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Molnupiravir: Last of the Small-Molecule Coronavirus Hopes?

Update: the day after this post appeared, Merck and Ridgeback announced some preliminary positive data on reduction of viral load in treated patients. The full Phase II data should be coming soon?

A lot of people have been wondering about what’s up with a small-molecular antiviral compound that’s been in the news on and off during the pandemic. That’s molnupiravir, below, also known as EIDD-2801 and MK-4482.

It has all those numbers because it has some history behind it. The compound was discovered at Emory in the university’s Drug Innovation Ventures nonprofit spin-off, which has been working on antiviral nucleoside derivatives for many years. The compound was heading for clinical trials against influenza when the pandemic hit, and last March they did a deal with Ridgeback Biotherapeutics to accelerate its progress in coronavirus treatment. Ridgeback then partnered with Merck later in May for the clinical trials and scale-up.

The course of small-molecule antiviral drugs during the coronavirus pandemic has not been straightforward. Let’s just put it that way. Remdesivir has had a great deal of attention, and in the end seems to be somewhat useful but not exactly game-changing, and frankly it’s been the best of the bunch. Many other compounds were being talking about this time last year, but have failed to make much of an impression. A priori, though, that’s what you’d expect. In general, there aren’t that many effective antiviral drugs, and the ones we have are extremely concentrated in two areas: HIV and hepatitis C. Those in turn have been extensively, painstakingly developed against specific viral targets for those pathogens. It’s safe to say that there (so far) have been no really effective broad-spectrum antiviral small molecules.

But molnupiravir is one of the best shots at that. It’s a prodrug of N4-hydroxycytidine (NHC), a nucleoside analog that’s been investigated for decades now. Like many nucleoside analogs, it has its good side and its bad side. The good side is that these compounds can cause trouble (in several ways) for viral RNA-dependent RNA polymerase, an absolutely critical enzyme for the replication of any RNA virus. A common mechanism is what’s called an “error catastrophe”. These enzymes are notoriously error-prone to start with, and viruses over the eons have added several mechanisms to try to keep that under control – but remember, a background mutation rate is also a survival advantage (throwing off new variants), just so long as it doesn’t get out of control. Nucleoside analogs, in many cases, work by doing just that – pushing the RNA replication step into making so many errors that the end result can’t even produce a competent virus.

That’s the effect of NHC and of molnupiravir. What about the bad side? Well, auxh nucleosides can also be taken up by many other enzymes, including those that handle our own nucleic acids, so some of them are mutagenic. Indeed, that’s how NHC was first characterized, as a mutagen in bacteria. They also tend to be cytotoxic, via a number of mechanisms, and nucleoside drug candidates are notorious for wiping out in human trials due to toxicity in the liver, kidneys, and other organs. That was a feature of the 2012 scramble in the hepatitis C area, where Bristol-Myers Squibb paid 2.5 billion for a nucleoside addition to its proposed therapeutic cocktail, only to see it all demolished within a few months when it turned out to have severe problems in human trials. From this story and others you can also conclude that you don’t necessarily get a good reading on this stuff in animal trials – another feature of Fun With Nucleosides.

Molnupiravir itself has shown strong activity against a whole list of viruses in preclinical studies – it is indeed a very interesting candidate, even more so because it seems to have an unusually high barrier to resistance mechanisms. In December, animal studies showed that it could indeed protect against coronavirus infection. But you’d still definitely classify it as “high risk, high reward”. That means that this new paper comes as something of a relief: it’s first-in-human data from the Phase I trial.

So far, so good. There were no show-stopping adverse events (in fact, adverse events in general were higher in the placebo group), and the pharmacokinetics look straightforward: dose-proportional exposure, reasonable half-life, no accumulation on repeated or increased dosing, and plasma levels that appear to match the efficacious ones seen in the animal studies. The higher planned doses in the trial were in fact discontinued due to those levels being covered, which is always a good sign. Since it’s a prodrug, with that isobutyl ester rapidly cleaved in plasma, you mostly see the N-hydroxycytidine itself in these measurements, as you’d expect (about 99.8% NHC and 0.2% parent). Interestingly, only traces of either the parent or NHC show up in the urine, although elimination through the kidneys is a common route with nucleoside analogs. It appears that the NHC is getting pretty completely metabolized to cytidine and/or uridine (which would not be a bad profile, either, since those are common biomolecules that are soaking through every living tissue already).

The key, though, will be finding out if the compound is any good against the coronavirus in humans. And those trials have been underway for a while, with the latest news being that we might hear results this quarter. Which means by the end of this month? We’ll see – I hope that the news is good, because the world could use an orally delivered small molecule coronavirus drug, and it could also use a new antiviral in general (which this one, as mentioned, has a real chance to be).

Take a moment to think about the flip side of all this, though: here’s a known compound, already investigated against a number of viruses (in vitro and in animal models), with a promising mechanism of action that gave some confidence that it would have activity against a new RNA virus pathogen, and which was already heading towards human trials. You could not ask for a better-positioned small molecule; this is as good as it gets. So the time it’s taken to get the clinical read on whether it really works or not is about as fast a development as you’re going to see. Everything was lined up perfectly and a lot of the work had already been done. Keep that timeline in mind as a baseline!

95 comments on “Molnupiravir: Last of the Small-Molecule Coronavirus Hopes?”

  1. A Nonny Mouse says:

    What about Herpes and the first antiviral, acyclovir (valacyclovir). I suppose that we are a bit blase when things become over the counter drugs.

    1. Paulo Wageck says:

      I took Famciclovir when I had covid and it worked! I hope it gets studied!!!

      1. metaphysician says:

        No, you took famicyclovir, and then you got better. You do not know that it worked, because the vast majority of people with covid get better. It would take rigorous study to determine if it does actually help.

  2. Nick says:

    Hey Derek, could you explain to this tot layperson what the significance of a drug being “small-molecule” is?

    1. Moses says:

      @Nick
      Generally it’s a drug with a molecular weight of less than 900 (counting 12 for each carbon, 16 for oxygen etc) . This means they can pass more easily through various membranes and be absorbed more easily into the body. Usually they can be synthesized in the lab as opposed to large molecule drugs like insulin, which is a protein.

    2. David E. Young, MD says:

      Derek, I am so happy that you finally got around to commenting on this interested drug.

      One of the benefits of the “small molecule” Molnupiravir is that it was absorbed orally. Remdesivir gets degraded in the GI tract and therefore must be given intravenously. Molnupiravir is not terribly tedious to manufacture (as is Remdesivir) and there are several articles that suggest easier ways to manufacture Molnupiravir.

      Being oral is good. But it raises a few issues. One, expect it to be costly and while intravenous drugs given in a physicians office are covered by part B of medicare, oral drugs are covered under part D, which many people don’t have. And then there are the medicaide HMO’s, who will try to not authorize payment. And even if there is payment it may be incomplete so that there is a high co-pay. And authorization may take a few days, which are precious when you recognize that these drugs work better when given earlier. Another issue is the poor person who has nausea with their Covid19 and can’t keep the oral drug down. Or someone on a PEG tube because of another disease… might be hard to administer. Are there other drugs (PPI’s for example) that might decrease absorption? (I don’t know if there are.)

      Still, Molnupiravir will be approved for outpatients who are earlier in the infection. I understand that viral shedding is eliminated within two days of starting Molnupiravir, so the drug may decrease spreading of disease. I hope that the large trial (at about 76 locations) will meet accrual soon (it should!).

      1. Shawn says:

        I just went on Medicare Part D, so thanks for the warning. It’s a reminder we still need health care reform, including drug pricing. Aside from the morality of the issue, it makes no economic sense to fail to pay for a drug that could help one avoid a very long, expensive hospital stay.

    3. David E. Young, MD says:

      If you want a little more detail, read about the Lipinski rule of five: https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five

  3. JJ Walker says:

    The trials have been enrolling for a long time and the expected completion date keeps getting pushed back…. are they having issues getting people to enroll?

    It is also disappointing we have not heard the results from ACTT-3 yet. The study was completed 2+ months ago. If the regimen worked I would think we would have heard about it by now, even if they are waiting to publish the full results.

    1. Isidore says:

      I wonder how enrollment in a study of a small molecule antiviral drug might be affected by all the vaccine trials enrolling at the same time. I expect it would be affected adversely.

      1. David Young says:

        Different group, probably. The small molecule antivirals are for those who have come down with Covid19 infection. They are best suited for early treatment. The vaccines are for those who have not yet contracted the disease. What about those who had vaccine shot one and then get Covid19, are they eligible for the small molecule? I don’t know, perhaps not, but that is a very small minority of people. Look, we have, what 50,000 new cases each day of Covid19? You would think that they could complete enrollment in a few days. But no, the study is open at 75 institutions and it takes “forever” to enroll because of the difficulties in getting willing people, early enough and patient enough to go through the enrollment process and understanding that they have a 50% chance of getting the placebo.

        One of the biggest mistakes of the previous administration is that they did not push, advertise and advise people to participate in clinical studies.

        1. Isidore says:

          I have no direct experience with enrolling in a trial, but I understand that it takes at least a few days, probably longer. I do have direct experience with coming down with COVID-19, however, and by the time I might have considered enrolling in a trial my symptoms were pretty much gone, so what would have been the point? Admittedly, my symptoms were quite mild and lasted only a few days, but then so have been for most of those infected and many have not shown any symptoms at all, and one suspects that the asymptomatic group has been vastly undercounted because, well, because people in this group showed no symptoms and have often not even been aware of having been infected. The bottom line is that if you are not especially ill and your symptoms go away after a few days you are not especially keen to enroll in a trial and probably not eligible anyway. And those with severe symptoms who were hospitalized were often isolated and obtaining their informed consent for participation in the trial would have been difficult. I cannot speak to the previous Administration’s policies, but it seems to me that the President being treated with a drug that was still in clinical trials (the Regeneron mAb cocktail) would have been sufficient advertisement. Maybe the sponsor of the molnupiravir clinical trial has not been aggressive enough in recruiting eligible patients.

          1. David E. Young, MD says:

            For that reason, the trial may have been looking for Covid19 patients who are at higher risk for bad disease (I’ll have to check clinical trials . gov). Those would be more motivated to be on trial. But yes, generally I agree with you. To make an early antiviral trial enroll, you are going to have to get people on the drug (or placebo) right away…. same day or the next day. That means that if labs are necessary (normal renal function, normal liver enzymes) they are going to have to run those tests right then and there. (turn around time in the fastest lab would be about an hour).

          2. David Young says:

            The outpatient study is for anyone over the age of 18 with proven Covid19 within 7 days of symptoms and who are not ill enough at that time to require hospitalization. (There is a separate study for those ill enough to be hospitalized). Can’t have a platelet count under 100,000, which will exclude a few people who deserve to be on study. They had better enroll them earlier than 4 days, otherwise they might skip the treatment if they are already getting better.

  4. Philip says:

    I hope the phase 3 trials for Molnupiravir are done with people very early in their infections. If it is another WHAT (Worthless, Hopeless Antiviral Trial) that looks at patients in the hospital or that are very sick, we will learn almost nothing of value.

    For any antiviral to work well, it will have to prevent COVID-19, not treat it. The only way to prevent COVID-19 once a person is infected with SARS-CoV-2 is to knock the virus down before the body’s immune system overreacts.

    Please note I am being precise with my usage of COVID-19 and SARS-CoV-2. COVID-19 is the disease that is caused by the SARS-CoV-2 virus. You can be infected with SARS-CoV-2 and never develop COVID-19.

    1. metaphysician says:

      Re: “WHAT”

      *citation needed*

      1. Philip says:

        Sorry, no citation for WHAT. I made up that acronym for antiviral trials for acute viral infections where the intervention is given long after infection and has almost no hope of being effective.

        Here is a citation about the need for early intervention WRT SARS-CoV-2:
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323384/

    2. Ian Malone says:

      A drug that you need to take before you know you need it take it is of limited use. It would have to be given to everyone infected, rather than those who became ill, and would be no help to those who found out they were infected because they developed symptoms (which may still be most cases in many countries). We now have effective vaccines which fill that preventative role much more efficiently since they don’t require testing and diagnosis, don’t need to be given at exactly the right moment or for an extended period of time, and can safely be given across the population (people who worry about vaccine side effects should read the warnings on some of the antivirals). The only thing they don’t offer is an immediate claim that we’ve ‘cured’ covid and no longer need to worry about it.

      1. Philip says:

        Which is why we need effective contact tracing and a good way to score the risk for an individual. This is not an easy nut to crack. Vaccines are the way to go at this point in time. Early in the pandemic if we had done better trials with remdesivir we would have known when and who to give it to, if anybody.

        For the next pandemic it would be nice to have broad-spectrum antiviral small molecules ready to go. But even having antivirals on the shelf, we would need to run a trial to see if they are effective against the new virus. That is when we would need testing and tracing coming up to speed very quickly so we could run a good trial.

      2. Thomas says:

        Having such a drug may actually promote contact tracing. “Inform your friends, they can take this pill and not get sick” instead of “when you inform your friends they will have to isolate”.

      3. Ron says:

        IF we had RAPID At-Home COVID Testing the drug(S) would be given at 1st positive indication. Testing twice a week would do it–3 times even better.
        This protocol is the same as IVM & HCQ (INCLUDING all the other otc drugs, Vit D, Zinc, etc). These have been shown, and continue to be shown, as effective Out Patient treatments.

      4. MTK says:

        Agreed on your point that a drug that is only effective very early on is of limited use. See Tamiflu.

        I can see Philip’s point about contact tracing too, but just don’t think that no matter how well you contact trace it will overcome the fact that these drugs may need to be administered very early on.

  5. Dr. Manhattan says:

    “could you explain to this tot layperson what the significance of a drug being “small-molecule” is?

    It’s a way to distinguish molecules that usually have molecular weights in the 200-800 Dalton range. These are usually chemically synthesized, (heart medications captopril, candesartan), natural products (e.g. antibiotics such as erythromycin, penicillin) or chemically modified natural products (e.g, azithromycin). Many but not all are orally dosed.

    The other class of macromolecular compounds have molecular weights in the tens (insulin) to hundreds of thousands. Best new examples are the monoclonal antibodies used in immune (e.g., Humira) and cancer conditions (e.g. Trastuzumab, alemtuzumab). These proteins all are made in cell cultures and have to be injected.

  6. Stephanie says:

    But would mutagenicity even show up in a short trial? Ima pass on this one.

    1. David Young says:

      Don’t hold your breath. Molnu is probably mutagenic. But not particularly potent if taken for 7 days. Don’t take when pregnant, of course. But in the scheme of things, taking 7 days of Molnu would not likely cause leukemia. Probably in the range of one chance in 10 million if even that.

  7. Joe says:

    Derek–really good read on this and it is high time this drug gets ore press. Ralph Barick gave a virtual talk last year in an NIH seminar and I was blown away that something so simple and already vetted to some degree was looking as good as this was. I immediately thought of the simplicity of the synthesis relative to remdesivir. This paper shows the initial preclinical work
    (Sheahan, et al., Science Translational Medicine, Apr 2020). Thought it looked good then and glad it is doing well in trials. I did some digging and N-hydroxcytidine has pretty rich history going back to the 1960’s and even papers with Francis Crick I believe…..as you say, this may have a shot as the best small molecule antiviral for SARS-CoV-2

  8. Vladas says:

    Hi, Derek,
    It would be really interesting to get your view on COVID Moonshot [1], an open science attempt to get an orally dosed small-molecule antiviral. It has a some promising inhibitors for Main protease [2, 3] that have been successful in plaque reduction assays. Maybe a bit too early to know if this will make a drug (hoping for animal efficacy studies in a month or two), but the progress for the last year has been quite impressive and noteworthy.

    [1]. https://covid.postera.ai/covid
    [2]. https://twitter.com/covid_moonshot/status/1367457761911582724?s=20
    [3]. https://covid.postera.ai/covid/activity_data

  9. Todd Wills says:

    This goes to show that even well-explored regions of chemical space may still contain promising new drugs. Based on a CAS analysis, molnupiravir resides in an older and very populated region of chemical space as its shape was first reported in 1878 and there are currently more than 3,000,000 other reported substances on this shape including 26 NMEs that were approved by the FDA.

  10. Daniel Barkalow says:

    Something like this seems like it would be more useful against the viruses behind more frequently fatal outbreaks, where you have a better idea of who could benefit from it and when. On the other hand, we’re almost certainly going to want to already know sometime in the next couple of decades whether this will significantly interfere with coronaviruses in general and SARS-related ones in particular. If the fact that we’ve got working vaccines now is largely due to past research, better responses to future potential pandemics depend on present research, even if that research isn’t especially useful for the present pandemic.

  11. cynical1 says:

    I’m not sure I understand the negative sentiment in some (but not all) of the comments. There is going to be a significant percentage of the population who refuse to get vaccinated (who will probably extensively overlap with the morons who refuse to wear a mask). There are going to be people for whom the vaccine does not work (immunocompromised). There are the emerging variants which may (eventually) escape the vaccines. There are countries that will not have access to vaccines for some time. There is also the potential of use as prophylaxis in exposed unvaccinated people. We don’t know how long the vaccines will maintain their efficacy (beyond 3 months). I personally don’t want to have to get two injections weeks apart every six months until I kick the bucket if I don’t have to. So a safe, oral, inexpensive antiviral that could be given at suspected symptom onset for a short course would be pretty amazing thing if you ask me and I spent decades working in antiviral drug discovery. It would probably not be a drug I would give to pregnant women by looking at it but I would pop some pills of that stuff in a heartbeat. Thanks for the post, Derek.

  12. john says:

    This reminds me of Gilead’s slow feet dragging to test this drug https://www.barrons.com/articles/gilead-sciences-stock-covid-19-antiviral-remdesivir-51614786990
    It is orally available and related to remedesivir

    1. David E. Young, MD says:

      Stat had an article on that drug many months ago. I tend to agree. Molnupiravir has a lot of promise. Should be used early on, within a day or two of symptoms / diagnosis. Favipiravir might be a decent drug as well, but no one is willing to a large study to really find out (meaning 1,000+ patients on a randomized study.) All the studies have been puny. There is a half-decent study of Favi in nursing home patients, aimed at about 850 patients enrolled, if I recall.

      1. theasdgamer says:

        850 high risk patients would be an excellent study for an antiviral. The signal ought to be very clear, assuming that patients were treated early.

  13. LdaQuirm says:

    Could a small molecule, broad spectrum, antiviral like this be used to clear viruses from tissue culture? You could probably dose much higher, because the mutagenic property would be less of a problem; you can just screen out mutated cell lines.

  14. Doug H MD says:

    Meanwhile, we have some great repurposed candidates out there that should have more data soon, like Fluvoxamine. Not small molecule, but if it works as well as the first RCT, why would we need this?

    1. Some idiot says:

      Fluvoxamine is _definitely_ a small molecule…!

      1. Doug H MD says:

        My mistake!!

        so why does Derek choose to ignore it?

        1. Great question – he certainly has been made aware about it, returning nothing but static in response:
          https://twitter.com/nairobih3/status/1369020226596134914?s=21

          I’m afraid that when the pandemic’s dust is finally settled, our (humanity’s) mainstream med chem community is going to have a lot to answer for.

        2. theasdgamer says:

          If I were going to eliminate a class of competitors, I would destroy their brand. Hence the concerted effort by pharma against hydroxychloroquine and ivermectin. This is part of pharma’s overall strategy against antivirals.

          Pharma is following the strategy of controlling the research just like tobacco did. An expensive antiviral might be allowed, but never a repurposed generic.

          1. Derek Lowe says:

            Dexamethasone. Please, consider my request from earlier in the day to find yourself another outlet for your thoughts than this blog.

    2. Rob says:

      A bit of a nitpick, but the first trial wasn’t randomized.

  15. Erik Dienemann says:

    As a 31-year employee at Merck, who retired a little over a year ago, but has been consulting with for Merck for the past year, it’s pretty cool to see this drug getting close to potentially being useful for COVID (and maybe other viral diseases), especially since I’ve been working specifically with my old group in the Process R&D area (chemical eng’g; in an ironic twist, the guy leading the project form the process side was in my group for 10 years, but now he’s my “boss” lol, which we chuckle about).

    We’re working on the 5-step synthetic process to make the active ingredient, which has been largely unchanged for years (it was pretty simple, so we went with it, mostly just doing optimization work and putting together a massive supply chain should the clinical data look good. Our chemist friends have developed a 3-step biocatalysis alternate route which was published recently and could be invoked if the drug gets approved as 2 steps are usually eaiser than 5 (although biocat processes tend to be more finicky at scale).

    https://chemrxiv.org/articles/preprint/Evolving_to_an_Ideal_Synthesis_of_Molnupiravir_an_Investigational_Treatment_for_COVID-19/13472373

    As Derek said, hoping to see large scale clinical results by the end of March, but I rarely got to see those in advance when I was full time there and I won’t see them now. The world still needs an orally bioavailable antiviral for COVID, so let’s hope it works. By the way, mutagenicity for a very short-term course of treatment for a potentially lifesaving drug is likely not a major concern, plus Ames tests are notoriously unreliable and in-vivo studies are ongoing from what I heard.

    1. Jon Polak says:

      Does the isobutyl ester break cleave in every species with the same kinetics?

      1. An Old Chemist says:

        Esters get hydrolyzed (cleaved) by the action of enzymes called esterases. Esterases are ubiquitous in all the species, and so, yes, the hydrolysis of any ester (including isobutyl esters) in all the species happens with the same kinetics. In my own experience, the ethyl ester prodrugs of my compounds got cleaved to free acids in rat, dog, and cyco monkey with almost the same kinetics.

        1. Jon P says:

          Did you find this same kinetics after oral dosing or IV dosing? we’ve got a double prodrug with an ethyl ester that has totally different kinetics in rats vs cyno when infused iv. The kinetics change from minutes to days. Check out the chemistry section on the link in my profile. Email me if you can using the contact us link.

          1. An Old Chemist says:

            @John, P.: My investigational compound was also a double prodrug, one being an ethyl ester, and we found that hydrolysis/cleavage data after the oral dosing. Here is a link to my paper in J.Med. Chem.

            https://pubs.acs.org/doi/10.1021/jm030354b

  16. luysii says:

    Interrupting what SARS-CoV-2 does inside the cell probably will be the way we’ll be treating COVID19 in the future. Remember that we are still working on a HIV1 vaccine, and have been for 40 + years and we still don’t have one. Nonetheless, AIDS is now a chronic treatable (but probably not curable) disease, because of antivirals similar to Molnupiravir

    1. Thomas says:

      What does an HIV1 vaccine have to do with Covid? Because Covid vaccines work, the only thing we don’t know is how well they work. And neither do we know how well a next generation may work.
      (I expect some development on a vaccine that targets the immune-disrupting parts of SARS-CoV-2 – like with the malaria vaccine recently mentioned. Having two targets in a vaccine is way better than one).

      1. luysii says:

        We have fought HIV1 to a draw without vaccines, and as you note there may come a time when our current vaccines no longer work, so research on ways to attack the virus once it gets into our cells is worth pursuing.

  17. An Old Chemist says:

    If Molnupiravir does get approved, I am wondering if it will quickly become the top selling drug of the world ever, considering that remdesivir generated revenues of $1.9 billion in one quarter alone, and that another antiviral sovaldi generated peak sales of $10.3 billion in 2015. Moreover, at this time, Molnupiravir is the only oral antiviral drug under development for covid-19 and hopefully for its new daughter variants.

    1. David Young says:

      Big question is how fast can they ramp up production. If it works exceptionally well, we could really use a lot of it…. NOW.

      1. Joseph Barchi Jr says:

        Very Simply—see above. Walter White could do it

    2. FoodScientist says:

      It would never be a top selling drug. Maybe if you took it every day of the year, but not with the 7 day course.

      Aren’t people going to freak out about the mechanism of action? That it could cause a virus to turn into some kind of airborne Super-AIDS?

      1. FoodScientist says:

        One of the links showed they tried Balapiravir in the clinic for denuge/hep c. The Balls it must have taken to take a drug to the clinic with a chiral azide(N3).

  18. Barry says:

    RNA-dependent RNA-polymerase is an exciting target because it’s critical to a whole family of pathogenic viruses and has no role in host (our) biology. There’s no reason a-priori that inhibitors have to look like nucleosides. That’s where we started (search decades before we knew any of this biology. And the farther inhibitors get from nucleosides, the less likely they are to mess with host/our biology. The diffraction structure of SARSCoV-2 is solved and published.
    https://www.rcsb.org/structure/6M71

    1. cb says:

      so turn on the AI engine of Google and create the drug………..so easy nowedays

    2. Bill Laird says:

      wow, not one mention of safe ivermectin that already achieves the endpoints. Nor the vicious coordinated attack by MSM and big pharma.

      You would have to be a mad scientist or compulsive gambler to take or prescribe this molecule over ivermectin.

      Heartbreaking to see the scientific dysfunction coming from the US on therapeutics

        1. theasdgamer says:

          Thanks for proving Bill Laird’s point.

    3. theasdgamer says:

      It would be so cool if something like zinc already did that. Oh, wait.

  19. albegadeep says:

    As soon as I saw the image for molnupiravir’s structure, I said “That looks like a duck.” Am I the only one? Maybe it’s having small kids…

    1. Kaleberg says:

      Yes, it looks like a duck. Let’s hope it quacks like one.

  20. T says:

    Maybe I just missed this, but what is auxh?

    1. Sc says:

      An obvious typo for ‘such’.

      1. T says:

        Thanks. A very condescending clarification (it’s not obvious to everyone) but a useful one nonetheless.

    2. sgcox says:

      Well, with a N-hydroxy plum more like mandarin duck, but yes :0

  21. lizzy says:

    Trial completion dates just got pushed back to late June.
    There are two trials: One outpatient (< 7 days from + pcr) one inpatient (<10 days from + pcr). Both are still recruiting.
    https://www.clinicaltrials.gov/ct2/show/NCT04575597
    https://www.clinicaltrials.gov/ct2/show/NCT04575584

    1. David E. Young, MD says:

      What a shame, if true. 75 institution aiming for a total of 1450 over the past 6 months. With thousands upon thousands of new patients they could not recruit one patient per week?

      1. theasdgamer says:

        And the crowd yelled, “VACCIIIIIIIIIIINE!!!!!!!!!!!!!!”

        This is the day of sheep running science.

  22. one man CRO says:

    is the isobutyate a prodrug?

    1. An Old Chemist says:

      Yes, transforming a free carboxylic acid group to its ester (ethyl, isobutyl, and MANY other substituted alkyl esters) is a sure way to create a prodrug of it. There are *countless* examples of it in literature.

      https://onlinelibrary.wiley.com/doi/10.1002/9783906390444.ch8

      1. Jon Polak says:

        Derek: isn’t this an isopropyl acid esterified to the pyranose sugar?

  23. lizzy says:

    Favipiravir, as mentioned above, is the other oral small molecule antiviral. It’s approved in Japan for influenza and in Russia for Covid 19 infections. There is a published study in hospitalized Covid 19 patients. It’s a small study, and there was a positive effect although not groundbreaking IMHO.
    https://reference.medscape.com/medline/abstract/32770240
    There are three trials of this drug looking at Covid 19 exposure and earlier disease. All appear stalled.

  24. Tony says:

    Atea’s AT-527 compound seems to show the most promise for all the antivirals out there being developed and under going trials. From what I’ve heard and seen so far, it could be the next game changer to control coronavirus and its variants for good. Does not have the mutagenicity of Molnupiravir and it’s efficacy and safety profiles look good if not better than most.

  25. Erik Dienemann says:

    Good news from Merck on their antiviral, molnupiravir. While this is only a small trial (202 patients is small), seeing a statistically meaningful reduction in viral reduction in mildly ill COVID patients is very encouraging, as per the excerpt, below, from the press release; safety looks good also. We definitely still need effective treatments, especially an orally bioavailable antiviral in capsule/tablet form (remdesivir is marginally effective and only available by IV). Having consulted on process development for this new drug for the past 6 months (retired from Merck after 31 years a year ago), this is very gratifying to see. Let’s hope the phase III data look good.

    https://www.businesswire.com/news/home/20210305005610/en/Ridgeback-Biotherapeutics-and-Merck-Announce-Preliminary-Findings-from-a-Phase-2a-Trial-of-Investigational-COVID-19-Therapeutic-Molnupiravir

    𝑇𝑜𝑑𝑎𝑦’𝑠 𝑝𝑟𝑒𝑠𝑒𝑛𝑡𝑎𝑡𝑖𝑜𝑛 𝑑𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑 𝑓𝑖𝑛𝑑𝑖𝑛𝑔𝑠 𝑓𝑟𝑜𝑚 𝑡ℎ𝑒 𝑠𝑒𝑐𝑜𝑛𝑑𝑎𝑟𝑦 𝑒𝑛𝑑𝑝𝑜𝑖𝑛𝑡 𝑜𝑓 𝑟𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛 𝑖𝑛 𝑡𝑖𝑚𝑒 (𝑑𝑎𝑦𝑠) 𝑡𝑜 𝑛𝑒𝑔𝑎𝑡𝑖𝑣𝑖𝑡𝑦 𝑜𝑓 𝑖𝑛𝑓𝑒𝑐𝑡𝑖𝑜𝑢𝑠 𝑣𝑖𝑟𝑢𝑠 𝑖𝑠𝑜𝑙𝑎𝑡𝑖𝑜𝑛 𝑖𝑛 𝑛𝑎𝑠𝑜𝑝ℎ𝑎𝑟𝑦𝑛𝑔𝑒𝑎𝑙 𝑠𝑤𝑎𝑏𝑠 𝑓𝑟𝑜𝑚 𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑠𝑦𝑚𝑝𝑡𝑜𝑚𝑎𝑡𝑖𝑐 𝑆𝐴𝑅𝑆-𝐶𝑜𝑉-2 𝑖𝑛𝑓𝑒𝑐𝑡𝑖𝑜𝑛, 𝑎𝑠 𝑑𝑒𝑡𝑒𝑟𝑚𝑖𝑛𝑒𝑑 𝑏𝑦 𝑖𝑠𝑜𝑙𝑎𝑡𝑖𝑜𝑛 𝑖𝑛 𝑉𝑒𝑟𝑜 𝑐𝑒𝑙𝑙 𝑙𝑖𝑛𝑒 𝑐𝑢𝑙𝑡𝑢𝑟𝑒. 𝐴𝑡 𝑑𝑎𝑦 5, 𝑡ℎ𝑒𝑟𝑒 𝑤𝑎𝑠 𝑎 𝑟𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛 (𝑛𝑜𝑚𝑖𝑛𝑎𝑙 𝑝=0.001, 𝑛𝑜𝑡 𝑐𝑜𝑛𝑡𝑟𝑜𝑙𝑙𝑒𝑑 𝑓𝑜𝑟 𝑚𝑢𝑙𝑡𝑖𝑝𝑙𝑖𝑐𝑖𝑡𝑦) 𝑖𝑛 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒 𝑣𝑖𝑟𝑎𝑙 𝑐𝑢𝑙𝑡𝑢𝑟𝑒 𝑖𝑛 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤ℎ𝑜 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑚𝑜𝑙𝑛𝑢𝑝𝑖𝑟𝑎𝑣𝑖𝑟 (𝑎𝑙𝑙 𝑑𝑜𝑠𝑒𝑠) 𝑐𝑜𝑚𝑝𝑎𝑟𝑒𝑑 𝑡𝑜 𝑝𝑙𝑎𝑐𝑒𝑏𝑜: 0% (0/47) 𝑓𝑜𝑟 𝑚𝑜𝑙𝑛𝑢𝑝𝑖𝑟𝑎𝑣𝑖𝑟 𝑎𝑛𝑑 24% (6/25) 𝑓𝑜𝑟 𝑝𝑙𝑎𝑐𝑒𝑏𝑜.

  26. Greg says:

    I believe that Brilacidin (a defensin mimetic) is also considered a “small molecule” drug. It is currently in a Phase 2 trial for Covid. Brilacidin has a Selectivity Index of 426 and had a ~98% kill rate on the Covid virus in human lung tissue in the lab. It also beat Daptomycin against ABSSSI in a Phase 2 trial so we know that it works in the human body. I believe there is every reason to be optimistic about Brilacidin’s chances in the on-going Covid Phase 2 trial.

    1. Greg says:

      So I don’t think that “Molnupiravir” is the “Last of the Small-Molecule Coronavirus Hopes?”

    2. Farrell says:

      Brilacidin for Covid19 is currently in a Phase 2 FDA trial . Preclinical in vitro testing at independent government Regional Biodefense labs show its primary mechanism of action is virucidal which is unusual for antiviral medications. Testing showed it also blocked viral cell entry. Brilacidin was shown to disrupt the viral coat which suggests rapid viral death and viral clearance. It also makes it more likely to be effective against variants and less likely to develop resistance. A previous clinical trial demonstrated Brilacidin to be a safe broad spectrum antibiotic and equivalent to Daptomycin in treating bacterial skin infections, including MRSA. Preclinical testing results were recently published in Viruses:
      https://www.mdpi.com/1999-4915/13/2/271
      More information at:
      http://www.ipharminc.com/press-release

  27. james says:

    I agree Greg. BRILACIDIN has been tested by Regional Biocontainment Laboratories and produced the 97% effectiveness against covid. 99.85 when combined with Remdesiver.
    The 426 SI is off the charts. Also the RBLs wanting to fund testing BRILACIDIN against a variety of other viruses is a plus.
    Covid mutations won’t effect BRILACIDINs effectiveness.
    Two phase 2 trials going right now in Russia and USA.
    FDA fast track designation is also a major plus. We will know soon.

    1. An Old Chemist says:

      Brilacidin is being investigated as an IV Drug as opposed to Molnupiravir which is oral.

      A Study to Evaluate the Efficacy and Safety of Brilacidin in Hospitalized Participants With COVID-19 (ClinicalTrials.Gov)

      Treatment period (Day 1-3 with potential to expand to Day 4-5): Randomized subjects will receive blinded study treatment once daily for 3 days by IV infusion, in addition to SoC.

      https://clinicaltrials.gov/ct2/show/NCT04784897

      1. James says:

        BRILACIDIN being a antiviral, immuno/ anti inflammatory and anti microbial all rolled into one drug gives it a great chance for success against this virus and many others. The safety factor is huge.
        Praying for normality to be restored.

        1. An Old Chemist says:

          It is surprising that BRILACIDIN has not yet been approved for any indication despite having such a broad therapeutic profile against pathogens. Could the reason simply be that it is not an oral drug? An oral drug would certainly be preferred for covid over an injectable one.

          1. Slowdive says:

            oral def has its advantages – myself am interested to see if Ridgeback’s oral translates into solid results… the data they just released positive — but will it translate into sicker populations, as they are trialing in other studies?
            most virologists say IV / systemic the best way to go after viruses — hit it everywhere, even if side effects increase.
            re Brilacidin, take a look at their peer review.
            https://www.mdpi.com/1999-4915/13/2/271
            the MOA also worth noting – cidal, blocking, ie, does not rely on infection. why brilacidin should be advanced as a prophylactic via inhaled delivery imo. true sweetspot, as support in the lit by other peptides/analogs in pre-clinical studies.
            EIDD also does not have anti-inflamm/immunomodulatory properties, unlike brilacidin – should help with hospitialized patients.
            hopefully either/both help treat COVID, as it is not going anywhere.

  28. james says:

    needless to say, there is more than one small molecule drug in the barn. One that been effective in multiple trials for a variety of ailments.

  29. William Laird says:

    Remdesivir somewhat useful? LOL. Tell us how you really feel.

    I had a conversation with some Lab guys on twitter that explained the MOA in great detail as to why Remdesivir is such a flop. Not sure what they were going after there. We should just focus on vaxes and delegate therapeutics to the WHO. If we had done that, we would have already moved on from plasma, remdesivir, most mAb, and adopted Ivermectin.

  30. lizzy says:

    Looks like Molnupavir just delayed their report date on their 2 Stage 2/3 trials. Now they are not reporting outcome until late June.

    1. Erik Dienemann says:

      lizzy – you are completely misinformed. Trust me.

  31. An Old Chemist says:

    COVID-19 pill effective in preliminary testing may be ‘holy grail’ of pandemic, Dr. Marc Siegel says (Fox News):

    https://www.msn.com/en-us/health/medical/covid-19-pill-effective-in-preliminary-testing-may-be-holy-grail-of-pandemic-dr-marc-siegel-says/vi-BB1ekWM8?ocid=msedgntp

  32. Erik Dienemann says:

    One other finding of note in the Saturday press release is that Merck also did an extensive in-vivo study of mutagenicity in animals, demonstrating that the compound is not mutagenic or genotoxicc, which should override the positive Ames test in bacteria.

    “Of 202 treated participants, no safety signals have been identified and of the 4 serious adverse events reported, none were considered to be study drug related. In addition to the ongoing clinical studies, Merck has conducted a comprehensive nonclinical program to characterize the safety profile of molnupiravir. This program included assays such as Big Blue and PIG-a designed to provide a robust measure of a drug or chemical’s ability to induce mutations in vivo. Animals were administered molnupiravir for longer and at higher doses (mg/Kg) than those employed in human studies. The totality of the data from these studies indicates that molnupiravir is not mutagenic or genotoxic in in vivo mammalian systems.”

  33. An Old Chemist says:

    Leprosy drug (clofazimine) fights COVID-19 in hamsters (C&E News, March 20,2021)

    https://cen.acs.org/pharmaceuticals/drug-development/Leprosy-drug-fights-COVID-19/99/i10

  34. An Old Chemist says:

    Pfizer Begins Human Trials of New Pill to Treat Coronavirus (03-23-21):

    https://www.bloomberg.com/news/articles/2021-03-23/pfizer-begins-human-trials-of-new-pill-to-treat-coronavirus

  35. An Old Chemist says:

    Kaleido Biosciences says oral drug cuts COVID-19 recovery time, hospitalizations

    https://www.reuters.com/article/us-health-coronavirus-kaleido-idUSKBN2BG1GO

  36. An Old Chemist says:

    Pfizer unveils its oral SARS-CoV-2 inhibitor (April, 7, C&E News)

    https://cen.acs.org/acs-news/acs-meeting-news/Pfizer-unveils-oral-SARS-CoV/99/i13

  37. RG says:

    Interesting that it’s a hydroxamate “mimic” structure. I wonder if it has some antibacterial activity too. Would be an interesting but appropriate side-benefit in this case!! Or it maybe just my pipe-dream, can’t help being intrigued with structures and mimetic!!

  38. theasdgamer says:

    Here’s a clever way to undermine the competition. Do a study on it that seems to be on point, but leave enough slack so that the study returns the desired affirmation of the null hypothesis or at least the _appearance_ of confirmation of the NH.

    For example, Boulware and Skipper tests for HCQ PEP/early treatment were designed to show no significant benefit. Those two studies were beginning to show benefit with significance for hospitalization, but were shut down a little before enough patients had been recruited. Still, benefit was shown and the study was underpowered (by design, apparently).

    Also, medication was shipped and there was a variable lag in time to first treatment, so that about half got the treatment too late to help. And there was significant patient bias in the Skipper study because 22 patients assigned to the HCQ arm never took the treatment. And the endpoint was symptom reduction, so this would impact even low-risk patient studies. The authors claimed that the fake participants weren’t removed because that would introduce researcher bias. But there’s no way to avoid bias and the goal is to minimize the impact of bias.

    This is how you sabotage the competition. It was well done and most people were fooled.

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