Molnupiravir’s Rush should Remind us to take a Cautionary Approach
The push to approve COVID therapies should not come at the cost of unknown side effects.
Just this morning (I am typing this up right before midnight) Merck published a press release indicating that results from a Phase 3 clinical trial of molnupiravir, a drug I previously covered, indicated a reduction of COVID hospitalization or death by half. These results were so good that they decided to end their clinical trial abruptly.
As stated in the press release:
Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics today announced that molnupiravir (MK-4482, EIDD-2801), an investigational oral antiviral medicine, significantly reduced the risk of hospitalization or death at a planned interim analysis of the Phase 3 MOVe-OUT trial in at risk, non-hospitalized adult patients with mild-to-moderate COVID-19. At the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 following randomization (28/385), compared with 14.1% of placebo-treated patients (53/377); p=0.0012. Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo. At the recommendation of an independent Data Monitoring Committee and in consultation with the U.S. Food and Drug Administration (FDA), recruitment into the study is being stopped early due to these positive results. Merck plans to submit an application for Emergency Use Authorization (EUA) to the U.S. FDA as soon as possible based on these findings and plans to submit marketing applications to other regulatory bodies worldwide.
This drug is being lauded for such phenomenal results, so let’s see if there is anything to be concerned about.
Lack of Extensive Clinical Data
If we look at the clinical trial participants within the trial arms were administered molnupiravir for 5 days and within 12 hours intervals. A total of 10 doses were given indicating 2 doses/day.
Outcomes were based on the following:
Note that one of the primary outcomes is to look for adverse events up to 7 months after the clinical trials, yet none of this data seems to have been reported; there is an indication of adverse events, but not of what those adverse events are. Therefore, we can’t measure the possible adverse events until more data is released. A little bit concerning when the study was ended early due to such great results meaning that long term adverse events may go unreported. Remember that these clinical trials have not been peer reviewed yet as well, leaving even more room for skepticism.
The Media’s Misreporting
I reported that one of the concerning factors with molnupiravir is its mechanism of action (MOA). Because it operates as a mutagen, there needs to be some concern taken that it may act as a mutagen on our own cells, as indicated in the Zhou et. al. 2021 study.
I also indicated that not many mainstream news publications have reported about this mechanism of action. In fact, they seem to have a lot of trouble describing how this drug works.
Merck does not even include its MOA in its press release:
Molnupiravir (MK-4482/EIDD-2801) is an investigational, orally administered form of a potent ribonucleoside analog that inhibits the replication of SARS-CoV-2, the causative agent of COVID-19. Molnupiravir has been shown to be active in several preclinical models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission. Additionally, pre-clinical and clinical data have shown molnupiravir to be active against the most common SARS-CoV-2 variants. Molnupiravir was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University, and is being developed by Merck & Co., Inc. in collaboration with Ridgeback Biotherapeutics. Ridgeback received an upfront payment from Merck and also is eligible to receive contingent payments dependent upon the achievement of certain developmental and regulatory approval milestones. Any profits from the collaboration will be split between the partners equally. Since licensed by Ridgeback, all funds used for the development of molnupiravir have been provided by Merck and by Wayne and Wendy Holman of Ridgeback.
How about this Ars Technica Piece? It actually does, albeit a bit too enthusiastically (emphasis mine):
Molnupiravir is a small molecule that wallops the work of a viral RNA-dependent RNA polymerase, an enzyme critical for making copies of RNA viruses, such as SARS-CoV-2. The drug had been in the works for years before SARS-CoV-2 emerged and, in March of 2020, it was on the verge of entering clinical trials for use against influenza. At that point, Ridgeback partnered with the drug's non-profit developers at Emory University to turn it against SARS-CoV-2. A few months later, in May, Ridgeback and Merck announced a collaboration to develop the drug, then called EIDD-2801, into a COVID-19 treatment.
Molnupiravir delivers a precise blow to viral RNA polymerase by posing as a building block for RNA. In the body, molnupiravir is forged into a deceptive ribonucleoside that the polymerase unwittingly incorporates into new strands of viral RNA instead of cytidine. This is essentially lethal. Researchers call the effect a "viral error catastrophe," in which the rate of genetic mutations or errors exceeds a threshold compatible with the virus surviving.
These types of nucleoside decoy drugs raise concerns of creating problems for human enzymes, too. For this reason, pregnant people were carefully excluded from trials. However, so far, all the animal and clinical trials have suggested good safety results.
What’s actually alarming is that Newseek, Sky News, and Politico did not even mention how the drug works- a little bit of effort would be nice, especially if you want to inform your readers.
Even still, there are many concerning trends with how information is being reported here.
If we take a look at the Ars Technica piece it actually indicates that it supposedly leads to genetic mutations that result in “viral error catastrophe”. But what it gets wrong is that it may cause concern to human enzymes. SARS-COV2’s genome is not comprised of proteins, the building blocks of enzymes, and ours certainly don’t as well. It seems the author may have conflated enzymes with genetic material, and it’s actually a big mistake to make. We are arguing about concerns with incorporating molnupiravir into the genome of human cells, not enzymes.
What many news outlets seemed to have picked up on is molnupiravir’s effectiveness against SARS-COV2 variants, which also makes an error, and it’s a very common error people make.
Variants have mutations in their genome that alter the amino acid sequence of proteins, and this mutation may cause alter the way proteins function. It’s this change in function or binding that alters how therapies or antibodies may target a virus.
But molnupiravir targets the viral genome, making this point erroneous. Unless variants can alter the RNA dependent RNA polymerase (RdRp) or the exoribonuclease to selectively remove molnupiravir this should not be a point of concern. It is also very unlikely; nucleoside analogues are designed to mimic typical nucleosides so selective removal of molnupiravir is unlikely to occur happen frequently.
So why bother mentioning it? Maybe there is some secret that I am unaware of (that actually would not be hard to do) but it seems to be more media buzzwords driving reporting of information. Just consider how often you hear people mention the Delta variant and you may see why mentioning a therapeutic can target variants may make it sound super tempting. It may also be lack of writers understanding what they are writing about, or maybe I’m just being a bit too picky when it comes to the media- I think I have a right to that.
Abandoning the Precautionary Principle
A letter from Troth et. al. 2021 refuted the claims made by the Zhou et. al. 2021 piece I cited in my earlier Substack piece. There were many criticisms, with the authors noting that the assay conducted was an in vitro assay and that their in vivo assay suggested no evidence of mutagenicity.
The original authors replied to the letter, concluding the following:
It is hard to argue that a ribonucleoside precursor to both RNA and DNA goes into one but not the other. Also, the known mutagenicity of hydroxylamine (which generates dNHC in DNA) suggests that if DNA repair could target such a small change in a base, it must do so in an incomplete way. This leads to the conclusion that treatment with molnupiravir will lead to mutations in host DNA in dividing cells. Using negative results to justify this risk as being unimportant is to create a blind spot for potential long-term harm. Until a better understanding of treatment with molnupiravir is achieved, we would argue that its use should be limited to people with co-factor risks for coronavirus disease 2019 who are likely to receive the greatest benefit while being exposed to the unknown long-term risks of exposure to this mutagen.
Safety should be a top priority and the lack of any information on the long term safety of this drug should caution its usage until more information is available.
A lot of weight is being put onto the in vitro Zhou et. al. Study because it seems to be the only study out there that attempts to look at possible side effects.
We need constant transparent information. Ending a study due to phenomenal findings (remember this happened to remdesivir) does us no good when we are concerned about the safety and efficacy of a new drug, and it’s really concerning when the institutions that have prided themselves in waving the mantra of “safe and effective” for vaccines are not bothering to check whether many of these experimental treatments are safe.
This is an even more egregious position to take when we consider the demonization of ivermectin. Ivermectin has been strongly castigated for both the treatment and prophylactic use against COVID, with many people saying there is no body of evidence pointing to it’s effectiveness and its safety profile.
How is it then, that these same institutions are singing the praises of molnupiravir when we hardly have any clinical data for a trial that was ended abruptly with no real measure of adverse events. What’s worse, Pfizer’s drug and molnupiravir are being considered for post-exposure prophylaxis use.
Once again, we are seeing how many cheap, widely used drugs must meet the gold standard of rigorous testing procedures when many of these therapeutics are being rushed through with such minimal data. Our medical and scientific bodies should not be allowing for such hypocrisy. Many people have already lost trust in medical and science authorities, and it does no one any good to continue such a façade.
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Merck. Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study Taken from 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/
Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002) Taken from https://clinicaltrials.gov/ct2/show/NCT04575597?term=molnupiravir&draw=2&rank=2
Zhou et. al. 2021 (1). β-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/
Mole, B. Meet molnupiravir, Merck’s Thor-inspired pill that hammers COVID Taken from https://arstechnica.com/science/2021/10/meet-molnupiravir-mercks-thor-inspired-pill-that-hammers-covid/
Landen, Z. What is Molnupiravir? First Oral COVID Treatment Could Be Issued By Year's End Taken from https://www.msn.com/en-us/health/medical/what-is-molnupiravir-first-oral-covid-treatment-could-be-issued-by-years-end/ar-AAP2kHS
Phillips, A. COVID-19: UK shows interest in antiviral pill molnupiravir after trial shows it could halve hospitalisations and deaths Taken from https://news.sky.com/story/covid-19-uk-shows-interest-in-antiviral-pill-molnupiravir-after-trial-shows-it-could-halve-hospitalisations-and-deaths-12423286
Morello et. al. Merck’s promising experimental Covid-19 drug raises hopes for pill to fight virus Taken from https://www.politico.com/news/2021/10/01/merck-covid-drug-514888
Troth et. al. 2021. Letter to the Editor in Response to Zhou et al Taken from https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab362/6319402
Zhou et al. 2021 (2) Reply to Troth et al Taken from https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab363/6320086
So I have been trying to process this information over the past few days ... the Ars Technica piece (while it does a great job with the hammer synonyms) was obviously written by someone who never took a basic genetics course. This drug is basically a cytidine (one of the RNA building blocks) with a self-implosion unit attached to it. When the virus replicates it will occasionally insert this drug in lieu of a real cytidine and cause enough chaos to essentially prevent the virus from replicating its RNA genome correctly. We humans also use cytidine to transcribe our DNA into RNA so we can make proteins (enzymes are a type of protein that does things) so it is quite conceivable that this drug could ultimately interfere with our protein making (note that RNA is generally short-lived in our cells and always freshly transcribed from DNA). Also, as Zhou et al. pointed out it is conceivable that this drug can easily be converted to DNA precursors via ribonucleotide reductase. That means you now have a deoxycytidine with the self-implosion unit ready to be incorporated into your dividing cells (extra bad for female fetuses and spermatozoa). The lack of long-term affects (as is so unrefreshingly common nowadays) is unacceptable. On the surface it is a brilliant drug, but we really need to look at it from all sides. We have gotten do many things wrong in the past (lead-paint, asbestos, talcum powder, hey - let's use plastic for everything) - do we just forego safety to satisfy an immediate need (albeit for an underwhelmingly fatal virus) - prophylactic use at this point would be quite scary.
"U.S. pharmaceutical giant Merck has agreed to share its license with a nonprofit so that its experimental covid-19 drug, molnupiravir, can be manufactured widely around the world in a deal that would expand access to the treatment in more than 100 countries."
"Last week, the Bill and Melinda Gates Foundation announced what it said was an initial investment of up to $120 million to incentivize those drugmakers to begin producing the treatment now — even before it has been approved by regulatory bodies."