Nov 1, 2021,10:06am EDT|3,852 views
Supercharging New Viral Variants: The Dangers Of Molnupiravir (Part 1)
William A. Haseltine
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An image showing mutations caused by NHC, the active component of molnupiravir to all genes and ... [+]
J VIROL. 2019 DEC 15; 93(24): E01348-19As much as people are justifiably excited about the prospect for orally available drugs that can prevent and treat Covid-19, I believe the FDA needs to tread very carefully with molnupiravir, the antiviral currently before them for approval. My misgivings are founded on two key concerns. The first is the drug’s potential mutagenicity, and the possibility that its use could lead to birth defects or cancerous tumors. The second is a danger that is far greater and potentially far deadlier: the drug’s potential to supercharge SARS-CoV-2 mutations and unleash a more virulent variant upon the world.
My next two articles will explore both of these concerns in much greater detail. But let me be very clear right from the start: I am a strong believer in antiviral drugs in general as a means to control the pandemic, having spent much of my early career focused on developing antivirals for the world’s last major pandemic, HIV/AIDS. But I have also spent many years — at Harvard especially where I founded and chaired the Division of Biochemical Pharmacology — studying mutagenesis and the long term effects of damaged DNA.
My concern with molnupiravir is because of the mechanism by which this particular drug works. Molnupiravir works as an antiviral by tricking the virus into using the drug for replication, then inserting errors into the virus’ genetic code once replication is underway. When enough copying errors occur, the virus is essentially killed off, unable to replicate any further. The FDA will soon be debating the safety of molnupiravir for high-risk individuals with Covid-19, something which I will explore in greater detail in my next piece. But my biggest concern with this drug is much larger than the health of any one person, it is molnupiravir’s ability to introduce mutations to the virus itself that are significant enough to change how the virus functions, but not so powerful as to stop it from replicating and becoming the next dominant variant.
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In a series of pre-pandemic experiments to determine whether coronaviruses could become resistant to molnupiravir (the answer: yes, they can), researchers tested the active form of molnupiravir against two other highly pathogenic coronaviruses: MERS-CoV and the mouse hepatitis virus (MHV). To identify mutations associated with these phenotypes after passage, the authors sequenced complete genomes of two MHV lineages and two MERS lineages. With MERS, there were up to 41 mutations scattered across the genome (see Figure 1). With MHV, there were more than 100 mutations which occurred at every part of the genome (see Figure 2).
Figure 1. Resistance and mutational profiles of MERS-CoV after 30 passages in the presence of NHC, ... [+]
J VIROL. 2019 DEC 15; 93(24): E01348-19.
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Figure 2. Resistance and mutational profiles of MHV after 30 passages in the presence of NHC, the ... [+]
J VIROL. 2019 DEC 15; 93(24): E01348-19
Overall, the study showed a dose-dependent increase in mutations for both coronaviruses, including in the all important spike protein which is the focus of so much attention today in SARS-CoV-2 variants of concern, like Delta.
      
Critically, the researchers found that the viruses could survive and replicate to high titers despite such large numbers of mutations in every gene and protein. The viruses tested did show a slight replication disadvantage — though they still replicated to the same high titers, they did so slightly less rapidly compared to the original non-mutated viruses. However, outside of the lab, as the drug is given to millions of people with active infections, this disadvantage may quickly disappear as we would likely provide a prime selection environment to improve the fitness of the virus.
While it’s possible that at the optimal concentration, the drug may very well cause enough mutations to prevent replication and onward transmission of the virus, the impact of suboptimal doses is still very much unknown. The current protocol for the use of molnupiravir is an 800mg dose, given as pills, twice a day for five days. At that concentration, molnupiravir would theoretically take no prisoners, leaving not a single viral genome to escape unscathed. But there is a strong likelihood that in the real world, people will not take the full course of pills. A slew of studies on adherence to daily oral antibiotics suggest that many patients — as many as 40% — fail to complete the full course of treatment. At these suboptimal concentrations, molnupiravir could have the unfortunate effect of introducing mutations across every gene and protein of the virus, including the spike, but not necessarily killing it off.
The drugmakers, Merck and Ridgeback, as well as the FDA are exploring whether molnupiravir is safe for personal use in high-risk individuals with mild to moderate disease and whether its benefits outweigh any potential risks. But they should also be determining the broader danger, and how to prevent the drug from unleashing new and deadlier variants across the globe. Already SARS-CoV-2 has shown a remarkable ability to mutate and survive under pressure. The drug’s manufacturers, Merck and Ridgeback, are entering into licensing deals that would allow the drug to be made and sold widely in more than 105 countries, which means that, if approved by regulators, we will soon have very little control over the drug’s administration and dosages delivered.
We are potentially headed towards a world class disaster. If the FDA does grant approval for the drug — and there is an argument to be made that better and safer antivirals are already on the way — it should be on a very narrow basis and include a black box warning to emphasize the potential danger of using the drug at suboptimal doses or for large numbers of people for preventive purposes. What we know with certainty is that his drug is far from the magic bullet we might hope for with an antiviral for Covid-19. The next article in this two part series will explore the potential risks and dangers of the drug for patients themselves.
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William A. Haseltine
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I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I
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Harming Those Who Receive It: The Dangers Of Molnupiravir (Part 2)
William A. Haseltine
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Healthcare
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Yesterday I wrote about the potential dangers the antiviral drug molnupiravir could unleash by supercharging new SARS-CoV-2 variants. Today, my focus is on the people who may receive the drug as a treatment and the possibility that molnupiravir could lead to cancerous tumors in those patients and birth defects in the unborn.
Molnupiravir is a relatively new drug, initially developed as an antiviral treatment for influenza. Molnupiravir’s metabolite, an active compound called NHC, has been known and studied for decades. The metabolite works by creating havoc with RNA polymerase, the enzyme critical for viral replication. As I described in yesterday’s article, the drug inserts errors into the virus’ genetic code every time it copies itself. Insert enough errors and you essentially kill off the virus, preventing it from replicating any further.
Against other coronaviruses, like MERS-CoV and mouse hepatitis virus (MHV), the drug was found to create up to more than a hundred mutations at every section of the viral genome. Against SARS-CoV-2, molnupiravir’s manufacturers Merck and Ridgeback say that the drug’s antiviral effects are powerfully effective, limiting the virus’ ability to proliferate unchecked and cutting the risk of hospitalization and death by half among those infected. The trouble with the drug, however, is that its mutagenic powers may also create havoc among other enzymes in the body, including the nucleic acids in our own healthy DNA.
As far back as 1980, researchers have been trying to understand just how damaging NHC, molnupiravir’s metabolite, can be to our own healthy cells. Earlier this year, a study published in the Journal of Infectious Diseases found that the metabolite could indeed be incorporated into and mutate within our host DNA. As others have pointed out, just because something is mutagenic doesn’t mean it’s entirely bad — even sunlight is mutagenic. But, just like sunlight, overexposure can lead to long term ill effects, like cancer. In the case of molnupiravir, the drug may not just lead to the growth of cancerous tumours but also, potentially, to birth defects, either through sperm precursor cells or in pregnant women.
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Molnupiravir has been tested for mutagenicity in animals before being moved to human trials, where it is being tested for safety. But that doesn’t mean the drug is fully in the clear. The pool of participants in the clinical trial — around 1,500 patients — is too small to pick up on rare mutagenic events and the early nature of the trial is too short-term to provide a proper view of issues that may occur months, if not years, down the road. Merck would do well to remember their experience with Vioxx, a painkiller that was deemed safe based on initial studies, but later proved deadly. The FDA originally approved Vioxx based on a safety database that included around 5000 people. Five years later, the drug was recalled after a broader and longer term study found a definitive link between the drug and rare cardiac events. There is evidence that during the time the drug was on the market it may have killed up to 56,000 people and left up to 140,000 with heart disease.
I believe Merck and Ridgeback know there are questions around the possible mutagenicity and teratogenicity of molnupiravir that need to be answered. Both male and female participants in the trial were asked to abstain from sex or use contraception during and shortly after the trial. And reporters have asked the manufacturers about potential mutagenic effects, which Merck has answered by saying that, “the drug will be safe if used as intended and at the concentrations where we have looked and in the concentrations which we are achieving in patients.”
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This isn’t the first time a mutagenic drug has been tested for antiviral activity. In that respect, our prior experience with another antiviral drug, favipiravir, may be of interest. It too is an antiviral that targets RNA polymerase, initially developed as a treatment for influenza and, like molnupiravir, now being tested against SARS-CoV-2. The two drugs work in a similar fashion, interchanging two of the four letters of the viral RNA code to create copying errors — molnupiravir switches uracil (U) and cytosine (C), while favipiravir switches guanosine (G) and adenosine (A). Like molnupiravir, favipiravir works by creating enough copying errors during replication to essentially kill off the virus.
The study on mutagenicity of the molnupiravir metabolite in the Journal of Infectious Diseases earlier this year also tested favipirivir. The study found that the molnupiravir metabolite, NHC, was a far more potent mutagen than favipirivir (FAV) (see Figure 1), which is a drug that has widely known issues related to teratogenicity and links to birth defects.
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Figure 1. The left side of the panel shows the genotixicity of molnupiravir metabolite, NHC, in ... [+]
SHUNTAI ET AL., THE JOURNAL OF INFECTIOUS DISEASES, VOLUME 224, ISSUE 3, 1 AUGUST 2021, PAGES 415–419Because of this, favipiravir has not been approved in the US or the UK, and is only approved in Japan under the strictest of regulations and for the most severe form of influenza, for which no other drugs exist. The challenge with approval of any drug, even under the strictest of regulations, is that once approved it can be used for many purposes, off-label. Favipiravir is already reportedly being distributed and used in Hungary as a treatment for Covid-19, despite no clear evidence of its value and its known risks. This is a danger not just to those receiving the drug, but also — as I wrote about in my previous article on molnupiravir — a danger to all of us, given the potential of drugs like these to supercharge the creation of viral variants.
In November, the FDA will debate the use of molnupiravir only as a treatment for high-risk individuals with mild to moderate disease. But an initial emergency use approval for the drug may lead to unknown harm to all those who receive it. Yesterday, I wrote that if the FDA approves the drug it should be only on a very narrow basis and include a black box warning to emphasize the potential danger of using the drug at suboptimal doses or for large numbers of people for preventive purposes. To that, I add the need for specific warnings for men and women who are actively trying to become pregnant and for women who are already pregnant — under no circumstance should these individuals receive this treatment. I hope that Merck, Ridgeback, the FDA and the CDC explore the dangers of molnupiravir thoroughly before granting emergency use approval of the drug, especially as other potentially safer antivirals are already on the way. This drug could harm the very people it’s meant to help, those receiving the drug and all of us around them, should new more powerful variants be unleashed.
* Shuntai et al., The Journal of Infectious Diseases, Volume 224, Issue 3, 1 August 2021, Pages 415–419, full caption: HPRT assay to detect genotoxicity of rNHC, RBV, FAV, AZT, 3TC, and TDF in CHO-K1 cells. A, 6-thioguanine-resistant colony counts in 2 separate HPRT mutagenesis experiments. In the HPRT experiment 2, an additional round of initial cleansing for spontaneous HPRT mutations was conducted to limit background mutations. Each compound/dose group had 3 replicates. Average numbers of colonies are shown on the top of each bar. Significance compared to vehicle control (* P = .01–.05, ** P = .001–.01, **** P <.0001) was determined using the unpaired t test calculated using the GraphPad Prism version 8.3.0 built-in function.
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William A. Haseltine
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I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I
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