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Merck Keeps Plowing On

I last wrote about the small-molecule antiviral molnupiravir here, and we finally have more information from Merck and Ridgeback about its effects in clinical trials. An interim analysis of the Phase II data from trials in both outpatients and in hospitalized coronavirus patients has been completed, and the news is. . .mixed.

In the outpatient study, Merck says that “The percentage of patients who were hospitalized and/or died in Part 1 of the MOVe-OUT study was lower in the combined molnupiravir-treated groups versus the placebo arm; the number of events reported are not sufficient to provide a meaningful measure of clinical effect.” So that didn’t exactly ring the bells – the lower number could be meaningless, as far as we know. The release does say that viral loads were definitely lower in the treated patients, in a dose-responsive manner, so there’s that. They had 200, 400, and 800mg doses in this study, twice a day, and they plan to move into Phase III at 800mg t.i.d. They’re also changing to bring in only patients who are in the very earliest stages of the infection, and who have other risk factors as well.

Meanwhile, the data from the hospitalized patients were even less encouraging. Merck has decided not to even go ahead with a further phase III in that group, which makes sense if they’re even moving the outpatient selection up to the earliest stages possible.

What I’m seeing here is an attempt to do everything possible in the Phase III to find patients in which molnupiravir will actually show a useful effect. That’s fine, but we need to realize what that means: the “molnupiravir as game-changer” story is probably now dead. There was never too much hope for that one from the beginning, honestly – there are no game-changing single-agent antiviral therapies so far, although one could always hope. The only viral diseases we can really beat down with small molecule therapy are those where we have several specifically targeted drugs, mechanistically distinct, that can be administered at the same time. That’s the case with HIV and hepatitis C. So while we could use a broad-spectrum small-molecule antiviral, we have to be prepared for it not being that great for any particular virus.

And as I mentioned in the last molnupiravir post, keep in mind that this is about as fast as it gets for a new small molecule agent to be deployed in a pandemic. The Phase III is enrolling later this month with the changes above in mind and it will be finished. . .sometime on in the summer? I hope that molnupiravir comes through in that trial and that it shows enough efficacy to be useful. If it turns out to be a drug for high-risk patients to start taking right after they’re diagnosed, then fine, if it really does keep them out of trouble. But that last part needs to be proven.

As several people have mentioned on social media today, Merck is not having a particularly effective time of it during this pandemic. Their two vaccine candidates – neither of them poor ideas prima facie – both wiped out due to lack of efficacy. And in another news release today, they announced that they are abandoning MK-7110, picked up via a buyout of OncoImmune last year. That was a shotgun wedding under the Operation Warp Speed framework – OncoImmune had tried their immune-modulated fusion protein out in a small trial of coronavirus patients, and Merck stepped in to bring more resources into its development.

But that hasn’t worked out, either. The newer  data don’t seem to have been compelling enough, and the FDA has said that they would need more clinical proof before any EUA or approval. Merck has noted that this would put rollout of the drug – if it actually works – on into 2022, and it’s just hard to make the case for that. So MK-7110, formerly CD24fc, is no longer in the pandemic picture. It looks like Merck is out a good amount of money on this deal – they had an OWS contract for $356 million after buying OncoImmune for $425 million, but now nothing will be delivered, and I don’t know what the terms of the contract have to say about that. Under the most generous interpretation, it would seem to be a loss of at least $70 million, but who knows?

I have no idea what Merck paid Ridgeback for rights to Molnupiravir, by the way – as far as I can tell, that figure has never been disclosed. Clinical research is indeed hard, and it ain’t cheap, either.

 

110 comments on “Merck Keeps Plowing On”

  1. John Wayne says:

    At this point small molecule antiviral projects are charity work. Kudos to Merck for doing it anyway.

    1. David E. Young, MD says:

      My guess is that these antivirals would have meaningful benefit is started within two days of symptoms. They might be better results with combinations. But since these studies allow participants who have been sick for 6 or 7 days, the results a mediocre, at best. It’s too bad that clinical science has not taken the small molecule antivirals (molnupiravir, outpatient Remdesivir, possible Favipiravir, et al) more seriously back in September and set up more trial sites and easier ways to identify early patients. Then again, given the administration last year and the difficulty of science to be trusted, I can understand the difficulty. It hurt us all, but it also hurt the prospects of using antivirals effectively in early disease. Now no one believes an oral antiviral can be a helpful drug.

      1. theasdgamer says:

        Didn’t the RECOVERY Trial HCQ arm have a treatment baseline where the mean was 9 days post symptom onset (range 5-13)?

        Yet it was touted as great research.

      2. theasdgamer says:

        Congrats on following the science.

        I was on the zinc kick until I finally realized that lots of people don’t have zinc deficiency (old men and type 2 diabetics excepted). Back in June I realized that early treatment was key after studying pathology reports, the progress of covid, mean time to viral clearance, mean time to peak viral load, mean time to progress to moderate covid, etc.

        The penny dropped when I saw the CDC recommendation from Jan. 2020 to treat high risk flu patients early with antivirals. CDC and pharma, sitting in a tree…

  2. theasdgamer says:

    Oh, dam, I thought that this was about Ivermectin, which Merck developed and is now generic.

    Inexpensive and effective with RCTs to back it and a long safety track record.

    Yeah, we know what killed it for treating covid.

    Inexpensive.

    1. John Wayne says:

      Also, Ivermectin probably doesn’t work for Covid.

      There is no conspiracy to keep cheap options to address Covid from people. How do I know? Doctors can prescribe any approved medication for any reason. They aren’t giving ivermectin to their patients because it isn’t clearly a good idea. If there is a conspiracy out there, all the doctors are in on it. This isn’t likely.

      1. theasdgamer says:

        Doctors are now skittish about recommending anything not approved by the FDA. And often their partnerships will not allow them to prescribe anything not approved. Because insurance.

        It’s very sad.

        Perhaps you have an explanation for the CDC recommending that hydroxychloroquine be given late (“compassionate use”) when it would be unlikely to help.

        1. Moron says:

          Inexpensive like famotidine? It does have antiviral properties

          1. theasdgamer says:

            I’m sure famotidine has over 10k covid patients who have taken it with a dozen hospitalizations and a handful of deaths.

        2. John Wayne says:

          Doctors may be unlikely to prescribe things off label. On the other hand, ivermectin is cheap even without insurance coverage and you can get an internet doctor to prescribe almost anything not dangerous. This takes a lot of the ‘conspiracy’ wind out of your sails; people are still people.

          1. theasdgamer says:

            The problem isn’t whether insurance will cover the cost of a drug, but whether malpractice insurance prevents administering or suggesting a drug for a use which is not approved by the FDA.

        3. Charles H says:

          The explanation is that Trump was pushing it, and it was known to be (relatively) safe. That doesn’t say good things about the FDA, but I’m going to need proof before considering any other explanation to be more probable.

          1. theasdgamer says:

            But why _late_ instead of _early_?

            Consider that in Jan 2020, two months before the CDC recommendation that hydroxychloroquine be given late, the CDC was advising physicians that flu antivirals be given _early_ to high risk patients–even before laboratory confirmation.

            ” This health advisory notifies clinicians that influenza activity remains high in the United States…Because influenza activity is elevated and both influenza A and B virus infections can cause severe disease and death, this health advisory also serves as a reminder that early treatment with antiviral medications improves outcomes in patients with influenza. Early treatment with antiviral medications is recommended for…high-risk outpatients, including children younger than two years. Clinicians should…promptly start antiviral treatment of severely ill and high-risk patients with suspected influenza without waiting for laboratory confirmation.”

            So why would the CDC recommend _late_ treatment with an antiviral where it would do no good a mere two months _after_ the CDC had advised physicians to treat high risk flu outpatients _early_, even before laboratory confirmation.

            Then, the FDA removed the EUA for hydroxychloroquine based on a retracted Lancet study. Ok, we could assume that this was a mistake and could be corrected. Maybe not resume the EUA, but the CDC could issue an advisory that there was no evidence against the effectiveness of hydroxychloroquine. But the CDC did not do that. No correction or admission of a mistake.

            The CDC also did not focus attention on the mistake of recommending late treatment of antivirals for covid and correct their errors. No admission that the CDC made a mistake.

            I am pretty confident that the FDA takes its guidance from the CDC about stuff like this. I don’t blame this on the FDA.

      2. Irene says:

        Merck makes ivermectin. Merck says not to use it for COVID. Seems like (a) they ought to know and (b) their bias should be all the other way.

        1. theasdgamer says:

          Yeah, because Merck has done so much testing of ivermectin as a treatment for covid.

          Think how much money we’ll save if we can avoid that pesky, expensive experimental research and simply18 rely on statements from eminent authorities.

          1. DTX says:

            It’s ironic to see the idea that Merck didn’t progress the development Ivermectin for Covid because it wouldn’t make a profit off of it. Merck has been donating ivermectin for more than 30 years for treatment of river blindness. The river blindness program is one of the best examples of charity from pharma there is (yet we have an example of an uniformed individual using it to posit an evil conspiracy). Is there a better one? One that has helped more people over such a long time?

            I realize most reading this blog appropriately dismiss the comments and that factual information won’t persuade those who don’t use facts to make suppositions, but it was important to set the record straight for others that may not know the background to Merck & ivermectin.

          2. theasdgamer says:

            DTX,

            Does Merck donate ivermectin to treat river blindness because Merck is a charity? Is it doing so despite having a more expensive treatment for river blindness? Is river blindness a problem for western countries which might spend beaucoup bucks to treat it?

            Was Merck trying to develop vaccines for covid which failed? Would ivermectin have undercut vaccines if shown to be successful.

            I note that you _still_ can’t provide a rational explanation for the CDC specifying that HCQ be given to patients _late_.

            smh

    2. P says:

      Inexpensive like dexamethasone?

      1. theasdgamer says:

        Yes, dexamethasone is an excellent antiviral.

        1. Another Idiot says:

          Dexamethasone is an antiviral?

          News to me.

          1. theasdgamer says:

            left off the /sarcasm

    3. anon says:

      Run your own phase III then?

        1. anon says:

          You’re the one who wants it. Fund it yourself.

          1. theasdgamer says:

            I don’t have funds for random funding of research. That takes big pockets. But pharma won’t fund it and no one wants to do RCTs on cheap antivirals–either because of ethical problems (the pro-antiviral side) or because of lack of belief in antivirals.

            It would take a mandate and funding from the FDA to make this happen. They have no interest in it for some reason.

          2. D says:

            Why don’t the insurers fund trials of inexpensive drugs? It should be in their interest to get affordable medicines. Except perhaps it isn’t, because it is the fear of the extravagant costs of healthcare that persuade healthy people to pay for health insurance.

          3. theasdgamer says:

            D,

            Part of the problem is a lack of incentive on the part of major players to fund RCT research into repurposing inexpensive drugs.

            Those physicians who have used those drugs and written up retrospective studies have an ethical problem withholding lifesaving drugs (as they view them) from their patients. And those who have no faith in those drugs have no incentive to do those studies (except as an academic exercise).

            What we are left with is retrospective studies as the only real evidence on the table, assuming they are well-designed. And, of course, there is the risk of confounders. But if the level of benefit is large, like an 80% reduction in hospitalization, then the retrospective studies have enough weight for clinical use pending RCTs (if they ever are done).

          4. anon says:

            Then raise money and run for office.

          5. Druid says:

            theasdgamer – I know you are not a fan of the RECOVERY trial because of its (mis-)treatment of antivirals, but they are in a hospital setting and I think you are looking for drugs for either prophylactic or pre-hospital use, probably self-medication. The indicators of recovery in hospital are improving as result of treatments tested by physicians without massive investment.

            Perhaps community pharmacists would have to be the agents of a randomised trial in the community, and then you just have to get the “patients” (customers) to report on outcomes. They could test vitamins and herbal remedies as well as re-purposed meds in a controlled way. The big chains could play a big part in this. Unfortunately pharmacists are as busy as other healthcare professionals. (Mistakenly replied as D last time.)

    4. LittlePharma says:

      Do we only have to ignore pharmacology to believe your nonsense or do you recommend we ignore other fields of science too?

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404744/

      1. theasdgamer says:

        Is there some connection between the link and your rant?

        1. A Thinking Human says:

          Is there some connection between your brain and objective reality? The article clearly states that at the maximum clinical dose of ivermectin, the free plasma concentrations of ivermectin are 250x lower than those that inhibited viral replication in vitro. Since you can’t achieve an effective circulating concentration in vivo at reasonable or even large doses, the drug is highly unlikely to work for this purpose. You should try learning some pharmaceutical science before lecturing people who have dedicated their lives to the development of novel therapies.

        2. theasdgamer says:

          Maybe there is another factor, like the availability of zinc? Somehow doctors who prescribe HCQ in outpatient settings _consistently_ get excellent results.

          Yet another reason why in vitro doesn’t necessarily reflect reality in human health.

          Why did RECOVERY test late treatment of HCQ instead of early treatment? And why did the CDC mandate treating with HCQ late in hospital settings?

          If you can’t see it, remove your hands from your eyes.

          1. Marko says:

            “Maybe there is another factor, like the availability of zinc?”

            So, the new plan is to roll out the “but zinc” defense for ivermectin, just like for hydroxychloroquine?

            This nightmare will never end….

          2. theasdgamer says:

            No, Marko, it’s not about zinc. It’s about early treatment v late treatment.

            Zinc is only important if someone is deficient and some groups that are deficient have been identified.

            The discussion in this thread has been about in vitro evidence which certainly isn’t my strength.

            With antivirals, the key question is: “Is treating high risk patients early with [insert antiviral name here] better than doing nothing?”

            It seems that pretty much any RNA antiviral stands a good chance of answering yes, including remdesivir. Toxicity and cost are factors besides effectiveness.

      2. theasdgamer says:

        Thanks for the link, btw.

      3. Özgür Demirtas says:

        Does your understanding of pharmacology include the difference of in vitro and in vivo? It is interesting actually, if the IC50 concentration in the petri dish were easily achievable with low doses of Ivermectin, you would probably shoot the same argument instantly: “It is only in a petri dish, you can also try salt water bla bla”

        This article is quite “old” in the context of the pandemic. May be you can update your limitless knowledge of science by tens of in vivo and real life data that emerged after July 2020 regarding the use of Ivermectin in treating COVID-19.

        Moreover, Caly et al from Monash actually updated their study with new cell lines and the concentration turns out to be much lower then their previous results.

        See, even some people follow from a year behind, science evolves…

        1. theasdgamer says:

          Very interesting information about the lower concentration. Thank you.

    5. Shandyman says:

      You’re forgetting something, or willfully ignoring it, companies and people don’t always do things for short term motives. Imagine the kudos and enhanced reputation for Merck if Invermectin was a game changer or even remotely useful. This would be priceless publicity for them that I suspect they would not turn away from because Invermectin Covid19 use would not make them much profit.

      1. theasdgamer says:

        Good will has an intangible value. Successful vaccines for a URTI have a value which can actually be measured.

        1. Shandyman says:

          But they haven’t developed a successful vaccine so why not take the goodwill?

          1. theasdgamer says:

            Maybe they have another plan, like a more expensive novel antiviral.

    6. sean fhearsalach says:

      just one word – dexamethasone ($1/dose)

      1. theasdgamer says:

        Dexamethasone, of course, is no competition with new, expensive antivirals or vaccines.

    7. Carl Pham says:

      Bear in mind we only know it was “inexpensive” that killed ivermectin if our aluminum headgear is tuned to the same frequency as yours. Otherwise we might know it was politics, or International Jewry, or the Illuminati, or the same people who hid the existence of chemtrails and the aliens at Area 51.

    8. Buzz says:

      Merck gave away millions of doses of ivermectin to cure river blindness in Africa for decades

      Get your facts straight before posting drivel, we are actual scientists here

  3. David E. Young, MD says:

    Maybe I am misinterpreting clinical trials, but isn’t this study phase III and intended to be completed in June (was May, and before that, was April…. they seem to have trouble recruiting). https://www.clinicaltrials.gov/ct2/show/NCT04575597?term=molnupiravir&cond=covid19&draw=2&rank=2

    Data collection will continue through next December, but the last recruitment should be in just a few months.

    1. theasdgamer says:

      Mild _or moderate_ covid?

      Covid viral load peaks three days post symptom onset (mean) and is cleared after 8 days (mean)…moderate symptoms develop seven days post symptom onset (mean).

      Another late treatment test of an antiviral, looks like. smh

      Start treatment within 3 days of symptom onset to get the antiviral benefit. It looks like antibodies on the spike protein cause the more severe effects, doesn’t it?

  4. Philip says:

    Just another example of the need for rapid, frequent testing and robust contact tracing. Without those two, getting antiviral therapies to patients in time to be beneficial, is very hard, if not impossible.

    1. theasdgamer says:

      Why couldn’t public health authorities educate the public to see their physician as soon as they experience URTI symptoms? And set up nursing home guidelines informing them to make sure that residents are seen by a physician within one day of symptom onset?

      Where is the need for contact tracing?

      1. David says:

        “Why couldn’t public health authorities educate the public …”

        You mean the public that smokes, eats junk food, doesn’t exercise, and drives after drinking alcohol? Or do you mean a different public?

        1. theasdgamer says:

          Smoking and eating junk food have addictions in common. Covid, not so much. But the mentally impaired in care homes would be at risk.

          But the media likely wouldn’t help because there’s no click bait in it. So you may be correct that some sort of public health intervention would be necessary. It might just be alerting care homes appropriately.

      2. Philip says:

        Contact tracing can find people before symptom onset. Then add rapid testing and you could get to a lot of people very early in their infection.

        1. theasdgamer says:

          Why wait for test results before treating? Best case, 20% are false negatives 3rd day post symptom onset.

      3. Barry says:

        Many in the U.S. won’t “see their physician as soon as they experience URTI symptoms” because
        1-they don’t have a physician
        or
        2-they can’t afford the deductible on their health insurance
        or
        3-they don’t have health insurance

        1. theasdgamer says:

          And most of those are young, low-risk people. The poor have medicaid and the old have medicare. The old poor have both.

          It’s the people with dementia who are most at risk, but most of them have caretakers.

          The PHA’s are really about educating the primary care physicians as much as anyone.

    2. Charles H says:

      It’s not clear that even WITH early detection, “anti-virals” will have a significant success rate. First you’ve got to find one (or a combination) that will do the job, which is what Merck appears to be trying to do here…but which nobody has done for COVID so far…or for most other viral diseases.

      1. theasdgamer says:

        Um, there have been several antivirals that have “done the job” in observational studies. The weight of the scientific evidence is based on the better observational studies, currently.

        If you don’t like the current state of the evidence, do your own study–observational or RCT. Just try to test the key hypothesis which includes words/phrases like “early treatment” and “high-risk patients”. And try not to rely on shipping companies that may delay the time to 1st treatment so that it ends up not being early.

  5. Dylan says:

    Off topic, but figured I’d take the opportunity of having some fairly knowledgeable people in the room to ask a question. My wife and I both got our first dose of the Moderna vaccine about 3 weeks ago. Subsequently, we both came down with Covid, developing symptoms about 9 days after the first dose. Her symptoms were worse than mine, but we’re both getting back close to full health. Our mandated isolation period ends about 5 days before our 2nd scheduled dose. Should we consider postponing the 2nd dose? Mostly worried about the potential of increased side effects this close to having it.

    1. John Wayne says:

      I’m sorry that this happened to you and your wife; that is some bad luck. You are asking a very hard question. Medical science is like weather prediction, it is much more accurate once it has already happened. Since this is so new, there are probably limited case studies that describe your situation.

      If I was you, I would reach out to a practicing doctor in infectious diseases and ask them for their thoughts. That doctor is going to make an educated guess that will be better than talking to a bunch of psuedoexperts (like myself.)

      1. Dylan says:

        Thanks for the feedback. Have been planning to reach out to a doctor, although I’m not sure I’ll get connected to an expert in infectious disease. I know that with things being as new as they are, anything is going to just be an educated guess…but was hoping to get at least a few opinions that are more educated than mine.

        My wife had a fairly rough time of it, not as bad as it could have been of course, but still had trouble getting out of bed for a few days. Not looking forward to potentially repeating that in just one week. On the other hand, it would of course nice to get it behind us if there’s no reason to suspect that the response would be worse because of such a recent infection.

        1. John Wayne says:

          If I had to guess, the doctor will recommend you get the shot. Your immune system should be bored by the vaccination after a real bout with actual Covid, but that is just a guess. Please still ask.

          I would think about being extra careful the day of your second shot. Sleep and eat well, no booze or recreational drugs. Hang out in the recovery area near immediate medical help for longer than the mandated 15 minutes (bring a book.) Drink lots of water. It sounds like you and your wife are on the same vaccination schedule. If you want to be really conservative, have somebody else around to keep an eye on you two for 24 hours. If something goes wrong, you want to get medical help immediately. If you are both a little groggy the other might not be with it enough to decide something is an emergency.

          This may sound a bit paranoid, but a little forethought can save a life. Take my comments with a grain of salt; I have almost a dozen fire extinguishers in my house. I like mitigating risk.

          1. Dylan says:

            Thanks Mr. Wayne. Really appreciate the advice. I’m going to go and schedule a phone call with a doctor via my new insurance company now. See what they have to say.

          2. Doug H MD says:

            “Your immune system should be bored by the vaccination after a real bout with actual Covid,”
            the data say the exact opposite in terms of immune response
            https://twitter.com/MonicaGandhi9/status/1378768089601298434

          3. Anecdata says:

            I would recommend anyone with potentially complicating conditions, especially inflammatory and autoimmune disorders, to consult with their specialist in addition to their primary care doc.

            Take this for the anecdote that it is, but a friend, 38yo physician-assistant with lupus (ie already had elevated inflammation and autoimmunity) had a bout with Covid before the vaccines had been released. His case wasn’t bad and passed without major incident. Working in health care, he was front of the line when vaccines were available and got both shots as advised by the CDC and his primary care doc at the time. No problem with the first shot.
            Massive amounts of pulmonary inflammation after the second. He’s off steroids now after two months, but still uses supplemental oxygen. When he spoke to his rheumatologist they lamented that he hadn’t checked with them as they would have advised no more than a single dose given his previous infection. Point is, data are still emerging on how to best use these vaccines in all patient subpopulations. The first people to see the red flags will be the providers who specialize in those subpopulations.

        2. Charles H says:

          My *guess* would be that you should get the second shot, but be prepared for a *strong* reaction to it. I’d guess that there would be about a 70% chance that you don’t need that shot, as your immune system is already up to speed on COVID.

          CAUTION: I’m a programmer, not a medic. And let me emphasize more strongly that this is a guess.

    2. Daniel Barkalow says:

      I’d contact the site where your appointment is (ahead of time) and ask what guidance they got for cases like yours. There’s probably a recommendation from Moderna, since they must have done something with the people in the studies who tested positive at that point. And if you can’t know what the best thing to do is, you can at least do the usual thing.

    3. therealestg9 says:

      You don’t need a vaccine after being exposed to the virus and recovering. Even if you had a mild case and were asymptomatic. T cell first line of defense against certain common cold coronaviruses has been known to last for decades.

      Read:
      Dan, J.M., Mateus, J., Kato, Y., Hastie, K.M., Faliti, C., Ramirez, S.I., Frazier, A., Esther, D.Y., Grifoni, A., Rawlings, S.A. and Peters, B., 2020. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection. BioRxiv.

    4. cynical1 says:

      This study was published yesterday in the New England Journal of Medicine. It might suggest that you may wish to wait three months and then get a single dose but the study was in people who had never got a single dose just prior infection. https://www.nejm.org/doi/full/10.1056/NEJMc2103825

  6. Danish vikingj says:

    Sorry, I know this is a bit off topic. An EU MEP recently made the statement below about why mRNA vaccines are supposedly “better” than vector vaccines:

    “But the most important advantage is that they can be adapted to mutations more quickly and in a more targeted way.”
    https://www.politico.eu/article/eu-bets-on-mrna-vaccines-in-future-pandemic-fight/

    Is this really true?, and if, why ?

    1. sgcox says:

      I really doubt that. Both mRNA and adenovirus vaccines can be adopted to new variants in weeks. Moreover, I am almost 100% sure all of the companies involved already have samples of modified vaccines for SA and Brazilian in their freezers. Time consuming is as usual the actual testing in animals and later humans. Will take exactly same time in either vaccine platform. And which one to focus on ?? We need to know somehow what might become a prevalent problem before scaling up and go for trials. It may be actually some new one…
      Best way forward right now is indeed to drive global infection rate down so much less chance of new dangerous variants.

      1. Danish vikingj says:

        Yes, that is what I also thought? Why would it be any easier or faster to create and amplify an RNA vs a DNA molecule? Maybe creating very large amounts of a vector is more time consuming than creating very large amounts of an mRNA? Or maybe it is something else in the sample (other than DNA and RNA, respectively) that may be more difficult in DNA vaccines? Or maybe this simply one of those cases where a politician is speaking nonesense?

      2. Carl Pham says:

        Sure, but you can’t give the adenovirus vaccine to a given person more than once, so it’s not going to do any good as a booster regime. So far as we know you can give lipid nanoparticles as many times as you like.

        1. Barry says:

          AstraZeneca does recommend two doses of their Adenovirus-based Covid vaccine. They report that it is less effective if two full doses are given rather than a half-dose followed by a full dose, perhaps because in the former scenario, the booster isn’t blunted as badly by host-vs-vector immunity.

          https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00528-6/fulltext

    2. John says:

      I speculate that this is true. The reason would be because, as Derek has mentioned several times, there is no cell culturing involved. All it would take is a minor tweak to the mRNA already there, as in a few nucleic acids. The process for producing mRNA vaccines would not really have to be changed. Changing an adenovirus vector vaccine is a different ball game. They may likely have to grow a new cell line as people who have already gotten the first could be immune to the viral vector they originally used. There are likely several other reasons than just these.

      1. sgcox says:

        No, you use exactly same HEKs transfected with E1/E3 proteins for virus replication. Minor nucleotide changes in Spike insert are irrelevant here. As for the switch to a new Ade strain ? My gut feeling it is a purely hypothetical problem which has merit in theory but not in practise. AZ antibody response clearly benefited from the second dose and Janssen uses common human variant. After all, if prior adenovirus infection switches robust response, why do we suffer common cold year after year ?. Yes common cold is caused by other virus too but somehow it stays with us forever.

      2. Danish vikingj says:

        John, Thank you.
        I suspected that Derek would have covered this issue. Can you remember in which blog entry?

        1. sgcox says:

          I think this one:
          https://blogs.sciencemag.org/pipeline/archives/2021/02/08/how-you-make-an-adenovirus-vaccine
          But there have been so many covid vaccine posts, my head is spinning..

          1. Danish vikingj says:

            🙂
            Thank you!

          2. John says:

            That one is very good, but pretty much any of his vaccine round ups involve him talking about the woes of cell culturing. The rest is from my own experience as a grad student in a cell and molecular bio master’s program. Again, I’m still a novice with some of this stuff, but I felt strongly enough about that answer to respond.

    3. therealestg9 says:

      $$$

  7. bewick says:

    can you keep using the same adenovirus vector repeatedly or do you build immunity making the vaccine less effective?

    1. LL says:

      For systemic applications, you can’t use the same vector multiple times because the immune response against the virus will greatly diminish effectiveness of expression for the cargo.

    2. Charles H says:

      That’s something many people have been worrying about. So much that one company used a different adenovirus for the followup to the first shot. But there’s no real *knowledge* in this particular situation AFAIK. We know it’s possible. We suspect it may happen. If there have been tests as to whether it does happen, I haven’t heard of them.

  8. Barry says:

    A priori, RNA-dependent RBA polymerase is as good a Target as is reverse transcriptase. Humans need neither, (some) viral pathogens need them. RT has proven quite a fruitful target

    1. Barry says:

      Aaaargh. “RNA-dependent RNApolymerase”, of course.
      fat fingers

  9. LL says:

    A small molecule Covid anti-viral will be a game-changer provided it is really efficacious, has good tolerability, and does not develop resistant mutants very rapidly.

    Worldwide vaccinations will go on for years to come – keeping large populations very vulnerable. With the spotty vaccine coverage in developed countries (because for some reasons, sizable groups of people refuse vaccinations) eradication of Covid is very far away, if it will ever happen.

    In this context an oral antiviral drug that can be applied anywhere for comparably low costs (compared to expensive i.v. administrated monoclonal antibodies, which are also harder to store, typically can’t be self-administrated at home) will make a huge difference.

    Again, such a drug needs to work, be safe, and stay active (no rapid resistance developed) – and if it does, it is a breakthrough. There are more candidates in development and I sincerely hope one of them makes it.

    1. Wallace Grommet says:

      Prevention always beats treatment. How many people develop immunity of a lasting sort from HCQ,Zinc,antivirals, or holy water?

      1. theasdgamer says:

        Prevention beats treatment except when it doesn’t. Viruses have a way of mutating, which may defeat antibodies.

      2. LL says:

        Of course, where and to the extent possible, prevention by way of vaccination and other means is always best.

        My point is that with a virus that will likely go around, even might get endemic pretty much worldwide, there will be a need for treatment. And if effective, an oral small molecule drug that can be stored without fridges and freezers for a long time and taken in rural Afrika, beats antibodies which are tricky to store and need iv administration – and are very expensive on top of that.

        Plus, we will see a sizable group of people under chemo, people with weak immune system etc where vaccines either don’t work or are not an option.

        So, small molecule drugs will be an element of a multi-pronged approach which of course also contains vaccines and prevention measures.

      3. theasdgamer says:

        People begin to develop immunity as soon as the immune response begins–on the first day of symptom onset. Administering antivirals before the peak viral load is achieved might limit the antibody response, which might not be a bad thing in the case of covid because most of its damage is done by the immune-instigated coagulopathy. Even after clearing virus, some antibodies will remain and so will the immune memory cells. So, if reinfection occurs, the immune response will occur more quickly and the max viral load will likely be less. And you can still take antivirals and you will end up with more antibodies left than the first time, right? And you will likely have T-cell immunity after the second infection. Right?

        So where’s the problem with antivirals?

    2. Thomas McEntee says:

      Re development of resistance to small molecule antivirals, in 1975 for a customer, I developed a plant process for the production of adamantylamine (“Symmetrel”) from the well-known literature route starting with dicylopentadiene. We produced several thousand kilos of the hydrochloride and shipped the batches to the customer. They ultimately decided to produce in-house to supply their FDA-approved influenza Type A market. Within 4 years, resistant strains appeared and by the early 2000s, FDA no longer endorsed its use. We heard rumors that the development of resistance was due, in part, to its being used indiscriminately in swine feed in a large Asian country…but I haven’t pursued this rumor. It was a fairly challenging manufacturing process…titrating a methylene chloride solution of the amine with hydrogen chloride in a 2000-gal glass lined Pfaudler reactor…

  10. Frank says:

    On the other hand, one may be curious about the outcome of this study: cyclophyilin inhibitors, specifically alisporivir

    https://www.europeanpharmaceuticalreview.com/news/140512/phase-ii-trial-to-establish-whether-alisporivir-can-prevent-covid-19-progression/

  11. Mactoul says:

    What about nitric oxide nasal spray (NONS) which I believe has been approved in Israel and New Zealand.

  12. Groucho says:

    “Merck Keeps Plowing On”

    Was that so obvious that everyone ignored it, or so subtle that no one noticed?

    Derek, surely it was intentional…

  13. Christian Weisgerber says:

    Atriva Therapeutics Doses First Patient in Phase II RESPIRE trial in COVID-19
    https://www.atriva-therapeutics.com/news/press-releases/14-news/107-fpi

    “Atriva’s lead product ATR-002 is developed specifically to treat diseases such as influenza and COVID-19, caused by RNA viruses. ATR-002 is a clinical stage MEK inhibitor drug candidate targeting the intracellular Raf/MEK/ERK signaling pathway. This pathway is central for replication of many RNA viruses, such as the influenza virus, hantavirus or respiratory syncytial virus (RSV) and also SARS-CoV-2, the virus that causes COVID-19. In influenza virus infected cells, the interaction of ATR-002 with MEK (MAPK/ERK kinase) prevents export of the viral genome protein complexes (ribonucleoprotein, RNP) from the nucleus to the cytoplasm, thus blocking the formation of functional new viral particles. This ultimately reduces the viral load in the body. In addition, ATR-002 has the potential to modulate the pro-inflammatory cytokine response of the body, avoiding overshooting cytokine response that can be caused by such viral infections. MEK inhibition can reduce the gene expression of some of the cytokines involved, like TNF-α, IL-1ß, IP-10, IL-8, MCP-1 and MIP-1a, and thus mitigate the overactive inflammatory response in the lungs of patients who are severely ill with influenza or COVID-19.”

  14. Jeff says:

    Why even bother testing an antiviral closer to onset at this point? There are multiple highly effective vaccines rolling out at massive scale. Isn’t anywhere that would have a chance of effectively rolling out an antiviral needed at early onset going to have everyone who wants it vaccinated by the time the trials are done?

    1. theasdgamer says:

      1. There are a large no. of people who will refuse the vaxx.

      2. We don’t know if viral mutants will end up becoming a major threat.

      3. We don’t know if we will discover hidden dangers in vaxxes several years out.

      4. Don’t put all your eggs in one basket.

  15. theasdgamer says:

    “What I’m seeing here is an attempt to do everything possible in the Phase III to find patients in which molnupiravir will actually show a useful effect. That’s fine, but we need to realize what that means: the “molnupiravir as game-changer” story is probably now dead. There was never too much hope for that one from the beginning, honestly – there are no game-changing single-agent antiviral therapies so far, although one could always hope. The only viral diseases we can really beat down with small molecule therapy are those where we have several specifically targeted drugs, mechanistically distinct, that can be administered at the same time. That’s the case with HIV and hepatitis C. So while we could use a broad-spectrum small-molecule antiviral, we have to be prepared for it not being that great for any particular virus.”

    Everything possible? Lol, more like finally figuring out the key hypothesis to test. (Are you into well-poisoning? Meh, we’ve seen that done way better by the CDC and Lancet.)

    Single agent? Cool straw man. Brian Tyson in El Centro treated over 2,000 covid patients with no deaths…with HCQ, ivermectin, zinc, vitamin C, vitamin D, and other stuff. 100% reduction in deaths over the no-treatment SOC.

    1. John says:

      thegasdgamer as soon as you mention HCQ you loose all credibility with this crowd. Its over and does not work. I could prescribe a glass of water for out-patients as a doctor and get the same results. Truth is most people just get better

      1. theasdgamer says:

        dam, if you are correct, there are so many dummies

      2. theasdgamer says:

        What is the mortality rate of covid in nursing home patients? Around 20%?

        In the general population? Around 0.1%?

        In patients of all ages triaged for age or comorbidities? Around 3%?

        No, you don’t get Zelenko’s results by “treating with a glass of water.” His data shows 80% relative reduction in hospitalization for patients treated with is cocktail compared with no treatment in the same community. Out of 141 high-risk patients Zelenko treated with his cocktail, he had only one death (who was a very sick cancer patient and only received a single dose) and four hospitalizations (2.8% v. 15% control). The data is from March.

        But a lot of you don’t bother to read the section on limitations in journal articles. Or even realize when the limitations section is missing (cough-RECOVERY-cough). A competent reader would not apply RECOVERY conclusions to outpatient settings. Other journal articles on similar late HCQ treatment on hospitalized patients pointed out that their results did not apply to outpatient settings, where presumably patients would be treated with antivirals in a timely manner.

        1. theasdgamer says:

          Data is from March thru may and is sequential with 100% followup.

      3. theasdgamer says:

        Mokhtari’s study of about 29k patients in Iran showed a relative reduction in hospitalization of 39% when treated with HCQ within 7 days of symptom onset. The relative reduction in death was 73%.

        https://www.sciencedirect.com/science/article/pii/S1567576921002721

        Please let me know if you see any problems with the study, which is the largest so far (which hasn’t been retracted).

        1. John says:

          population-based national retrospective-cohort study…lol who cares

          1. theasdgamer says:

            The science is totally in favor of the hypothesis that early treatment of high-risk patients with [HCQ or ivermectin] reduces hospitalization significantly. There are several high quality studies supporting it (Derwand, Procter, and Mokhtari) and no high quality studies that support the null hypothesis.

            It’s unethical for doctors who accept the hypothesis to do RCTs. So it’s up to those who question the affirmative hypothesis to come up with RCT evidence in favor of the null hypothesis.

            The case fatality ratio for covid is estimated to be between 0.1% and 0.35%. Brian Tyson has treated 2,000 patients with 0 deaths, while the estimates would have projected between 2 and 7 deaths. That looks like another win for the affirmative hypothesis.

            You don’t reject good evidence just because it’s not overwhelming. That’s not good science. If you want overwhelming evidence, you do a _high quality_ RCT that tests the affirmative hypothesis. ALL of the early treatment retrospective studies have affirmed that it would be good for such a RCT to be done.

            You don’t do RCTs that are underpowered or questionable about time from symptom onset to treatment. You don’t put spin in the media about “dangers” of hydroxychloroquine or ivermectin. You don’t claim that late treatment studies prove the null hypothesis. That is all rhetoric and not solid science. We’ve seen these kinds of tricks from the tobacco industry when they were doing “research” in order to control the science.

      4. theasdgamer says:

        Cool rhetoric, btw. Do you also do science?t

  16. An Old Chemist says:

    Amid Humanitarian Crisis in India, Merck Announces Voluntary Licensing Agreements with Five Indian Generics Manufacturers to Accelerate and Expand Global Access to Molnupiravir, an Investigational Oral Therapeutic for the Treatment of COVID-19

    04-27-21 (BioSpace):

    https://www.biospace.com/article/releases/amid-humanitarian-crisis-in-india-merck-announces-voluntary-licensing-agreements-with-five-indian-generics-manufacturers-to-accelerate-and-expand-global-access-to-molnupiravir-an-investigational-oral-therapeutic-for-the-treatment-of-covid-19-/

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