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Clinical Trials

What’s Happening With Remdesivir?

Well, everyone was just dealing with the news that Gilead’s antiviral remdesivir had had two trials suspended in China, when Stat‘s Adam Feuerstein and Matthew Herper broke news last night about a trial here in the US.

125 patients had been recruited at the University of Chicago to receive daily doses of remdesivir, and the only reason we have news of what’s going on is because of a series of mistakes. A Chicago infectious disease specialist overseeing the trial there mentioned during a video chat with colleagues that most of these patients had been discharged, with only two fatalities. The video was recorded and then leaked to Stat. And let’s be honest about this part: this was a severe breach of the trial protocol, the sort of thing that under other circumstances could lead to the whole thing being invalidated and not accepted by the FDA as evidence. That’s not going to happen here; everyone is just going to roll their eyes, kick their desks, and find a way to deal. But this is not the way to handle trial data – it complicates everything at a time when we don’t need to be doing that. The Chicago trial supervisor should have known better than to discuss results like this to a crowd of people over video, and whoever leaked it should have known better than to do it. Let’s not have any more of this.

Should Stat have published? That’s a classic journalism question: this was certainly news, and journalists report news. It seems certain that if they had declined that the video would have been sent to any number of other news outlets; the cat was already exiting the bag. Someone was going to run with this story, and overall I’m glad that this got sent to Feuerstein and Herper rather than to Sean Hannity or Dr. Oz. I don’t like this leak at all, but the parts I like the least are the steps that happened before the news got published.

But now that it’s out there, let’s talk about what’s in the leak. Gilead stock jumped like a spawning salmon in after-market trading on this, and one of the reasons was that that 113 of the 125 patients were classed as having “severe disease”. People ran with the idea that these must have been people on ventilators who were walking out of the hospital, but that is not the case. As AndyBiotech pointed out on Twitter, all you had to do was read the trial’s exclusion criteria: patients were not even admitted into the trial if they were on mechanical ventilation. Some will have moved on to ventilation during the trial, but we don’t know how many (the trial protocol has these in a separate group).

Note also that this trial is open-label; both doctors and patients know who is getting what, and note the really key point: there is no control arm. This is one of the trials mentioned in this post on small-molecule therapies as being the most likely to read out first, but it’s always been clear that the tradeoff for that speed is rigor. The observational paper that was published on remdesivir in the NEJM had no controls either, of course, and that made it hard to interpret. Scratch that, it made it impossible to interpret. It will likely be the same with this trial – the comparison is between a five-day course of remdesivir and a ten-day course, and the primary endpoint is the odds ratio for improvement between the two groups.

So we will have the choice to like remdesivir or to love it; there will be no direct standard of comparison for how these patients will have done without it. Everyone will be trying to synthesize such a comparator from other clinical trials and reports, but that’s a dangerous business. I hope that we can learn something from the subgroup analyses, but there’s a limit.

Bottom line: I’m sounding like a defective parrot here because I say this so often, but we have to wait for controlled trials in order to say anything definite. Such trials are underway, with actual comparisons to standard of care, but they take longer. Fast trials are generally not very interpretable, interpretable trials are generally not fast. I will be glad to see these numbers when they appear, but don’t believe anyone who runs with a “Cure for Covid!” headline, because it’s extremely unlikely that remdesivir (a single agent with a broad mechanisms that’s not optimized for this virus) is any such thing. Remember, there are as yet no single-small-molecule antiviral cures for anything, coronavirus or not. My hope for the drug is that it is effective enough to get people out of the hospitals more quickly and to keep more of them off ventilators than if they were not taking it. For that hope to be realized, we need that comparison to the people who are not taking it. This trial doesn’t have it.



149 comments on “What’s Happening With Remdesivir?”

  1. passionlessDrone says:

    In before an onslaught of trolls accusing you of being an ivory tower socialist elitist who wants society to be shut down because you hate small business. Also that you don’t know anything about science or medicine.

    1. Hap says:

      That would be consistent with the normal nature of trolls not actually reading the site. At least they can’t mansplain Dr. Lowe, or we’d have to sift through that brown porridge, too.

    2. Derek Lowe says:

      Getting used to that! You should see my Gmail queue. . .

    3. Edmund Brown says:

      This has a ‘Dear Leader’ sentiment.

      1. x says:

        There’s been an onslaught of generally unscientific opinion on this blog recently – there’s the “we can’t afford to wait to see if this is a cure or not because it is definitely a cure!” variety, the “big pharma is trying to screw us when you can just use herbs” variety, and of course the partisan political bickerers for whom Trump is definitely either The True Answer or The True Problem.

        Given that Dr. Lowe is providing a free public service here, I see nothing wrong with a little sympathy for what he is surely dealing with, or a scowl for the peanut gallery that’s arrived to explain everything to us even though no one knows quite what’s going on.

        1. jz78817 says:

          I’m pretty sure at this point most of the partisan stuff is just being kicked up by paid trolls in Russia and Africa. they’re frickin’ everywhere. if they can drag politics into something and get them fighting, they will.

          1. Hap says:

            Some of it, but people are not entirely rational about politics, and since everything seems to be political now, it doesn’t take much to derail us. We can do it pretty well on our own.

          2. Mr David N Murphy says:

            Lots of apparent Chinese ones. Not sure why African ones would though.

            But as someone else noted there are those with particular political stances who attack everything, there are outright nut jobs, there are armchair things who claim to know something but can barely count..

        2. nobody says:

          It’s best to reserve judgement until pricing is known for any future COVID-19 treatments/vaccines (should they be developed soon enough to matter) before concluding that Pharma isn’t try to screw us.

          This is not advocacy for herbal treatments but rather a warning that the industry’s habitual price gouging will have severe economic and public health consequences if the industry is allowed to charge whatever it wants for life-saving, economy-saving, treatments.

          This is a discussion that needs to happen in parallel with drug development and can’t be postponed until the day arrives that the industry decides to extort 50% of GDP for a treatment/vaccine that allows the 30% of the economy that has been completely halted to resume business.

          The people who are doing actual work on this front deserve to be compensated but senior management, shareholders, and other freeloading rentiers, must not be given a blank check to profiteer from the pandemic.

          1. metaphysician says:

            Serious question time- So you tell all the big pharma companies “You will get paid enough to cover salary for the people working on a Covid-19 vaccine/treatment, but nothing else, because profiteering is wrong!”

            And then all the big pharma companies stop doing any work on Covid-19, because there is no chance of them even just not-losing money on the project.

            What then?

          2. Mr David N Murphy says:

            Profits lead to investment and development of medications. No profit kills off innovation. The pharma companies were screwed by the governments over Sars and Ebola and they are not charities.

    4. JasonP says:

      News today on Remdesivir, will be interested in the scientific eval of the results.

      Are we there yet?

  2. Philip says:

    Question/statement, isn’t it too late for clearing the virus by the time a person needs a ventilator? I assume that is why patients on ventilators were excluded from the study.

    1. Steven says:

      Of course not. Those are the people that need an immediate decrease in viral load. They have the worst prognosis. Decreasing viral load will likely lead to better recuperation of pulmonary function.

      1. Anon says:

        I think Philip is right and I question Steven’s reply. Late stage disease is probably too late to use antivirals.

        Late stage disease is thought to be driven by an over-active immune system, that’s why immunomodulators, like the anti-IL-6 antibodies sarilumab and tocilizumab, are being used in coronavirus clinical trials, even though their adverse effects include respiratory tract infections. Drugs like those would be contraindicated if the actual viral infection was the main factor driving the pathology at that point in the disease.

        1. Wali Colt says:

          sorry to disappoint you

          but back in the 80’s there was this same argument about HIV/AIDS (known by other names then)

          Gary Simon, MD, PhDs & colleagues at GWU argued: “It’s the virus stupid”

          w/c was made famous by Dr David Ho (Time Man of the Year 1996) years later who developed an effective triple cocktail antiviral therapy, when others advocated immunotherapy

          reducing viral load, even in advanced, late stage patients is a critical part of medical intervention

          1. Philip says:

            SARS-CoV2 vs HIV is the same as Apples vs Oranges. Both are fruits, but that is about all the share. On further thought, make that Apples vs Tomatoes.

          2. Pedwards says:

            Tomatoes are still botanically fruits.

    2. jk says:

      In mouse and macaque models if Remdesivir is given late there is already lung damage that the animal wouldn’t be able to recover from. It is likely the same in people. Clearing the virus will be beneficial, but it might already be too late and other interventions may be more important. While a virological endpoint would let us know that the drug is killing the virus, it might not matter clinically

      1. booba says:

        Even if such a drug may not significantly shorten the disease, it may still help reduce spreading the virus in hospitals and elsewhere. Imagine patients would take some pills for a few times and they would not shed any virus no longer…. could still make a big difference!

        1. PDINV says:

          No, they already said that remdesivir does not help with reducing virus shedding. So it doesn’t even help with that.

  3. Steven says:

    Finally a good review with actual objective analysis. Wall Street is desperate for a cure and using any excuse to prop up the markets.

    1. Vader says:

      In fairness, we’re all desperate for a cure.

      The difference is that many of us understand science better than Wall Street.

      1. cl says:

        I feel wall street isn’t desperate for the cure. They just want the market high for a few hours. Hence the nutters advocating everyone returning to work.

  4. charlie says:

    just a though: In the original posts on Angiotensin, one thing that was being noted that lung damage was being caused by excessive angiotensin-II protein which isn’t being soaked up.

    Again I understand the general rule antivirals work early, but in this case it may be working later — stopping the virus would reduce angiotensin-II protein levels.

    are angiotensin-II protein levels associated with the elevated il-6 as well?

    again the puzzle here is why such a mild virus hits certain subgroups (well defined ones) so hard — and angiotensin-II protein levels may be part of the answer.

    1. Oudeis says:

      I don’t think I realized how well defined the subgroups are–just a general “age, heart disease, smoking, and diabetes are bad,” which, you know, was said a few times before the coronavirus, too.

      Could you link to something about the well-defined subgroups?

    2. acetogen says:

      What is Angiotensin-II protein? There is angiotensin-II (Ang 1-8) which is the peptide and ACE-II which is the receptor that is the entry point in lung cells for SARS-Covid-2.

    3. Henk says:

      Dutch hospitals stared a clinical trial. 300something patients on valsartan and the same number as control.
      This over multiple hospitals.

  5. Fulcanelli says:

    Well, I wonder why it didnt take in China. I remember some positive news, but then it died down. If it is the Holy grail, then why did the Chinese blow it off. Would not have been motivated by commercial purposes to ignore it as they were desperate far anything at the time. I see stock manipulation at the core of this, especially how CNBC & Fox biz news have provided one sided coverage encouraging hope.

    1. B says:

      One plausible explanation might be that when Remdesivir was really picking up, China was already controlling their situation with pretty strict lockdowns. Enrolling more and more patients in Remdesivir trials may have been viewed as an admission that more people had/have COVID-19 than they were willing to allow. We now have a pretty good idea that they are not being very forthcoming with their numbers, so maybe that is why they just “suspended” their trials, rather than opting for more transparency.

      1. kismet says:

        While I am entirely sure this is not deliberate, your post does come off as anti-Chinese. Every country revises their case numbers from time to time and it is never downwards! France did recently, for example. This is not an admission of failure, if anything, it is an admission of honesty.

        1. x says:

          How dare anyone cast aspersions on a corrupt authoritarian regime known for dodgy science! Not that our own regime isn’t somewhat corrupt, but that’s not the issue at hand…

    2. BG says:

      Not an expert, but Dr. Gottlieb said this AM the Chinese ran out of patients to test as the epidemic receded so they suspended the test…have no idea if that’s true or makes sense.

      1. Pedantic Speaker says:

        This sort of thing happens in infectious disease clinical trials.

        I remember reading about a vaccine trial, from back when they used prisoners as guinea pigs, that ended up being useless: No-one they vaccinated contracted the disease, but none of the control group did either.
        I forget whether it was because the prisoners were mostly already immune or because the disease simply stopped being epidemic.

  6. deoWER says:

    But wait, why haven’t they tried administering remdesivir with zinc?

    Just kidding 🙂

    1. johnnyboy says:

      Don’t forget the azithro !

      1. celticgirl says:

        And Omeprazole !!

        1. Charles H. says:

          And that *is* a real problem. Perhaps some complex combination of ingredients would work better….but there are so many alternatives that nobody can really find the one that works best. It may turn out (eventually) that, say, extra zinc is needed to potentiate the desired result…for some totally unexpected reason. But the simple things should be tried first…unless there’s a really good reason to try something in particular that’s more complex.

          1. JP Leonard says:

            Hi Charles H,
            re: ” It may turn out (eventually) that, say, extra zinc is needed to potentiate the desired result…for some totally unexpected reason. But the simple things should be tried first”
            Unexpected? I’ve totally predicted it in my review of the research on zinc and hydroxychloroquine.
            (altho you could say it’s HCQ that “potentiates” the zinc.)
            Plus doctors claims complete success with it.
            We should do a trial of HCQ+zinc, and find out whose expectations are right.
            As for “simple things first”, zinc is an intracellular antiviral and HCQ is an ionophore that gets it into cells. Not that complicated .
            I’ve tried to follow scientific method within my capabilities. We have a claim by Drs. Cardillo and Zelenko that HCQ+high dose zinc is a cure. I don’t have a lab to validate it empirically. So I validated it as far as possible deductively with excellent results. That should be enough for someone with a lab and patients to test it empirically.
            Isn’t that how it’s always done? Before you run trials you have tested the idea deductively that it has some logical reason to work.

          2. mjs says:

            The anecdotal evidence and the questionable clinical trials suggest that Zn is somewhere between useful and essential in the HCQ treatment. If Zn is active, doesn’t that imply that Zn level can be a significant uncontrolled variable in clinical trials? And that the proper approach would be (1) to
            measure zinc levels in the patients, or (2) give the patients enough supplemental Zn to drown out variation in Zn due to diet, electrolyte balance, etc., or (3) do an actual clinical trial with Zn as a variable?

  7. Another Guy says:

    Not to be a fusspot, but hepatitis C viral infection is curable in the majority of patients using small molecules (DAAs). HCV may be the only chronic viral infection that is curable with small molecule drugs. Cure with DAAs do not however prevent re-infection. There could still be some miniscule amount of HCV remaining in the patient after treatment, however it seems not able to replicate or be transmitted. The nitpickers will say that is a functional cure because the virus was not 100% eradicated, and the clinicians say that is good enough to call it a cure. You say to-may-to, I say to-mah-to.

    1. Stub says:

      Derek remarked that no *single* antiviral is curative. The current treatments for HCV infection are cocktails of two to three drugs, none of which will individually clear the virus.

    2. Derek Lowe says:

      It is indeed – combinations of small molecules with different mechanisms, not a single agent, which is what I was trying to get across.

      1. Another Guy says:

        Hoisted on my own pitard, as it were.

        Events can indeed pivot on a single word.

        1. Some idiot says:

          “Petard”, actually…
          Sorry, I couldn’t resist that… Friday evening here, and I have a bad sense of humour! 🙂

          1. KazooChemist says:

            Actually, it is also “hoist”, not “hoisted”.

        2. Another Guy says:

          I should have googled the phrase before submitting …

          1. KazooChemist says:

            Or you could use your social distancing down time to read Hamlet!

  8. anon says:

    Why don’t people start with controlled trials? Why not run the most powerful experiment first?

    1. B says:

      I think some of these are retrospective from compassionate use?

    2. Hap says:

      People want to know if there’s a chance that a hypothesis will be true before they try it because trials are expensive and take time, and there are lots of hypotheses they could test (and not enough money or time to test them all). If you can run a killer experiment without taking much time or effort then you should, but that doesn’t seem true in this case.

    3. Cole says:

      Why run the hard trial when you can run the easy trial and still publish widely and massively inflate stock prices?

      1. Sue Fics says:

        Because it’s unethical? Oh… wait…

    4. David Young MD says:

      The controlled trials did start early on, in very early March, if I recall. Results of those studies should be available soon, I would hope, since it has been over 6 weeks. At least preliminary results. Gilead did allow patients to get Remdesivir on expanded access, and “experiences” at an institution can be reported earlier than the randomized trial as this one here has (and perhaps another one), so you get the impression that the drug started in these studies when it has not.

      I wish, wish, wish that Gilead (or the NIH) would have started a trial of Remdesivir in infected people who are not yet sick enough to need hospitalization to see if it prevents hospitalization. Such as study would require a control arm, of course. And it would take 5 to 8 weeks for results depending upon how fast the study accrues. If this study was started 6 weeks ago we would have a better idea of how the drug works in early disease. But such a study has yet to start. Tragic, in my opinion

      1. Anon says:

        Would be tough to deliver the IV dosing of remdesivir outside of the hospital

        1. I don’t see why it would too difficult. Yes, I can think of at least one obstacle, probably two. First, you have to bring the person in for the infusion, which means that they have to quit their own at-home quarantine to drive in, or be driven in, to get the hour-long infusion. (well, I don’t know how long the infusion is… my guess is an hour). Second, you would need to have a facility where you have brave, well-paid nurses who would super gown up to administer the infusion to a number of people. And you would need to dedicate a certain infusion room just for the Covid19 patients. Those are the two major problems. The other problem, which is more difficult to get a grip on, is whether or not your participants are loyal enough to come in for 8 days to 10 days. You would have to recruit only patients who are over… say over age 50 or under 50 with a co-morbidity. But you would have to also screen for patients who seem to really want to be on a clinical trial. And yes, you would have to have a control group. But one way to make the control group more palatable is to have four arms, with just one of the arms being no treatment (or possibly Hydroxychloroquine orally) and have one arm Remdesivir and a third arm Remdex plus Favipiravir and a fourth arm low-dose Remdesivir and Favipiravir (or something else in place of the Favir.). You would also have to re-assure that those who got worse and were then unblinded and found to be on the no-treatment arm that you then offer then Remdesivir (if the current studies show a benefit). If you re-assured people about that, they would be more willing to participate.

          Oncologists (such as me) are accustomed to administering intravenous medications and are accustomed to putting people on studies. But I can’t speak for every oncologist about the feasibility of using their infusion centers for treating Covid19.

          All the same, I think that these outpatient studies should have been started 4 weeks ago.

          1. PDINV says:

            Even if all of that is possible in a trial setting with limited number of patient, how would it work in practice after EUA, 10s of thousands visiting hospitals daily?

          2. David says:

            A trial could be run with home visits. Visiting nurses routinely manage infusions in the home settings, and trials can be run at “virtual” sites. There are practical challenges, but not overwhelming.

          3. David Young MD says:

            Not necessarily hospital outpatient facilities. Most oncologists have their own infusion centers and a lot of infectious disease specialist do as well (and the advantage of the infectious disease specialists is that their infusion centers are open on weekends). There could be a large number of people getting infusions, of course. But in time of great need, physicians and hospitals should be able to make more room, open new offices, etc. And not everyone would need Remdesivir. A 20 year old, robust man or woman might not need treatment. And I am not sure that you need daily infusions. With the relatively long half life of Remdesivir (wasn’t it about 36 hours) I have to wonder if giving a loading dose of 200 mg followed by 100 mg daily for 4 days followed by 100 mg every other day for three more doses may be plenty (and perhaps with less side effects). All of that could be determined in a clinical study….. if they every get on going……

    5. anon says:

      Why not more controlled trials? The argument is that when there is no standard of care, which would be the control arm, giving a placebo for something with a high rate of fatality is dubious on ethical grounds.

      1. Walter Sobchak says:

        How is a controlled trial different from the real world where lots of people are suffering from the disease and not getting the drug because there is so little go around. We can go back through charts of the untreated to find matches on things like disease state, SES, occupation, age, sex, race, etc.

    6. Barry says:

      The most powerful Phase III clinical is:
      1-really expensive
      2-hard to design.
      The design and the choice of clinical population are shaped by earlier, smaller, cheaper “Phase II” clinical studies

    7. PAaron says:

      Because they take longer to run, they’re generally bigger to get more statistical power, and they require a control group that is taking a placebo. It ca be hard to recruit patients if they know they may well not be getting the active drug

  9. Harvoni says:

    “Remember, there are as yet no single-small-molecule antiviral cures for anything, coronavirus or not. ”

    Not so – take for example the NS5A+nucleoside combo cure of HCV:

    1. jk says:

      My understanding of what Derek meant was that all other cures were combination therapies. Also don’t forget Mavyret

      1. Harvoni says:

        good point – generally you have to pair a nucleoside with a complementary DAA inhibitor for more robust and durable effect. but perhaps given the fidelity of its RNA replication, COVID-19 will be more sensitive to nucleoside mono-therapy?

        1. David Young MD says:

          Pardon me for saying it a third time. But what about Remdesivir and Favirpiravir? They work the same way, but may have non-overlapping toxicities perhaps. Second, Remdes overcomes the RNA repair mechanism that might make Favi more potent. Such a combination can be studied in vitro, of course, and should be. But such a combination should not be overlooked. (but sadly it will be overlooked).

          1. jk says:

            Favipiravir doesn’t work in vitro so I am not holding my breath that it will actually do anything (as a direct acting anti viral) in patients.

    2. loupgarous says:

      or the lopinavir/ritonavir combined (Kaletra) arm of WHO’s SOLIDARITY trial, because ritonavir’s just in there to increase lopinavir bioavailabilty by inhibiting liver and intestinal activity of cytochrome P450 3A4 in what would be subtherapeutic doses for ritonavir alone.

      Kaletra’s in two arms of SOLIDARITY, by itself and in another arm where it’s being tried along with interferon-beta. Both arms, if I’m reading this right, are also evaluated versus local hospital standard of care.

      1. Derek Lowe says:

        That WHO trial is adaptive, from what I know, and I would not be surprised to see that arm of it shrink as the data start to come back in, since these retrovirals really do not seem to have had much effect.

    3. Derek Lowe says:

      What I meant was “one compound” – that hep C one is two small molecules with different mechanisms, just dosed simultaneously.

  10. loupgarous says:

    Derek, what do you think of the prospects for WHO’s SOLIDARITY study? SOLIDARITY compares one of four study medications with “hospital standard of care” (big can of worms in places like Brazil where local hospital SOC can include chloroquine) worldwide.

    As you’ve observed before, it’s an “adaptive” design, which can be read as “Bayesian”, but that may be overly simplistic. Quoting from the wikipedia article (and things have come to a dire pass when wikipedia’s “neutral point of view” ethic makes it by far the closest thing to neutral in its narrative on Covid-19):

    “According to the WHO Director General, the aim of the trial is to “dramatically cut down the time needed to generate robust evidence about what drugs work”,[7] a process using an “adaptive design”.[8][9] The Solidarity and European Discovery trials apply adaptive design to rapidly alter trial parameters when results from the four experimental therapeutic strategies emerge.[6][10]

    Adaptive designs within ongoing Phase III-IV clinical trials – such as the Solidarity and Discovery projects – may shorten the trial duration and use fewer subjects, possibly expediting decisions for early termination to save costs if interim results are negative. If the Solidarity project shows early evidence of success, design changes across the project’s international locations can be made rapidly to enhance overall outcomes of affected people and hasten use of the therapeutic drug.”

    Done incorrectly, design changes can also cater to local governments’ preferred narrative on Covid-19 experience there. WHO’s already embroiled in controversy over their description of Covid-19 experience in China, at the cost of their credibility every place else.
    As you and others correctly observe, Covid-19 has changed what is deemed acceptable in clinical trials, for what can only be called political motives (“We want a cure NOW!” being the most understandable of those).
    Done badly, twiddling with traditional clinical trial protocols can lead us to a new place – part “the Village in The Prisoner” – a hall of mirrors in which no one’s sure what clinical trial findings mean, part “The Walking Dead” in which political definitions of “recovered” may sentence much of the world to never be free of significant SARS_CoV2 infection.

    1. Derek Lowe says:

      I wish I knew more about the trial’s design! Your worries are not unfounded, I would say. . .

      1. loupgarous says:

        Yeah, I wish I knew more about it, too. Especially their plans for dealing with “hospital standard of care in China” versus “hospital standard of care in Brazil” versus “hospital standard of care in Italy”, ad horrendam.

        It sounds great that they’re worldwide, but it’s not even a good retrospective study if control arms vary significantly by hospital. Statistical power doesn’t look great then – we can hope that North America, the UK, Germany and Central Europe will smooth out hospital standard of care and raise n enough for this to work.

        1. David says:

          We don’t know the study design. They could stratify randomization by country, or at least use country as a covariate in the analysis model.

  11. MagickChicken says:

    Forgive my bad science, but let’s do exactly what Derek didn’t want us to do. 113 “severe” patients, 125 total, and 2 died. We can hypothesize from data in other countries that the mortality rate is about 1-2%. This is a terrible control, but gives us a starting place. The 5% we are seeing across the US probably indicates a severe lack of testing (excepting NYC).

    Two out of 120ish fits right into that 1-2% range.

    Now, it doesn’t cover different endpoints, recovery times, viral loads, etc., but it doesn’t leave me jumping with joy.

    1. B says:

      The recent Kaiser study saw 18% mortality rate in patients in the ICU – presumably, those would be “severe”. The IFR appears to be 1-2% for all positive patients, not severe patients. If you include vent patients then mortality can jump to >50%!

      1. PDINV says:

        And how many of those sever severe enough to be on ventilators? Because in the Gilead/NIH study none of the patients were on ventilators.

    2. Interested says:

      But the denominator here includes only people with severe disease.

      1. James Millar says:

        Severe, but not *too* severe. You’re clipping at both sides of the curve, and I wouldn’t want to bet that excluding mild cases raises the mortality rate more than excluding ventilated patients lowers it.

        Largely because I am not a statistician – maybe I should ask my father, retired actuary.

    3. Pedwards says:

      The problem is that we don’t really have a solid understanding about what the mortality rate is for a number of reasons, varying from low access to testing to the fact that a lot of the deaths have active comorbidities that could have also played a significant factor in the deaths, and controlling for these is incredibly challenging (538 wrote an excellent piece on this in the context of modelling the disease, and it’s pretty relevant to this problem). As B mentioned, different patient populations will have different mortality rates based on factors that we don’t fully understand yet, and trying to control for these outside of a properly set up clinical trial with a control group is just going to send you down a statistical wild goose chase.

  12. Jon Tyson says:

    I’m not surprised to see Feuerstein around when there is a biotech scandal. Often he himself is the scandal.

  13. luysii says:

    Fun to watch you all attempting to deal with ambiguous or conflicting or downright fraudulent information, and recommend what’s best for the population in front of you. Welcome to the world of the practicing physician. A lot harder than organic chemistry isn’t it? Certainly not as intellectually or logically clean, but compelling non?

    Here is an idea which can be tested with built in controls and no placebo administration.

    1. what a jerk says:

      Not nearly as much fun as watching you being infected with those four coronaviruses from which your post posits. I think you should be patient number one. Anyone as smug and arrogant as you should volunteer don’t you think?

      You’re a neurologist, not an infectious disease doctor, so your arrogance and ego is not appreciated or earned. You give someone a bad diagnosis and mostly do nothing for them thereafter. Get over yourself. You do not treat patients with an acute life-threatening disease that will see it’s course in a couple weeks. When was the last time you treated patients on a routine basis where they would/could die in a couple weeks? Take your Ivy League (yes we know you went to Princeton) degree and place it appropriately.

      And some of us did/do organic chemistry for a living and it’s actually not intellectually clean. But our lives were/are not on the line so the comparison is puerile. And we actually get that.

      1. James Millar says:

        I have to admit I don’t understand your hostility here. I’m wondering if you missed the part in the blog post that suggests testing the hypothesis in a strictly observational study? If the results from that were encouraging, I would absolutely accept a “vaccine” of a cold-intensity coronavirus.

        And I have to say I think being a neurologist would be rather worse, as you get to watch in slow motion as no treatment helps.

        Your point on organic chemistry isn’t invalid, but it’s pretty obvious from the uneducated bleachers that there are many orders of magnitude more complexity, uncertainty, confusion and urgency in medicine than in any branch of chem.

  14. DTX says:

    Anon pointed out “Late stage disease is thought to be driven by an over-active immune system…” Can someone point me to which studies that have shown this with Covid-19?

    While there is good evidence for over-active immune response with Dengue, it would be helpful to see the studies with Covid-19. (And dengue would likely be different since the over-response only occurs from 2nd exposure and to a different clade of the virus whereas Covid-19 regards 1st time exposure).

  15. Ron Richardson says:

    Agree but note that all of the Hepatitis C phase 3 trials were run without placebo or SOC control groups–perhaps Gilead is going for an SVR type readout number? Or a response rate analysis?

    1. Another Guy says:

      The effect size of the DAA studies was very large (95%+ cure rate), and as I recall some of the phase II studies only had 30 patients or less in each study arm. The previous standard of care only got you about 50% cure (SVR), so it didn’t really matter what statistics you used to arrive at the conclusions. What is relevant in the current situation with COVID-19 is there is no reason to expect a large effect size given that remdesivir was never designed to work against SARS-CoV-2. HCV was only defeated with combination therapy minimum of 2 drugs specifically designed to do nothing but bind as tight as possible to their viral targets.

  16. Esteban says:

    The authors of the STAT piece gave a webinar today, for anyone interested:

  17. Ken says:

    Please forgive the probable ignorance of my question. I stumbled upon this discussion and although interesting, it is not my area of expertise. Why can’t they just identify a comparable control population based upon patient data (that meets their own study’s inclusion criteria) at other hospitals in Chicago?

    1. MrRogers says:

      “Comparable” is the key problem. You can try to identify things that you think make the population comparable, but in the end, the only way to be sure is to select patients and controls at random from the same population.

  18. steve says:

    Derek – Just want to thank you for the laugh of the day. “Gilead stock jumped like a spawning salmon.” Great simile. We enjoy your expertise but your writing style is a joy as well.

    1. JustPassingBy says:

      Go fish up his “Things I Won’t Work With” posts. But not while drinking coffee. I’m not even a chemist and laughed out loud.

      1. Olandese Volante says:

        Wouldn’t try to read those posts while drinking any type of carbonated beverage either.

        I cite, from a post about some people in Germany who made it their life’s goal to cram as much nitrogens as possible into moderately small molecules:

        “No, I didn’t type that with my elbows.”

  19. steve says:

    BTW, the correspondents above who are so sure about antiviral use in late-stage COVID-19 are wrong. The history of antivirals in respiratory disease (HIV is a ridiculous comparator) is that drugs like Tamiflu are useful only when given early on. What’s killing patients in late stage disease is the over-exuberant inflammatory response culminating in cytokine storm. That’s where drugs like Actemra, Calquence and others are better bets. You may need to pair them with an antiviral to prevent reactivation of viral replication after immune suppression but the idea that an antiviral alone will be useful under those conditions is pretty doubtful.

  20. Tom Boyer says:

    There’s been furious skepticism and suspicion aimed at the Marseille clinic and Roault, even though they have nothing to gain financially by promoting an old generic drug. Are we being sufficiently suspicious of the people promoting remdesivir, who have billions added to stock valuations every time it’s in the news?

    First the company authors what is essentially a PR release and somehow pulls enough strings to get it published in the NEJ. And now we have a “leaked” video that is more promotion — again with no control. Why are so many presuming Marseille can’t be real, but remdesivir is real? Is the American pharma press rooting for remdesivir simply because it’s a better story than a boring old generic drug invented in the 1930s?

    1. Peter S. Shenkin says:

      No serious person is asserting that Marseille cannot be real and or that remdesivir is real. People oppose Raoult because he opposes controlled trials. The proliferation of information about the remdesivir trial is in fact despicable and may very well have been issued to pump up the stock price. However, that is independent of whether the drug works, and the unfortunate remdesivir publicity as well as Raoult’s bizarre opposition to controlled trials are both independent of whether their respective drugs work. Considerable skepticism has been expressed about both remdesivir and hydroxychloroquine (as you must know if you read this blog) and in both cases the skepticism will be alleviated or deepened, as the case may be, by the results of controlled trials, a few of which have been completed and more of which are underway and planned..

  21. Yi Zeng says:

    Remdesivir works, China knows it and is withholding their data on purpose.

    1. Peter S. Shenkin says:

      Since China ran the study in the first place, why do you assume they stopped the trial because it worked? If they were going to do that, they probably wouldn’t have started the trial. Secondly, they know well that there will be other trials, so their stopping this one doesn’t get them anywhere. Third, what motivation do they have for hiding the fact that it works – especially since they know, in that case, that new trials will demonstrate that it works pretty quickly.

      1. ghost of q.mensch says:


        New data on Gilead’s remdesivir, released by accident, show no benefit for coronavirus patients. Company still sees reason for hope

        ”The antiviral medicine remdesivir from Gilead Sciences failed to speed the improvement of patients with Covid-19 or prevent them from dying, according to results from a long-awaited clinical trial conducted in China. Gilead, however, said the data suggest a “potential benefit.”
        A summary of the study results was inadvertently posted to the website of the World Health Organization and seen by STAT on Thursday, but then removed.

        “A draft manuscript was provided by the authors to WHO and inadvertently posted on the website and taken down as soon as the mistake was noticed. The manuscript is now undergoing peer review and we are waiting for a final version before WHO comments on it,” said WHO spokesperson Daniela Bagozzi.

        Gilead spokesperson Amy Flood said the company believes “the post included inappropriate characterization of the study.” Because the study was stopped early because it had too few patients, she said, it cannot “enable statistically meaningful conclusions.” “

        Speaking personally, as one who has been following the Worldometer covid stats, it is pretty apparent that China has been under reporting the magnitude of covid cases, in particular death data throughout the pandemic. So I think Gilead is being a bit cute and self-serving to latch onto the “too few patients” rationale in public statements to explain the unexpectedly early termination of the China REM study.

    2. loupgarous says:

      Why? So they can have all the remdesivir when everyone else gives up on it?

      Gilead stopped giving remdesivir out on compassionate use last month because they’re not tooled up to do that and supply all the clinical trials they want to.

      Are you saying Gilead Sciences signed an intellectual property transfer deal with China for remdesivir? It’s the only way what you’re saying makes sense.

  22. JB says:

    This whole thing reeks beyond belief. First off, Freuerstein was skewered by the Washington Post before for possibly being overly ambitious to tear down Northwest Biotherapeutics and short selling.

    Secondly, yesterday (4/16), someone or some entity bought 7500 15 cent $80 calls of Gilead that expire on 4/17. NO ONE who is sane would spend over $100k+ to buy something that’s about to be worth $0 in less 24 hours. And lo and behold the news breaks regarding Remdesivir right after that massive options purchase …Gilead rockets to over $80, and all of those calls are magically in the money and turned that $100k bet into well over $6 million dollars. Shenanigans, shenanigans, shenanigans. That stinks like someone had inside information to take such a huge risk like that and have it work for a multi-million dollar payout. The SEC should investigate this whole thing, but whoever pulled this off probably knows the SEC won’t do anything because there is a push to get the economy started up again, and because a lot of things are being let slide during the pandemic.

    This folks, is how America works. Regular people don’t stand a chance when the elite cheat and get away with insanity like this.

    1. anon says:

      Lots of regular people are getting paid not to work through loopholes in unemployment insurance.

    2. Derek Lowe says:

      You missed the part where the columnist for the Washington Post had to climb down in public from those statements. And what happened to Northwest Bio? I believe you can pick up their shares now for less than a quarter.

  23. GerryL says:

    My wife was for several years, involved in a stage 2 clinical trial for a drug used to treat a life threatening illness.We were told that the outlook was for survival of a couple of years at most. The drug worked but for various reasons the clinical trial was dropped. My wife is doing well but others with the same illness will not be as fortunate as we were.
    The drug is no longer available.
    Also I am a practicing MD for 40 years. I have seen in my specialty, drugs which were approved by the FDA which subsequently turned out to be of marginal efficacy and in at least 2 instances with life threatening side effects. One other drug was held up by the FDA for many years until being released turned out to be dramatically effective.
    As an aside do not forget that it was the FDA which in 1985 approved oxy-contin for sale, basically heroin in pill form. Over the next 30 years prescription drug overdoses claimed an ever increasing toll of young lives
    The FDA did nothing, even worse continued to approve dangerous opiates for sale until 2015.
    The drug remdesivir seems to work, we all hope.
    It is cruel and immoral that folks who are critically ill do not have access to this drug outside of a stage 3 clinical trial where there is a 50% chance of receiving a placebo. The company should be told to produce enough of this drug to treat all critically ill patients.
    The FDA should not block this action.
    The company in this emergency situation should be asked and strongly encouraged to be generous in their pricing.
    This is a time for emergency action. The drug seems to be reasonably safe. If the drug turns out to be ineffective we will have lost some money but if later trials show that the drug works then we will have saved potentially tens of thousands of lives.

    1. JP Leonard says:

      GerryL: “This is a time for emergency action. The drug seems to be reasonably safe. If the drug turns out to be ineffective we will have lost some money but if later trials show that the drug works then we will have saved potentially tens of thousands of lives.”
      Sounds marvelous – for remdesevir – but heaven forbid such sentiments for HCQ+zinc!
      I will laugh if the mystery buyer of Gilead options now buys a load of put options on it and the next day Trump starts touting zinc.
      Money makes the whirl go round all right. Wealth care not health care.

  24. JP Leonard says:

    Hmm… I missed a beat there. Cancel the put order.
    Dr. Trump evidently did shout out for adding zinc already on April 8th, but got shot down.
    Trump: “You should add zinc” to any COVID-19 treatment regimen. “I want to throw that out there because that’s where they seem to have the best result,” likely referring to Dr. Vladimir Zelenko’s … chloroquine plus zinc and an antibiotic remedied 100% of hundreds of cases … The President added: “So, you add the zinc and the antibiotic, and it’s been – we’ve had a lot of good stories.”
    The article is pretty good. It covers a lot of the same scientific literature as my own piece
    Author Bill Sardi continues ,
    “An online search (April 12) at the National Library of Medicine reveals 62 published reports dating back to 1987 involving chloroquine and coronaviruses, but inexplicably none mention zinc. Nor do product inserts list chloroquine as a zinc ionophore. This is a giant scientific oversight.” Good catch.
    In my piece I only noted one Chinese paper “Potential interventions for novel coronavirus in China: A systematic review.”[31] They take note both of Chloroquine (CQ), and of the action of zinc ionophores — but separately. One paper showing CQ inhibits SARS-CoV-1, the other about it being a zinc transporter…. Nobody in China and … nobody in France, apparently. Although the paper “Chloroquine is a Zinc Ionophore” was published in CHINA in 2014″
    Raoult seems to be zinc-blind as well. My guess is his results are spotty because HCQ can’t do much for patients with zinc deficiency. Zinc doesn’t show up on a normal blood test and doctors don’t look for it.
    “Giant scientific oversight.”
    It’s the Great Zinc Blind Spot. None are so blind as those who will not see.

  25. Imamanthatlovesbillnye says:

    If you check out the background, trump did this. He did this to remdesivir to mess up for the best of hcq. Pass it on science.

  26. Dan says:

    Just an few questions. Why a control group? There thousands of patients in hospitals all over the world where you can find ‘the control group’. Whith all information tecnology available now, how can it be a problem to get a very good (or does it really has to be 100 % exact?) idea about the chances of comparable patients? And what can placebo do here? The last question I can answer myself. Placebo cannot stop you from dying.

    1. Another Guy says:

      To avoid the ethical problem of giving one group a placebo and the other group a treatment that might help them is a delayed-treatment design. One group gets the drug immediately and the 2nd group gets the drug at a later time. All patients have confirmed COVID-19 and are in mild to moderate condition in hospital. The endpoint would be time before patient’s condition becomes serious and vital load reduction. If the treatment works, then It should be obvious the viral load is decreasing. There would have to be constant monitoring of the patients and ventilators ready if necessary. The other way is to vary the dose between study arms which I think is already being done.

      1. Tom Boyer says:

        *this.* But it sounds so hard to pull this off. You’d have to recruit volunteers in that extremely narrow window after fever and test results but before things get really bad.

        And it sounds like hospitals in the hot spots are so busy they’re not even dealing with those people right now, they’re sending them home until they have trouble breathing and can be admitted. It might be better done at an outpatient clinic. But I’m not sure such a thing even exists in the US because our official position on early treatment is that there is no early treatment.

        > To avoid the ethical problem of giving one group a placebo and the other group a treatment
        > that might help them is a delayed-treatment design. …
        > The endpoint would be time before patient’s condition becomes serious and vital load reduction.

        1. Another Guy says:

          That could be why the “dose-response” design is being used. Give the patient their meds and off they go.

    2. loupgarous says:

      You still have an excellent chance of dying if you are given the wrong drug for the wrong phase of an illness.

      Antivirals (no matter which kind) don’t have the evidence behind them to inspire confidence they’ll work in late-stage Covid-19, where the culprit seems to be cytokine storm, an immune over-reaction which causes fibrosis of the lungs and flooding of the alveoli with fluid. Then you’d want an immunosuppressant, perhaps given with an antivirus to take the place of the immune response you’re now suppressing.

      WHO’s SOLIDARITY clinical trial is doing that for one arm, testing Kaletra (two antivirals used in HIV, but only one of which works as a antiviral – the other inhibits part of the cytochrome system that metabolizes the “real” antiviral and lets it remain working longer) along with interferon-beta, which hopefully reduces the cytokine storm and prevents the lung damage that kills patients in late-stage Covid-19.

      SOLIDARITY ought to return results very soon by clinical trial standards – weeks, not months. What we don’t want is to work blind, guided by stories about what works that don’t have any scientific validity to them.

      Medicine, even modern medicine, is full of sad tales like Eli Lilly’s drug for sepsis – a highly touted “miracle cure” which when viewed through repeated clinical trials was no better than placebo at treating sepsis. Patients got billed for a wildly expensive drug that didn’t work, and diverted money and effort from treatments that did work.

      Eli Lilly’s sepsis drug Xigris was approved during George W. Bush’s administration, but we’ve had dropped spanners through many different administration – patient injury from fluoroquinolone antibiotics was a lengthy bipartisan cluster hump ranging from the 1990s (when French studies showed it was happening) to the 2010s, when FDA finally added a black-boxed warning only to use some fluoroquinolones when absolutely necessary. All the heat over whose administration did what wrong isn’t helping us.

      What will help us is turning back to clinical trials, which will both prevent wasted time in treatment of Covid-19 with drugs that won’t work, and patient injuries which may only show up once many thousands of patients get a drug for a certain disease.

      Odanacatib, a drug aimed at treating osteoporosis, was widely viewed as safe right up to Phase III trials. Then, when thousands of elderly women were treated with it, we noticed they had stroke much more often than usual – the very people odanacatib was designed to treat gave them strokes, and small trials didn’t show that happening. We needed to go big with clinical trials to discover that. And we need to go big with clinical trials to pick up any problems using old drugs in a radically new patient population. There’s no substitute.

      1. loupgarous says:

        Last paragraphs ought to read:

        Odanacatib, a drug aimed at treating osteoporosis, was widely viewed as safe right up to Phase III trials. Then, when thousands of elderly women were treated with it, we noticed they had stroke much more often than in the study’s control arm. The very people odanacatib was designed to treat for osteoporosis got strokes from it. Early trials didn’t show that happening. We needed big clinical trials to discover that in the intended patient population.

        And we need big clinical trials to find problems using old or new drugs in a radically new patient population. There’s no substitute.

  27. PDINV says:

    Dear Derek,

    On Friday they did a follow-up with some data on macaques 

    My take aways/comments are the following but your opinion would be appreciated

    My summary:
    They treated the monkeys daily starting 12 hours after infecting them with the virus. I assume the 12h timepoint was chose because they wanted to administer the drug “before the peak of virus replication”. The treated monkeys breathing and presence of pulmonary infiltrates on radiographs improved and they had lower viral load next day after treatment but not cured after 7 days. Despite the lower viral titers in the lower but not upper respiratory tract, virus shedding remained the same in treated animals as in untreated. The authors conclude that this data supports “early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.”

    My notes

    1. They did the exact same thing with ebola and other viruses yet it still didn’t work in humans

    2 . This is an intravenous drug, this means one has to go to the hospital to get the infusion. Even if we accept that the monkeys are 100% representative of humans, there is no way this can work at any relevant scale. The issue is those who get ill, they do so several days to even weeks after the virus had a chance to establish, not 12 hours.

    3. Even if we accept that the monkeys are 100% representative of humans, there is no way this can work at any relevant scale. The issue is those who get ill, they do so several days to even weeks after the virus had a chance to establish, not 12 hours. Daily visit to the hospital by everyone or even many people to get their dose is not only unfeasible in practice but also impossible (it would require a safety track record of several years before widespread use)

    4. If we accept the 12h timepoint as the optimal timepoint for treatment before replication peak in macaques, then we have to accept that macaques perhaps are not as representative of infection and disease progression (as distinct measures vs the undoubtedly important PK/PD and viral load reduction per se) which takes us back to point “1”.

    5. In the results and discussion, they say that remdesivir reduced overal viral load which seems accurate. However, even in the most optimal lab conditions viral load in the upper respiratory tract was not reduced significantly and the authors make the reasonable assumption that this is why viral shedding was not reduced in treated animals. But then they say “While our study demonstrates the presence of remdesivir metabolites in the lower respiratory tract, the drug levels in upper respiratory tract have not been characterized and novel formulations with alternative route of drug delivery should be considered to improve the distribution to the upper respiratory tract, thereby reducing shedding and the potential transmission risk.”
    Why didn’t they check for metabolites in the upper respiratory tract then, in the “Study design” they clearly state that they collected samples, so why not check? But they are going to do formulation studies anyway to improve availability in the upper respiratory tract. This is inconsistent, but more importantly, it leaves doubt about their viral titer results on the lower respiratory tract. Note that in a very similar previous study they did with MERS they did see reduction of viral titers in the upper respiratory tract (fig 3C,, also from other preclinical studies this drug seems more potent against MERS than SARS/SARS-2.

    6. The way this is going there is a chance they give it emergency use authorisation in the end but limit the profile of patients that would be eligible to get it (possibly in combination with an other drug) to something extremely specific. What worries me is that one one hand this make take away public spending from drugs that actually have a chance in saving lives/preventing future outbreaks (whether we are talking about imm unomodulators/other drugs or vaccines) and that the side effects are not as well understood as in drugs that have been in widespread use for some time.

    What do you think?

  28. Tom says:

    Just catching up, but it seems to me that we are approaching this disease backward. Anti-virals as a group work much better early in the disease progression. Seems like other than some preliminary tests for hydroxychloroquine as a prophylactic, none of the drug testing is taking the disease on early, when it might be more vulnerable.

    1. Gerryl says:

      Exactly, this is an example where a clinical trial would be helpful, to see if patients treated early on do better on Remdesivir than placebo.
      Information technology can be used outside of a phase 3 clinical trial and if the drug works we will find out quickly.
      But critically ill patients should all be allowed access to the drug .No reason for delays.

      1. Another Guy says:

        Yes, I made a reply to an earlier post that a delayed study design could work. Both groups of mild to moderate COVID-19 patients get the drug, one group gets it immediately, another at a delayed time. All patients get the drug if their condition becomes serious. If the treatment works, we should see viral load decline soon after each group took the drug. If we don’t use a control, then we don’t know if the patients simply got better on their own.

  29. mjp says:

    Waiting until a patient is on a ventilator is far too late in the disease. An early immune response is important as the patients who deteriorate do so in the 2nd and 3rd weeks of infection.
    6 fold increase in antibody titer to Hepatitis B virus

  30. John Wayne says:

    1. The usefulness of antivirals in late stage respiratory disease is an unknown. It depends on the viral load at that time, and what contribution the viral load has upon recovery (vs death.) This could go either way, but I would bet against miraculous efficiacy of any -ivir agent by itself against late stage coronavirus symptoms.
    2. I like the idea of the immune system modulators for late stage disease. Efficacy depends on the above, but I would bet for them being more broadly useful as a monotherapy.
    3. The most effective medicines that work against viruses fall into two broad categories: vaccines and combination therapies. Once we know enough, we are probably going to end up in both of these places. I recommend against taking a strong stand for any specific agent monotherapy; that is unlikely to be correct.
    4. If you can’t demonstrate that an investigator or organization has placed these stock market bets, please don’t imply that there is a conspiracy. In order for that to make sense, the person lying has to have the potential to benefit financially. In the USA, this is a violation of SEC rules. There is a huge gray area in between saying there is hope and overexaggerating positive results. Unfortunately, the average human responds better to a statements like ‘It works’ than a more nuanced statements like ‘it might work, probably in combination with other things.’

    The ‘fake it until you make it’ people now run the world, so dial in your expectations. Continual ranting that people aren’t following your moral code gets embarrassing after a bit. In other words, I agree with you but it doesn’t matter.

    1. PDINV says:

      There is no need to prove financial benefit in order to point out very clear and very serious misconduct

      1. Interim trial results are not communicated in conference rooms (unless in an official manner). That in itself is a serious issue, whether there is financial incentive or not.

      2. Something more nuanced. Back in February the WHO assistant Director General said ““There’s only one drug right now that we think may have real efficacy, and that’s remdesivir.”. This was again very strange and incredibly irresponsible. Context:
      At the time remdesivir trials hadn’t even begun or where at very early stages and at the same time there were at least 100 trials planned or had already begun for over 40 drugs. What if remdesivir turned out to have more adverse effects than expected in the context of covid19 (which is a different thing than the safety studies on healthy volunteers or other conditions), whould that mean that we would have had NO hope? Incredibly irresponsible and unprofessional comment comment but I shrugged it off at the time. In fact I even thought that this was very positive news. But what if a week or two after, remedesivir trials stopped for whatever reason. How would that have played out?

      We can’t ignore these things, whether there is a financial incentive or not.

  31. Inst says:

    I’m shocked that most people are congregating to Remdesivir as opposed to Favipiravir. Remdesivir might be superior in late stages of illness from anecdotal reports, but it can only be used in a clinical setting as it’s an injection.

    Favipiravir, on the other hand, beat out Remdesivir for Ebola (Remdesivir was considered safe, but useless) and comparison trials vs arbidol show that Favipiravir speeds viral clearance.

    Of course, the problem is that Favipiravir is no longer patented, so it doesn’t make much money for anyone. Moreover, the people operating it (primarily the Japanese, although the Chinese licensed it and created a derivative [JK-05] a while back) aren’t American. And, just like Remdesivir, the double-blind trials haven’t come out yet.

    1. A Nonny Mouse says:

      Yes, favipiravir itself is out of patent, but the good methods to make it are still patented. The key one is the “organic amine salt” patent which is in force until 2028 (DCHA salt which cleans it up nicely).

      Most of the methods to favipiravir involve a lot of black and brown crud (I speak from experience!).

    2. jk says:

      People are interested in Remdesivir over favipiravir because of in vitro data. Remdesivir has an EC50 in the 10-100s nM range while favipiravir EC50 is in the 10s uM. Meaning that Remdesivir is 100-1000x more potent.

  32. Wkw says:

    All this talk about Remdesivir, but Brilacidin imo should be on more radars imo

    Lots of lit validating glycopeptide and lipopeptide and Defensins (mimics) against SARS-CoV-2, likely dual MOA disrupting viral envelope and preventing ACE2 binding

    This scan of over 11,500 already FDA-approved drugs and compounds in clinical trials has Brilacidin on a short list of promising inhibitors of nCoV (spike protein target)

    Plus Brilacidin has shown preliminary antiviral activity against SARS-CoV-2

    Also anti-inflammatory—anti pro inflammatory cytokines and chemokines, inc IL-6, implicated in worsening prognosis for COVID-19 patients

    Maybe it’ll get into testing
    Strong argument for

    1. JLocke says:

      Looks like it’s Brilacidin’s time to shine.

      1. JLocke says:

        Protocol name
        Double-blind, placebo-controlled, randomized, multicenter Phase II study to evaluate the efficacy and safety of Brilacidin in patients hospitalized with COVID-19
        Therapeutic area
        Anesthesiology and resuscitation, Infectious diseases, Oncology, Therapy (general), Surgery, Cardiology, Pulmonology, Toxicology
        CI start and end date
        12/17/2020 – 03/31/2021
        RCT number and date
        No. 705 dated 12/17/2020
        CI organization
        Innovation Pharmaceuticals Inc. (Innovation Pharmaceuticals Inc.)
        Drug name
        Dosage form and dosage
        solution for intravenous administration, 50 mg / ml
        Barnaul, Kirovsk, Moscow, Nizhny Novgorod, Ryazan, St. Petersburg, Saratov, Yaroslavl
        Developer country
        Organization involved by the drug developer
        IPharma LLC, 143026, Moscow, the territory of the Skolkovo innovation center, st. Nobel, 7, Russia
        CI phase
        KI type
        The purpose of CI
        assessment of the efficacy and safety of Brilacidin in patients hospitalized with COVID-19
        Number of medical institutions
        Number of patients
        Where the research is done
        KGBUZ “City Hospital No. 5, g. Barnaul ”
        Altai region
        Martynenko T.I.
        GBUZ LO “Kirovskaya MB”
        Klinov A.S
        IKB No. 1
        Moscow city
        Nurmukhametova E.A.
        GBUZ “GKB No. 52 DZM”
        Moscow city
        Fomina D.S
        FSBI “Central Clinical Hospital with a Polyclinic”
        Moscow city
        Lomakin N.V.
        GUZ GKB No. 15
        Moscow city
        Gordeev I.G.
        FSBEI HE MGMSU them. A.I. Evdokimova, Ministry of Health of Russia
        Moscow city
        Vertkin A.L. , Rogova I.V.
        GBUZ “NII SP named after N.V. Sklifosovsky Research Institute for Emergency Medicine ”
        Moscow city
        Zhuravel S.V
        FGAOU VO First MGMU im. THEM. Sechenov Moscow State Medical University (Sechenov University)
        Moscow city
        Moiseev S.V. , Smolyarchuk E.A.
        GUZ NO GKB No. 3 (NGTs)
        Nizhny Novgorod Region
        Nizhny Novgorod
        Makarova A.E
        GBU RO “OKB”
        Ryazan Oblast
        Ivanova A.Yu
        SPb GBUZ “Nikolaevskaya hospital”
        St. Petersburg
        St. Petersburg
        Nigrieva Y.N
        SPb GBUZ “City Mariinsky Hospital”
        St. Petersburg
        St. Petersburg
        Mamonov A.G.
        S-Pb GUZ “City Hospital No. 38 named after N. A. Semashko”
        St. Petersburg
        St. Petersburg
        Popov A.V
        SPb GBUZ “City Hospital No. 15”
        St. Petersburg
        St. Petersburg
        Goloshchekin B.M
        SPb GBUZ “City Pokrovskaya Hospital”
        St. Petersburg
        St. Petersburg
        Khmelnitsky O.K
        FGBOU VO Saratov State Medical University named after IN AND. Razumovsky Ministry of Health of Russia
        Saratov region
        Schwartz Yu.G

  33. Lyndon Garcia says:

    Reading your article and all the responses/replies I don’t see any person in this site or group mention Leronlimab (PRO-140) as treatment for COVID-19 infection. Leronlimab has been studied and used as a CCR5 inhibitor which addresses the cytokine storm that is talked about a lot in this COVID-19 pandemic.

    Hidden in all the hyped news for Remdesivir from STAT, GILD updated their P3 trial for severe COVID infection yesterday 4/17/20 increasing the pop size for trial from 2400 to 6000. That is an additional of 3600. GILD did not give comment to Reuters who put out news. It would have been easy to say for GILD that they just want to have more people to avail of drug Remdesivir ASAP versus going through EIND. Just wonder whether adding 3600 patients will take longer to complete whole trial which increased enrollment size by 150%. I will leave other reasonings for increasing size for P3 study to statisticians/investigators out there more familiar with conducting trials.

    After reading about the Remdesivir P3 open label trial for severe infection, few things in trial criteria (inclusion/exclusion) limits the use of Remdesivir and makes it less superior to Leronlimab.
    1) Open label trial versus RDB trial with Leronlimab’s P2 (mild-moderate COVID infection) & P2/P3 (severe COVID infection)
    2) Requiring mechanical ventilation at screening (an exclusion criteria) which means study does not include critical patients unlike Leronlimab at screening
    3) Mechanically ventilated for >4 days are excluded
    4) Evidence of multiorgan failure are excluded
    5) Creatinine clearance of <50 mL/min (which is fairly high threshold for severely ill patients)

    Likewise using mainly mortality rate as primary endpoint for Leronlimab is more aggressive & difficult to achieve unlike the composite 7 point Ordinal Scale which can show a positive result but mortality rate will be the same as placebo/SOC which we will not know due to Open Label design for Remdesivir. Majority of people infected with COVID-19 do recover with supportive care. What we need is a treatment that will save lives, reduce ventilator use and shorten hospital stay (patients are kept longer in the hospital due to respiratory failure otherwise they are discharged).
    We shall see in the next 4-6 weeks which trials (Leronlimab or Remdesivir) will show the best treatment for COVID-19 infection.

    1. loupgarous says:

      Lyndon Garcia:

      Reading your article and all the responses/replies I don’t see any person in this site or group mention Leronlimab (PRO-140) as treatment for COVID-19 infection. Leronlimab has been studied and used as a CCR5 inhibitor which addresses the cytokine storm that is talked about a lot in this COVID-19 pandemic.

      Googling leronlimab, half the first page of results are the entry (which isn’t as optimistic as you are in describing leronlimab), clinical trial listings, or press releases written by its manufacturer CytoDyn Inc. or investment advice in seekingalpha, FoxNews, or Yahoo!Finance (which has never seen a corporate press release it didn’t run verbatim).

      I’d say that explains why more of us aren’t lauding leronlimab to the skies. Come back with some clinical trial numbers. In fact, stun us and make those numbers from a randomized, controlled clinical trial.

      1. Lyndon Garcia says:

        Exactly, based on your response it appears it is the first time you have heard about Leronlimab. PRO-140 (Leronlimab) was acquired by Cytodyn from Progenics Pharma in 2012. A lot of research has been done with focus on HIV & cancer (breast & prostate). COVID-19 treatment just arose in which disease process fits Leronlimab’s MOA through CCR5 inhibition. Ongoing P2 & P2/3 trials are both randomized double-blind trials with 2:1 ratio treatment:placebo.
        Suggest you watch video by Dr. Richard Pestell about CCR5:

  34. Patrick says:

    Two studies have commenced. It appears from your response it doesn’t fit the narrative you are looking for. Perhaps BOTH Remdesivir and leronlimab could be used in combination? Remdesivir doesn’t combat the cytokine storm that is what is killing most of those with severe COVID-19. Optimistically, Remdesivir might successfully be used to keep those infected from migrating to ventilation and a meager 20% survival rate. Try to be more objective. We will know a lot more about Remdesivir and leronlimab in 2-4 weeks.

    1. loupgarous says:

      I’d be delighted to see study results showing a benefit in the treatment of Covid-19 from remdesivir or leronlimab. I just don’t recall a disease process or a postulated mechanism of action involving CCR5 in Covid-19 (remember, SARS_CoV2 binds to angiotensin-converting enzyme II to facilitate cell entry. CCR5 facilitates cell entry for HIV, plague, smallpox – but the only mention of CCR5 inhibition in the treatment of SARS_CoV2 infection is in CytoDyn’s literature).

      But, as you say, we’ll see.

      1. Toni says:

        What I understood so far is, that the CC chemokine CCL5 (RANTES) is a natural ligand of CCR5. The CCL/CCR5 axis is known to be linked with IL-6.

  35. Jon says:

    My apologies for going slightly off topic, but are the tests specific for SARS-CoV-2? Or will they return a positive result for any coronavirus infection?

  36. ghost of q.mensch says:

    04/17 CNBC clip on remdesivir:

    My read: Feurstein touts anecdotally; Gottlieb pans diplomatically.

  37. Michael Bell says:

    To quote a scene from a very inebriated Deanna Troi from Star Trek “First Contact”: “Timeline?!? This is no time to argue about time! We don’t have the time!”

    In any other circumstance, I would agree that scientifically based, controlled study trials of therapies for Covid-19 is warranted and preferred to prove their usefulness; in any other circumstance. In this circumstance, where people are literally held hostage in their homes for what could be months or possibly years by officials acting on data sets that are almost certainly incorrect, we do not have the luxury of “following procedure” on this. If a trial medication offers even the slightest anecdotal evidence of efficacy, it has to be approved for treatment. We can ask the whys and hows later.

    We are putting our livelihoods and the futures of our children at risk to protect a select few who may be adversely affected by this virus. Even scientific logic must give way to reason.

    1. drsnowboard says:

      The death of the few for the good of the many?
      Which few? Are you a fan of Logans Run?
      What constitutes few enough?

      1. Bannem says:

        > The death of the few for the good of the many?
        > Which few? Are you a fan of Logans Run?
        Those who do not make a meaningful contribution to society as a whole.
        > What constitutes few enough?
        I think most developed countries could tolerate a 5% death rate.
        This is a global pandemic, for which there is currently no effective cure or treatment known. People have died and are going to continue to die.
        The question is merely how many and who . . .

  38. flem says:

    what is the biological explanation why some get infected but remain asymptomatic carriers? Is it merely a function of your immune system. Does the same phenomenon exist for other viral infections? Apart from lung disease is there a common link between the other risk factors: obesity; hypertention; CHD, diabetes, males, age. I know lack of testing makes it difficult to answer but do we know the characteristics of asymptomatic carriers ? How many obese, diabetic, hypertensives, seniors fall under that categories?

    1. Dr. Manhattan says:

      An excellent and highly relevant question, but at this point it isn’t possible to sort out the biology around it. Recent but limited studies suggest that the asymptomatic population may be larger than suspected. In the long run we will certainly learn much more about both viral and host factors that bear on individual clinical outcomes.

      1. ghost of q.mensch says:

        Regarding: “Recent but limited studies suggest that the asymptomatic population may be larger than suspected…”

        According to MedCram Doc, Stanford/Santa Clara Student had ALOT of methodological and statistical shortcomings, and on top of that,

        Chris Martenson finds ALOT of signs of shoddy conflicts of interest by some of the Stanford study authors.

  39. Gd says:

    An oral drug would be better.
    Has sofosbuvir been tested in vitro at least?
    Does Remdesivir not have any oral bioavailability?

  40. Oudeis says:

    Wasn’t there an angiotensin post over the weekend? I’m not seeing it now.

  41. Thoryke says:

    And now a document, posted in error to the WHO website, suggests that remdesivierisn’t as useful as people had hoped… [link in name, per usual]

    It is going to take a while to get effective treatments, a vaccine, and ways to get these worldwide, so even when we make progress, we can’t just leap forward to the part where everyone gets what they need…

  42. GerryL says:

    Thanks to Mr O’Day and the folks at Gilead. We all, everyone of us hopes that this works.
    But donating to hospitals and ramping up production and pushing through these trials as quickly as they have done.
    I have been reading in this blog about another antiviral. Hope that this works and can be quickly developed. Please cut through the red tape and bureaucratic roadblocks,

    Let’s hope for the

  43. hatanakatoru says:

    At first, I thought that viral load (RT-PCR) result was strange, but “Nasopharyngeal and Oropharyngeal Swabs” means nose and mouth swab. There is no evidence that they are positively correlated with the viral load in lung alveolar cells. It’s possible that the drug does reduce the viral load in the target organ (lung). Otherwise, the day 11-day 8 difference may be a noise, and the effect may be an illusion.

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