A new drug to treat covid could provide a breeding ground for mutated viruses

Remark

On Thursday, the Food and Drug Administration made what may be the most momentous drug approval decision in its history: It granted emergency use approval for Merck’s molnupiravir to treat Covid-19. This approval is not important because molnupiravir is a particularly good drug, but because it is rather ineffective and dangerous. Molnupiravir, in particular, can create new variants of SARS-CoV-2 that evade immunity and prolong the pandemic.

The problem with molnupiravir lies in its mechanism of action. Unlike previous antivirals, molnupiravir only does one thing: it introduces mutations into the viral genome. We are already familiar with the fact that viruses naturally mutate to escape immunity; for example, the many mutations of the spike protein in omicron allow it to evade the antibodies created by previous infections or vaccines. Molnupiravir relies on inducing even more mutations, eventually rendering the virus’ proteins useless. Molnupiravir’s ability to mutate SARS-CoV-2 to death has been shown in the controlled conditions of a petri dish and animal cages, prompting Merck to test it in Covid-19 patients in clinical trials.

Best case scenario with ommicron will still be bad

But humans are not petri dishes or lab animals, and while molnupiravir works to some degree, it hasn’t worked very well in Covid-19 patients. In particular, molnupiravir reduced hospitalizations by only 30 percent. In contrast, Pfizer’s antiviral drug Paxlovid, which works by a different mechanism and was also approved by the FDA this week, reduced hospitalization by 89 percent. (My lab is investigating drugs that use the same mechanism as Paxlovid — inhibition of the viral protease enzyme — independent of any company affiliations.) This means that most of the time, given the chance, molnupiravir didn’t inhibit viral replication enough to let the patient avoid hospitalization.

Merck’s own research, published Thursday, explains why. It found that viable virus can still be detected in some patients on the third day of treatment with the drug. That means the drug is in the body for at least a few days to mutate the virus — but not all virus genomes have picked up enough mutations to die. During those first few days, the patient is thus a breeding ground for viable mutated viruses.

The first days of treatment with molnupiravir offer a clear chance that mutant viruses will be passed on to family members or health care providers. Viral evolution is a process of selecting for rare mutations that are beneficial to the virus. It doesn’t matter if just one of the billions of copies of viruses in an infected person mutates to a higher fitness level. That one copy, either by evading existing antibodies or by replicating to an even higher level of fitness, will be enhanced in either that patient or the next infected person.

The worst-case scenario is worrisome. As long as molnupiravir is used anywhere in the world, it can generate repeated cycles of new variants, with people desperately using the drug to combat the new variants it spawns, creating a vicious positive feedback loop and causing more suffering and deaths.

The low efficacy of molnupiravir may come as no surprise, as drugs that only mutate a viral genome have never been tested in humans before. In contrast, the previous antiviral drug that can mutate viruses, ribavirin, also had direct effects, including blocking the viral replication enzyme and boosting innate immunity — and that was with far fewer infectious viruses. We didn’t know how well a drug whose only function is to introduce mutations could work against a highly contagious, rapidly replicating virus. Now we know: not so good.

Just email Covid tests to everyone? Absolute. My government is doing it.

The FDA’s fact sheet for prescribers, also released Thursday, recognizes the risk that a mutated virus could escape. It states, “Completion of the full 5-day course of treatment and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2.” But how are we going to prevent people from stopping the drug, or forgetting a dose, or just talking and eating with family members without masks during treatment? This is just not realistic in the general population.

In addition, the fact sheet acknowledges that “changes in the spike protein occurred at positions targeted by monoclonal antibodies and vaccines.” Bafflingly, however, it adds, “The clinical and public health significance of these changes are unknown.” The importance of changes in protein positions by antibodies and vaccines is well known: these changes allowed any variant of concern – from alpha to beta to delta to omicron – to evade immunity from previous infection, vaccines or monoclonal antibody treatment.

What can be done? We can take some comfort in the fact that the FDA is asking Merck to report within three months the viral mutations induced by molnupiravir in clinical trial participants. Merck will also have to report viral mutations in immunocompromised patients, who are likely to carry viruses for longer. Since this crucial information should have been provided before approval, it would be a responsible approach to limit the use of molnupiravir to the best-controlled settings for the next three months. For example, healthcare providers may only prescribe it to people who live alone, or who live in managed care or nursing facilities where effective isolation can be implemented. And then it will be important that the FDA is ready to revoke the emergency use authorization if viable immuno-evasive variants do occur, even if only once.

The FDA and Merck have essentially engaged the public in a gamble with no public debate. They’re betting that any mutated virus copy transmitted from patients taking molnupiravir will be neutral, or will harm the virus itself and not its host — that there won’t even be a case of a lucky hit that a more capable or evasive virus. This seems like a bad bet as SARS-CoV-2 has a track record in this pandemic of winning its own bets. But now that the dice have been rolled, we must take all possible measures to use the drug responsibly and quantify its risks. Our ability to end the pandemic may very well depend on it.

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