you’re playing a game where you lose if you flip coins and they all come up tails. Would you choose to flip one coin only, or three coins? When you only flip one, you have a 50-50 chance of losing. If you flip three, you have a 12.5% chance of losing—and an 87.5% chance of winning. Flip a dozen coins and you’re exponentially better off.

We have masks as an option, and we recommend them where they are needed. We also have vaccines, which are recommended for basically everyone. These together reduce risk to vanishingly small levels for the typical person. For people with risk factors, however, there is still some risk even when wearing masks in indoor spaces and also being vaccinated. Even though potentially serious COVID-19 is unlikely in a vaccinated at-risk person who wears a mask, it can still happen more than we would like. Molnupiravir makes that kind of thing half as likely to happen.

It also has the potential to relieve pressure on the hospital system in a reality that we must accept—one where there are a large number of people who refuse to get vaccinated because they have been lied to about the vaccines in some way. Those people, especially when they have risk factors for serious disease, are numerous enough to clog hospitals. When hospitals are clogged with COVID-19 patients, people die—and not just COVID-19 patients. If there are no ECMO machines left because they’re all being used for COVID-19, they can’t be used to safe babies who are born with underdeveloped lungs. To save someone who didn’t get vaccinated, a baby dies in this unfortunate hypothetical situation—and that is far from the only possible way that an over-capacity hospital can see non-COVID-19 deaths that result from COVID-19 case surges. Molnupiravir will cut in half the number of COVID-19 cases in unvaccinated people that turn into hospitalizations. That means benefits for everyone.

What’s more, it’s an ORAL medication. You can take this as a pill. Other medications for COVID-19, like remdesivir (which doesn’t work as well as this) or monoclonal antibodies, are given as IV infusions, which require medical staff of at least some skill to administer, as well as a small amount of infrastructure for infusion. An oral medication doesn’t need any of that, making it a lot easier to deploy.

This is a really important advance. It doesn’t change everything, but it changes a lot. If you were worried about breakthrough cases, we now have a drug that will soon be available that makes it even less likely for breakthrough to result in serious disease—and it was not very likely before. If you’re a public health person concerned about health system collapse, you can rest a bit easier knowing that this drug can relieve some of the pressure. If you’re a patient with a non-COVID condition requiring hospital care, this drug will help keep beds free for you to get the care you need. It is another tool in our arsenal for making COVID-19 into a problem that most people don’t really need to think about. I’m really happy to see this.

But what about the mechanism? How does it work?

If you’re not interested in how this drug works, you’ve got the facts you need at this point. However, if you like the molecular science of these things, stick around, because this drug is so cool.

Molnupiravir is a “nucleoside analogue” drug.² Nucleoside is a term for a class of chemical building blocks for long RNA and DNA molecules. As an analogue, molnupiravir looks like an RNA building block, but it isn’t. It is also specifically intended to mimic RNA components as utilized by the viral RNA polymerase, the enzyme that constructs the virus genome and other viral RNA components.

As an RNA virus with no DNA component, SARS-CoV-2 has to include in its genome, and utilize, an enzyme called an “RNA-dependent RNA polymerase,” or RdRp. RdRps are unique to RNA viruses. Normally, DNA is turned into RNA which is then used to make protein. This is called the “central dogma” of molecular biology, and like most dogmas, it isn’t strictly true and overlooks key exceptions. In the central dogma, DNA-dependent RNA polymerases bind to DNA and make RNA molecules. These RNA molecules then are used to make proteins. RNA viruses are an exception to this dogma, and they use an RdRp to create more RNA. Viruses are often the source of exceptions to the big rules in biology.

Molnupiravir substitutes for a certain element of RNA in the RdRp RNA-to-RNA copy process. It was specifically developed to do this, because RdRps are only used by RNA viruses and not by mammals like humans. For an antiviral drug, it is good to be able to target something that only the virus uses that is unlikely to have an impact on the host. When something equally harms both virus and host, it stops being a drug and starts being what we call a “poison” in technical circles.

Anyway, after it is processed by the patient’s body, molnupiravir creates a derivative, NHC, that can take the place of proper nucleosides in the RdRp’s copying work, working its way into a critical piece of the SARS-CoV-2 life cycle: the creation of new RNA templates to replicate the virus genome. It may also find its way into virus RNA messages that are turned into protein, but it is probably less important in that context.

Once it is incorporated into the template for viral genome replication, the NHC begins its work of destroying the SARS-CoV-2 infection. How it works is really cool. RNA has four types of sequence “letters”, each corresponding with a specific nucleoside type—A, U, G, and C. Instead of looking like any one of these letters, the molnupiravir derivative NHC is able to look like either U or C, replacing certain locations where Cs should appear with random U code locations. This introduces an extremely high number of mutations into the virus genome, far more than the virus can tolerate. This is called “error catastrophe,” a term that I absolutely love.

You see, viruses mutate as a matter of course, and thus have evolved to tolerate a certain amount of mutation. They are adaptable and can handle a few changes to themselves with each replication cycle, here or there. Some copies will have mutations that make them totally nonfunctional, but on the whole a few mutations per single genome won’t be so bad. However, an “error catastrophe” happens when there are so many mutations in each genome copy that none of the copies are even close to functional.

In a way this is similar to how a small dose of a drug could be good for you, but a big dose of the drug can end you. Viruses rely on mutation to adapt, but too much mutation makes them nonfunctional. Mutation is one hell of a “drug.”

In this case, molnupiravir sends mutation into overdrive within the templates that SARS-CoV-2 uses to copy its genome. This churns out large amounts of useless genomes that do nothing, and in theory makes it harder for the virus to replicate overall. A nice mechanism, but plenty of nice mechanisms don’t turn out to do anything in real life in the clinic.

Here, though, the drug works. The mechanism seems to explain it. And since we are targeting a virus-specific protein, the RdRp, this mechanism impacts the virus much less so than the host. This drug can’t mutate your DNA. If it has any effects on DNA-dependent RNA polymerases they are transient ones from which a host can easily recover. I think that this may explain the apparently mild safety profile from the clinical trial, as I mentioned before.

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What am I doing to cope with the pandemic? This:

Bachelor party success

Recently, I was asked to plan the bachelor party of a dear friend of mine who I have known for longer than I can remember. In COVID-19, planning that kind of thing is not easy, but this friend made things a lot easier by having interests that were amenable to COVID-19 safe practices. We planned a day that started with a short puzzle hunt, led to an afternoon at a Japanese garden and tea house, and then ended with dinner around a fire pit that was lit using my friend’s outdoor survival skills—all activities that are well in line with my friend’s interests. I’m really grateful to the group of people who planned this with me, and it was a lot of fun to do.

I wasn’t able to actually attend the bachelor party itself (aside from the puzzle part, which happened at my apartment), because my daughter was born and she needs me around. Not only that, my wife is recovering from the surgery that brought our daughter into the world, and I’m on the hook to help her take care of anything in the apartment that may require lifting more than about 6-7 pounds (“don’t lift anything heavier than your baby,” we were told) or anything that may require her to use abdominal muscles. It turns out there are a lot of things that use your abs.

However, being unable to attend because I need to be here for my family isn’t something that would upset me. While I wish I could have been there, I’m glad I got to make something happen that I understand was a great time for everyone involved. It of course took a lot of teamwork to pull off this party, and when I had to take a step back, those who I was collaborating with stepped up to make it happen. The pictures show a resounding success and that makes me very happy.

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Thank you to those who reached out with congratulations about our daughter! We are home from the hospital now and very tired, but also very happy.

You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.

Join the conversation, and what you say will impact what I talk about in the next issue.

Also, let me know any other thoughts you might have about the newsletter. I’d like to make sure you’re getting what you want out of this.

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Part of science is identifying and correcting errors. If you find a mistake, please tell me about it.

Though I can’t correct the emailed version after it has been sent, I do update the online post of the newsletter every time a mistake is brought to my attention.

No corrections since last issue.

See you all next time. And don’t forget to share the newsletter if you liked it.

Always,

JS

1. Interim analysis is, generally, a planned check-in point in a clinical trial to see how things are going and determine whether the trial should be continued or not. It is typically not powered statistically to complete the trial, but rather to give some sense of how things are going, with the final analysis being expected to provide the most definitive results.

2. Actually, it is a “prodrug,” a molecule which the body turns into an active drug, and is processed further into something called NHC that is a more direct nucleoside analogue.