Evaluating the Evidence Around Molnupiravir (Perspective)

Part II: Examining "Prior Evidence" & Concluding Remarks

Was there Prior Evidence of Molnupiravir’s Mutagenicity?

Here we’ll focus on actual prior evidence to examine if there were any previous concerns about the drug.

Many news outlets have mentioned there being prior concerns, and yet all of them seem to cite this same Science article from May 2020.

The piece pointed to there possibly being prior evidence of a similar drug to Molnupiravir having mutagenic effects, and yet it doesn’t seem like they have indicated any recent concerns with the release of new clinical studies. So why was this article one of the first to sound any concerns, and yet now seems to have gone silent?

Well, let’s take a look at the title:

Once again it seems like the scientific community is plagued with politicization, and this presentation of Molnupiravir is no exception. Even though the article does a decent job of indication concerns about Molnupiravir, it was done in an attempt to point at possible cronyism and backdoor deals that would push a potentially dangerous drug forward.

Granted, I don’t care about the political allegiances of those in charge; cronyism is cronyism. Unfortunately, it seems like many people don’t view it the same way. Instead, things that were completely castigated due to the utterances of the previous president are now being swept under the rug as we are now having this drug be presented as a miracle cure.

Irrespective of what cronyism is occurring, the concern about mutagenic effects then, are still founded now.

So it seems like there were previous warnings about Molnupiravir. But what about this prior drug? How does this old drug relate to Molnupiravir, and is there any prior evidence that we should be concerned about?

Nearly any news outlet that indicated concerns with Molnupiravir drew their information from this paragraph (emphasis mine):

Raymond Schinazi, an Emory University chemist who has extensively studied the active ingredient in EIDD-2801 but has no connection to DRIVE, notes that his former pharmaceutical company, Pharmasset, abandoned it in 2003 after discovering its mutagenic properties. Schinazi says the small chemical tweaks made to increase the ingredient's bioavailability and transform it into EIDD-2801 are unlikely to change its mutagenicity. "Thank goodness someone is raising the red flag," about EIDD-2801, Schinazi says. "You don't develop a drug that's mutagenic. Period."

At a cursory glance I would agree with Dr. Schinazi that mutagenic drugs should be seen with extreme hesitancy, but let’s look at the other evidence.

This excerpt points to a previous therapeutic in development in 2003 as a joint venture between Pharmasset and Emory University. If there are any indications that Merck knew about Molnupiravir’s previous mutagenicity this would point to heavy cronyism. Unfortunately, and quite frustratingly, this does not seem to be the case.

Looking up “Emory University” and “Pharmasset” online brings up this Emory University Press Release (note that this is not a secure website) with this paragraph (emphasis mine):

ATLANTA — Incyte Corporation and Pharmasset, Ltd., have announced a licensing collaboration to continue development and commercialization of an anti-HIV drug invented by scientists at Emory University. The antiretroviral drug Reverset™, also known as RVT, D-D4FC or DPC-817 is currently in Phase IIa clinical trials and is targeted to HIV patients who have developed resistance to common antiretroviral drugs.

So the drug’s name is Reverset. Looking it up in Pubchem brings up the following structure, and we can compare it Molnupiravir’s to see any differences:

Reverset’s structure. The big difference is the addition of a Fluoride functional group (top circle) and the sugar ring’s double bond. Note that this double bond removes the 3’-OH group (bottom circle), removing a pivotal functional group for replication.

Molnupiravir’s structure. An -OH group is added to the nitrogenous base (top circle). The ribose sugar also has an intact 3’-OH group (bottom circle), meaning that Molnupiravir can be inserted during replication and exert mutagenic effects.

Although both of these structures are derived from cytidine, we can clearly see that these structures have serious differences, and these differences confer vastly different mechanisms of action.

Reverset (AKA Dexelvucitabine) contains an alkene sugar ring. For those unaware, cyclic molecules have very tight rotational movement, with most of the side chains of the cyclical carbons only able to move up or down. With an alkene (the double bond) the ring has even more rigidity.

What’s even more important though, is that the double bond removed a 3’-OH group, a group pivotal to replication.

Although I won’t explain it in detail, remember that genomic replication occurs in the 5’ (the bottom -OH, which is where the phosphate groups are added to form nucleotides) to 3’ (the -OH group to the left of the nitrogenous base).

Most typical nuceloside analogues will tend to have a modification at the 3’-OH group of the ring; loss or modification of this functional group inhibits replication since insertion of a therapeutic with this modification is unable to elongate the strand (remember that elongation occurs in the 5’→ 3’ direction). Therefore, a modification at this position usually leads to the halting of replication.

Why is this important? Because this means that Reverset cannot be a mutagen!

In order for Reverset to act as a mutagen it needs to be inserted into a genome and exert it’s mispairing effects after several rounds of replication. Instead, Reverset seems to operate in a similar manner to other nucleoside analogues and halts the replication process, halting HIV propagation.

We can also verify this by looking at the previous clinical trials with Reverset. There were only two clinical trials involving Reverset (one was comparing Reverset to Lamivudine for treating HIV while another just examined Reverset’s effectiveness against HIV in infected males) and we can see that both did not have similar criteria concerns as Molnupiravir (no mention of abstaining from heterosexual sex or becoming pregnant).

What’s so strange about this is that this should have been something that a researcher (Dr. Schinazi) should be able to notice. Whether it was due to bad intentions or naievity (I highly doubt a researcher developing nucleoside analogues would be this naive- although it does seem like Dr. Schinazi owns shares in a pharmaceutical competitor Eli Lilly) the media latched onto that excerpt and have used it in their commentary about Molnupiravir without doing any “fact checking”.

There’ doesn’t even see to be any evidence that Molnupiravir was developed on the back of Reverset. Even if it were, it would be absolutely difficult to argue that these changes are just minor when any small functional group change to a drug can greatly alter how it functions (Remdesivir is an Adenosine analogue where the only change is a cyano group swapping with the 2’-OH group).

It’s a shame that both a drug researcher and news outlets weren’t able to catch such an obvious misrepresentation, but nonetheless this indicates that there is no previous evidence indicating that Reverset (and Molnupiravir for that matter) had any prior history of mutagenesis.

So as it stands the concerns of mutagenicity with molnupiravir usage is founded, and yet concerns about this prior drug (Reverset) actually seem to be unsubstantiated. It once again highlights the notion that relying solely on one’s authority may be dangerous, and in this case the efforts seemed to be used for political measures instead of scientific ones, something that has been far too common with this pandemic.

The Science article points out concerns about Molnupiravir, but there absolutely does not seem to be any prior evidence. In fact, unless there is direct evidence, there doesn’t seem to be any ties between the two drugs. Even then, their mechanisms of action are different, and it’s amazing that this wasn’t looked into by media outlets before quoting the researcher.

Where does Molnupiravir Stand

I went into this writing with the idea that I’d find sure evidence of a dark history with Molnupiravir, mostly spurred on by that Science article. But going into the evidence it, unsurprisingly, seems like Molnupiravir must be viewed with nuance and a healthy dose of skepticism. It’s important that when we look at the evidence we make sure to engage with all of the evidence as it comes in and revise our thinking, especially if we are using an evidence-based approach.

From this I’d say some of the takeaways are the following:

• The pre-clinical data provides some confidence that mutagenicity may be low, but that also doesn’t mean that it will have a safe profile. More studies should always be encouraged, and until more studies on its safety occurs mutagenicity should still be considered a valid concern, especially when we consider that this drug is being fast-tracked for approval (something that should be really concerning with a mutagenic drug).

• There are a lot of alarming results from the clinical trials. The low sample size, and the lack of providing treatments to hospitalized/dying patients seems absolutely unethical. This brings up doubt as to whether this was done intentionally to fluff up Molnupiravir, especially when the control group was provided absolutely no treatment options. Just because something is better than nothing, doesn’t mean the something is effective. Instead, it may highlight the importance of early treatments, a position that many doctors have taken with severe castigation from medical and healthcare bodies due to off-label treatments.

• Even if evidence supports your position, make sure to check if the evidence is actually valid. When it isn’t, find evidence as to why not. The Science article, although convincing on its face, used evidence that does not seem to support the argument being made. Even though I still have concerns with Molnupiravir, the evidence of a previous drug (Reservet) being dangerous does not seem to be based on actual evidence and must be viewed with skepticism.

• If Molnupiravir does gain EUA, it would be very unlikely to see widespread usage. Instead, it would most likely be reserved for those not within child-bearing age, most likely the elderly, as well as those with serious comorbidities. This also brings into question if Molnupiravir would see widespread use as a prophylactic. The benefits of Molnupiravir should greatly outweigh the costs if it were to be prescribed.

As more evidence arises I’ll make sure to post updates. The evidence right now seems promising, although there are some concerns with the clinical data. Regardless, more research and more evidence should be conducted before I really feel comfortable with mass administration of this drug.

Thank you for reading my newsletter. If you enjoy my articles please consider becoming a free subscriber in order to receive notifications.

And share with others who may find these newsletters interesting.

Also, please consider becoming a paid member. The research and work put into these articles takes many hours and being a paid subscriber allows me to continue to do this full time.

Citations

1. Zhou et. al. 2021. 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/

2. Painter et. al. 2021. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2. Taken from https://journals.asm.org/doi/10.1128/AAC.02428-20

3. Merck and Ridgeback Biotherapeutics Provide Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19. Taken from https://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-progress-of-clinical-development-program-for-molnupiravir-an-investigational-oral-therapeutic-for-the-treatment-of-mild-to-moderate-covid-19/

4. 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/

5. Cohen, J. & Piller, C. 2020. Emails Offer Look Into Whistleblower Charges of Cronyism Behind Potential COVID-19 Drug. Taken from https://pulitzercenter.org/stories/emails-offer-look-whistleblower-charges-cronyism-behind-potential-covid-19-drug