The madness of molnupiravir

By December 1, 2021Academia, Biotech

A contentious vote

On Tuesday, an FDA advisory committee (“AdCom”) narrowly (13:10) voted in favor of emergency authorisation (EA) of a drug called molnupiravir (“molnu”), which is being sponsored by Ridgeback Biotherapeutics and Merck. In an interim analysis, molnu showed a promising 50% risk reduction of hospitalisations and deaths; however, FDA meeting documents showed that at final reading, this risk reduction had narrowed to about 30% (95% CI 1%-50%). All meeting documents can be found here, with a recording of the entire meeting available on Youtube. While the FDA generally heeds the advice of its AdComs, it doesn’t need to align with their recommendations. It should also be noted that several panelists who voted in favor of getting molnu to patients qualified their vote by stating that they support re-evaluation of the EA if / when an alternative, effective antiviral is approved. Notably, Pfizer’s Paxlovid, a combination of two protease inhibitors, has shown great promise in treating COVID with early data showing 89% risk reduction on the hospitalisation & death endpoint discussed above. Paxlovid’s development & regulatory review is hot on the heels of molnu’s, with Pfizer’s CEO displaying launch readiness with a recent tweet.


Molnupiravir is a mutagen by design, albeit one targeted primarily at viral RNA rather than human DNA. Leading up into the AdCom, much of the concern around molnupiravir has centred around its potential adverse impacts on patients, such as carcinogenic potential and the likelihood – substantiated in animal studies at high doses – that the drug can lead to birth defects. Somewhat famously, Dr. Rick Bright, the former head of BARDA – a U.S. agency whose mission is to anticipate biological threats and fund promising countermeasures – in his whistleblower complaint outlined the aggressive lobbying efforts employed to accelerate the awarding of BARDA funding to Ridgeback (no BARDA funding was awarded to the company during his tenure). The complaint and related e-mail correspondence describe how Bright’s insistence that BARDA follow due process in evaluating the application for government funding was met with scorn by his superior, Dr. Kadlec. It is worth noting that Kadlec, a Trump appointee, has been implicated in a more far-reaching public procurement controversy involving rather obvious conflicts of interest. Bright’s insistence on following due process in evaluating Ridgeback’s experimental antiviral stemmed not least from his awareness of the risks inherent in this class of drugs: “similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls.”

A discussion of the longer-term risks to human reproduction are outlined in this Pharmaceutical Times article featuring commentary by Prof. Ron Swanstrom:

Merck has acknowledged [molnupiravir’s] potential to mutate non-viral cells in its inclusion criteria for the Phase III study. Participants in the trial could not be pregnant or breastfeeding, and those of childbearing potential had to abstain from heterosexual sex or use highly effective contraception for 28 days from the start of study intervention. Individuals taking part in the study were also required to refrain from donating sperm.

In a foetus every cell, virtually, is dividing,” Swanstrom explains. “So every cell has the potential to incorporate mutations – that’s the worst of all possible times [to take a mutagenic drug].”

Swanstrom is also concerned about molnupiravir’s long-term effect on the sperm cells produced by those who take the pills.

“Merck’s talking specifically about just the generation of sperm during the treatment,” he says. “I worry more about a step back, the germ cells that are going to sit there and make new sperm cells next year or 10 years from now.

That’s another potential risk, that you’re actually making these really bad things, germline mutations, that affect the genes that are present in the next organism.”

The prevailing counterargument to these very real risks has been to recommend only a short course of molnu, to try and prevent pregnant women from being administered the drug and to impose abstinence or strict adherence to contraceptive use following a given period after administration of the drug – a tricky enterprise in and of itself.

A trojan horse

While the above already reads like a perfect setup for class action lawsuits down the road, an even more fateful risk associated with molnu has been largely ignored. Molnu could change the course of the pandemic, but not in the way its proponents would have you think. Based on its very mechanism of action (“MOA”), the drug is likely to act as a catalyst to the emergence and escape of new variants of concern (“VOCs”). The following thread by Michael Lin of Stanford University lays it all out very cogently:

Provided you read Prof. Lin’s thread, there isn’t much to add from my side. It all boils down to the following:

  • Molnu’s MOA relies on artificially ramping up mutations in SARS-CoV-2 until the virus loses its ability to function and replicate. This is called lethal mutagenesis.
  • However, it is possible, and in fact very likely, that this process of artificially and randomly introducing mutations via a drug will not be successful in reducing viral load in all patients to 0.
  • The rest is just a numbers game: given enough COVID-patients being administered molnu, the drug is very likely to lead to the emergence and transmission of highly mutated, novel variants.

These new variants, due to the random nature of forced mutagenesis, could be novel with regard to any and all of their constituent parts, including the spike proteins that are crucial for mediating viral entry into mammalian cells:

It should also be noted that a common trait of all known COVID-19 VOCs – the sudden emergence of a large number of mutations – is precisely what molnu is likely to foster:

Our global vaccination effort, which is currently our most powerful tool in the fight against this pandemic, relies on inducing a rather specific immune response to the above-mentioned spike protein.
It is incredible to think that a single drug could undo this entire effort – but here we are.

Skip it.

In the presence of drugs with similar and/or superior efficacy – therapeutic antibodies have rather consistently delivered around 70% risk reduction and Pfizer’s oral antiviral, which features a tried-and-true, non-mutagenic MOA looks likely to match or beat this while offering the convenience of molnu – it would seem that the world should abstain from playing Russian roulette with the mutagen molnupiravir.

Here’s hoping that reason and strategic thought will supersede greed and influence peddling. With viable alternatives already available and more pending review, there is absolutely no sound reason for rushing molnu through the regulatory process.

Jerome Verony

Author Jerome Verony

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