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Rethinking Molnupiravir

Dec. 01, 2021 6:52 PM ETMerck & Co., Inc. (MRK)PFE49 Comments
Derek Lowe profile picture
Derek Lowe


  • I was quite surprised by the efficacy that Merck reported for the viral polymerase inhibitor molnupiravir when those interim trial results were announced in October.
  • If you look at the sequence maps of where we've been seeing coronavirus mutations so far in the pandemic, you'll note that there are many parts of its genome that have been very quiet.
  • A lower dose of molnupiravir has the potential to add to the efficacy of the Pfizer drug and perhaps to extend its utility in the face of possible resistance.

Chemical formula of Molnupiravir on a futuristic background

Zerbor/iStock via Getty Images

I was quite surprised by the efficacy that Merck (NYSE:MRK) reported for the viral polymerase inhibitor molnupiravir when those interim trial results were announced in October. But the FDA just held an advisory committee

This article was written by

Derek Lowe profile picture
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek, email him directly: derekb.lowe@gmail.com (mailto:derekb.lowe@gmail.com)

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Comments (49)

jst profile picture
Excuses and more BS! Until Americans are told the truth about the origins of this virus, who was involved, and how it "escaped" from a lab in China, there will be no conformity to this conspired political nonsense.
PleaseJustNo profile picture
@jst We will never be told because it was our own doing. Fauci and Francis Collins will never be put on the stand. They should have known better than to trust China for lackadaisical compliance with critical safety standards. If they were to come clean, it would open the door to multi-trillion dollar lawsuits.

HIV-1 protease inhibitors (-navir) have their best efficacy against retroviruses.
NS3/4A protease inhibitors (-previr) have their best efficacy against hepatitis C.
Papain-like protease (PLpro) inhibitors have had efficacy in vitro but never in vivo:

3CL protease (3CLpro) inhibitors are also known as nonstructural protein 5 (NSP5) inhibitors or main protease (MPRO) inhibitors.
Shionogi's S-217622 is a 3CL protease inhibitor.
Enanta's EDP-235 is a 3CL protease inhibitor.
Todos Medical's Tollov‏ir is a 3CL protease inhibitor.
Pfizer's PF-07321332 is a 3CL protease inhibitor:

In the past, all HIV-1 protease inhibitors had their best efficacy against retroviruses and failed against RNA viruses.
Kaletra (lopinavir plus ritonavir) is a combination of two HIV-1 protease inhibitors that had some efficacy against retroviruses but failed against RNA viruses:

In the past, all HIV-1 protease inhibitors had a long list of bad side effects (liver damage, kidney damage, pancreas damage, heart damage, skin damage, immune system damage):

Pfizer's 3CL protease inhibitor, PF-07321332, needs to be swallowed together with the HIV-1 protease inhibitor, ritonavir:

Pfizer's Paxlovid (these 2 protease inhibitors combined) comprises of 3 pills that need to be swallowed twice daily.

Recently, shares of Shionogi, Enanta, and Pfizer have moved higher because of their claims that their 3CL protease inhibitors are very safe and highly efficacious against COVID-19:

We'll see if Shionogi, Enanta, and Pfizer can live up to their claims after the bad side effects of their protease inhibitors are first discovered in foreign research studies:

Dozens of 3CL protease inhibitors have been discovered, ranging from very safe (vitamin B12) to poorly tolerated (cancer chemotherapy drugs):

HIV-1 protease inhibitors for treating human immunodeficiency virus (HIV) are highly vulnerable to drug resistance:

NS3/4A protease inhibitors for treating hepatitis C virus (HCV) are highly vulnerable to drug resistance:

However, RNA-dependent RNA polymerase (RdRp) inhibitors (favipiravir, ribavirin) are less likely to encounter drug resistance. Ribavirin, which was invented in 1972, continues to be used today to treat hepatitis C virus patients:

While the FDA thinks 1500 Americans die daily.
thirdcamper profile picture
Smart idea, the combination therapy notion. Are you listening, MRK and PFE?
edaskew profile picture
@thirdcamper It won’t happen. Paxlovid is highly effective, and poses little risk. Molnupiravir has marginal efficacy and worrisome long term effects. Paxlovid alone is going to be the outpatient antiviral of choice for the time being.
thirdcamper profile picture
@edaskew That fits with what I've read, but they are both being approved around the world so I think we're going to see them both in use.
@edaskew you cannot say paxlovid is highly effective. The people the placebo group of paxlovid study had 1/2 the hospitalization rate as in molnupiravir study 7%vs 14 %. Therefore the people in pavlovid study had very mild infections so the drug looked better. Those who don’t know medicine should keep quiet.
AThinker profile picture
Comparing Molnupiravir to PFE's antiviral.
1. Patient enrollment date after infection. MRK - 5 days, PFE - 3 days.
2. Patients Enrolled: MRK - On Pill - 385, Placebo - 377, PFE - On Pill - 389, Placebo - 385.
3. Merck pill action route: Inserts errors into genetic code of the virus. PFE pill: Protease inhibitor, is designed to block an enzyme needed by the virus to multiply.
4. Active components of the antiviral pill: MRK - Molnupiravir, PFE - PF-07321332; Ritonavir.
5. Side effects of MRK's Molnupiravir: Headache, insomnia, and increased alanine aminotransferase (a sign of liver under stress). Side effects of PF-07321332 - Not yet released. Side Effects of Ritonavir: Possible inflammation of the pancreas (pancreatitis), heart rhythm problems, severe skin rash and allergic reactions, liver problems, and drug interactions. Reference source: clinicalinfo.hiv.gov/...
6. Hospitalization in the placebo group - MRK - 14.1%, PFE - 7.0% (Was it a different strain of virus which accounted for the difference or was it the later enrollment hence the patients were worse off starting out in MRK? Not known).
7. Since there are almost 300 potential coronavirus–host protein interactions whether these two methods are the best. Not known. But a lot of scope for better methods exist.
8. What is known: SARS-CoV-2 considerably affects the transcriptional landscape of infected cells by inducing inflammatory cytokine and chemokine signatures. Hence a drug which works after a longer period of onset may also be expected to have effects on dampening the immune system response, which is deadly for some patients.


I don't know about you, if I would get infected by Covid, I would rather have molnupiravir vs PF-07321332+Ritonavir combo. There is a trust factor in play here.
@AThinker you are the only scientific thinker on this subject thus far. Ritonovir is poor tolerated and has a ton of side effects. It’s better effectacy is only because it was given earlier!
Not sure I understand the rationale for a combination. PFE’s drug is highly effective in trials and in lab experiments also efficiently inhibits SARS-CoV and MERS. Drug resistance seems unlikely. Merck’s drug is marginally effective and perhaps has no reduction in deaths.

Respectfully I think you have the survivorship bias back to front. We don’t find meaningful mutations on 3CL protease (target of Paxlovid) because enzymatic activity is essential and the enzyme is highly conserved with other CoVs. SARS-CoV-2 is not HIV, the mutation rate is far lower, and prolonged infection is the exception not the rule. Paxlovid is treatment is only 5 days and such individuals will be self isolating and rapidly have their viral load dropped by multi-logs by the drug. Seems unlikely meaningfully Paxlovid resistant strains will spread patient to patient.

Even if we make the HIV analogy resistance to nukes (nucleoside / nucleotide inhibitors or reverse transcriptase) develops much more quickly than protease inhibitors, and resistance to integrate inhibitors hardly ever happens, so even the most diverse and mutating virus known to mankind has regions of genetic stability.

Combination therapy is only justified for chronic viral infections like HIV and HCV
A virus so deadly I'm yet to know a single person to die from it.
PauloCostaSilva profile picture
@AdNeMa I had it, it is shit and I know a lot of people who lost their relatives to Covid. It's not a flu like thing. Trust me ... I still feel the f+*çed up side effects 1 year later. Sense of smell and taste is completely twisted ( I suffer from parosmia ). Brain fog and sense of depression out of nowhere, many times during the day.
People can say whatever they want but those directly impacted by this virus have to be heard. I hope you never, ever get it.
I do, several
@PauloCostaSilva my grandson, who is 20 got Covid. He never fully recovered from it. After going back to school(three weeks later) he was hospitalized with bacterial meningitis and encephalitis--was in intensive care for 8 days(we thought he was not going to survive)-and to this day-
almost 7 months later-is still not able to function well.
Nice reading, although in the first sentence, Molnupiravir is identified as a polymerase inhibitor. In reality it is a prodrug of a nucleoside analogue. A lot of good points were made regarding Molnupiravir.
As far as using it in combination with the Pfizer medication Paxlovid, I would assume that Molnupiravir would first need to granted EUA by the FDA. Would it have any clinical utility in combination with Paxlovid, that remains to be investigated. The reason that the advisory committee voted to recommend approval for Molnupiravir was that it prevented death in 9 vs 1 patient in the placebo group. Clearly, many uncertainties remain.
edaskew profile picture
What I've noticed, and I'm not the only one, is that the sickest people we see with Covid are the ones first infected in the early stages of a wave, and then as times goes on, the patients we see are not as sick. I don't know why that is; maybe it's that the virus first effects those with the least resistance, then move to the more resistant individuals. Also, I wonder, if inhaling a lot of non-infectious viral particles from people who have recovered from Covid, but are still coughing up a bunch of virus that isn't competent (not capable of causing an infection since it's damaged by the immune system) isn't a sort of natural vaccine. So are we running into people at the end of a wave that have acquired some degree of immunity that way? Who knows? Anyway I think if you do your study at the beginning of a wave, you will find greater efficacy that you will at the end of a wave for any therapeutic agent. I believe we will see that for Covid as a whole. I bet 2 years from now, no one will care much about Covid, except maybe pediatricians. It seems to me that the virus is migrating to a younger victim as time goes on.
@edaskew all four human coronaviruses cause trivial head colds. Together they account for 20% of head colds, and individuals can be reinfected with the same strain on average every 2.5y.
I believe this is no accident. Humans and coronaviruses have coexisted for 100,000’s of years. I expect SARS-CoV-2 will evolve to an optimally efficient lifestyle causing trivial or no symptoms but spreading efficiently from person to person.
@edaskew it is also possible at the end of a wave all susceptible/ vulnerable in that area have already died!
@mechan1sm flu kills 80 to 100,000 in USA annually. Most other countries don’t bother to count as nothing can really be done to stop this. So careful when you say people don’t pay attention !
Final results are far from first reported. Worse, not only PFE's product shows better results (so far), PFE will give away IP right (some sort).

MRK's management perform poorly in comparison with PFE. As one of big 4 vaccine makers before the Pandemic. MRK didn't throw money in COVID-18 vaccine thus missed opportunity.

Not much investment value on MRK.
TruffelPig profile picture
I like the idea. Just like in HIV an inhibitor cocktail prevents resistance buildup.
CSYJ profile picture
Heo Derek,

PhD in chemustry does not automatically make you an expert in molecular biology, viral evolution, and infectious diseases, FDA approval pricess, drug industry collaboration, right?

What is wrong with just not prescribing molnupiravir to pregncncy age women?

Why was remdesivir aproved so readily?

What would be compelling business reason for Merck and Pfizer to collaborate for a potential combo?

Yoy are negkecrung the mist umporyant yestuon, i. e., hiw much woyls be the oruce fir bith drygs when apprived! IMO akl other cinsuderatuons are of munir umpirtance.

Last about survivalship bias and armaments, was the US Army wrong in enhancing the Humvee doors and the Bradley Fighting Vehicle floors in Iraq? Toynshoyld confune your observations to topics you know well. FYI I have a family member whi served during the Iraq War. I have an advanced degree in microbiology focusing on virology, plus 30+ years stint in the biopharma industry working on R&D and regulatory operations spanning across three major US based global corporations.
Oil Can profile picture

Hi - you might consider re-posting; something didn't translate properly.
PleaseJustNo profile picture
> Yoy are negkecrung the mist umporyant yestuon, i. e., hiw much woyls be the oruce fir bith drygs when apprived! IMO akl other cinsuderatuons are of munir umpirtance.

"You are neglecting the most important question, i.e. how much would be the cost for both drugs when approved. IMO, all other considerations are of minor importance."
The pfe drug is already more than 90% effective, so any improvement from the mrk drug combination will be very small.

Pfe owns the new pill IP rights, so pfe will really benefits from this drug over the coming years to come. Potential sales can be 30-50 billions a year!! Amazing. Pfe, very strong buy
What a thoughtful and outstanding piece. This is a huge outlier from typical SA articles on medical product development, particularly Covid. Very nicely done.
PleaseJustNo profile picture
Money drives actions, not science. As per academic studies and reviews, vitamin D alone is sufficient for preventing all death from Covid at a blood level of 50 ng/ml. If you're looking for pure rationality, you won't find it anywhere, certainly not in government. As a nation and as a people, we stand divided, so much so that we want others to perish; this is basically why we can't be motivated to do the right thing.

Reference: PMC8541492 (although there exist many more)
@PleaseJustNo can you reference the science study about your vitamin D claim?
PleaseJustNo profile picture
@OldBike Here:

This is just one of many such reviews. Anyway, I will not debate this reference here. It however bears mentioning that the average and median levels are far too low relative to this goal.

Here is its conclusion:

> Conclusions: The datasets provide strong evidence that low D3 is a predictor rather than just a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/mL to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.
@PleaseJustNo no data, just conjecture, they even say they need a good study! Good luck with your D3! Follow it up with some ivermectin just to be sure.
MikeFromNZ profile picture
"That leaves me pinning more hopes on Pfizer's (PFE) protease inhibitor - and it also leaves me wondering why there hasn't been a trial started with these two drugs in combination."

There's an easy answer: money. It costs money to run drug trials, and no-one has sufficient financial incentives to run such a trial.
CSYJ profile picture

You know anything about combo drug develoment?

Let me ask you a few key

Why should Merck and Pfizer collaborate? Who should sponsor, conduct clinical studies, submit for approval fir, manufacture, do marketing and sell the combo? Who decides on the price? How should the profit be divided? If there are subsequent product luability lawsuits due to mutagenicity, who must defend the lawsuits?

Al of the above questions must be addressed and sorted out befire the two comanies woud even consider discussing collaboration. You should stop your idle seculatuon and wushful thinking since the bioharma industry does not operate like that!
@CSYJ yes many companies have combo therapy
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