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About Remdesivir and About “Game-Changers”

We’ve had several releases of remdesivir data, and this was not exactly one of those controlled-release formulations. No, this was more in the “chaotic mess” category, with news items coming from several sources with partial information. I decided not to blog on it until the loud banging noises stopped, and I’m glad I did, since I would have had to have revised (several times) whatever piece I managed to crank out.

Recall the previous state of affairs: we had a readout in 53 patients as reported by Gilead in the NEJM (of all places – future readers will be able to tell that they’ve hit the 2020 stratum in the literature when they run into a bunch of papers on clinical virology that all seem like they’re in the wrong journals). That one was interpreted as somewhat positive, although there was really no way of knowing. Then there was the news that a remdesivir trial had been suspended in China, which took everyone by surprise and did not breed confidence in anything: the drug’s prospects, the results themselves, the Chinese, you name it. A day or so later came word of leaked data from a trial in Chicago that sounded much more positive, and that threw some people’s opinions back the other way.

Now we have bits of data from an NIAID/NIH trial of the drug that began enrolling in Nebraska in late February (the first patient was one of the Diamond Princess cruise ship passengers, which seems long enough ago by now that it might as well be the Titanic). This one was double-blinded and placebo-controlled: patients in the treatment group received 200mg of the drug the first day and 100mg each day thereafter, for up to ten days. Participants needed to test positive for the virus and have evidence of lung involvement in the disease. The primary endpoint was improved time to recovery (discharge from the hospital or ability to return to normal activity), and it appears that remdesivir was statistically better than placebo: 11 days versus 15 days. The team also monitored overall survival in the >1000 patients, and there was a possible trend towards the drug, but it did not reach statistical significance (8% mortality in the treatment group, 11.6% in the placebo group).

That’s it. Those are the numbers we have. The rest will be in a “forthcoming report”, and we’re going to have to wait until it comes forth. This release was after an April 27 meeting of the data and safety monitoring board, and it’s worth noting that had there been “clear and substantial evidence of a treatment difference” during the trial that the DSMB was to have halted the study at that point. We can infer that nothing rose to that level, then: we have a difference, but not substantial enough to have ended the trial prematurely. And I have to note another issue: if you look at the Clinicaltrials.gov record for the trial, it appears that the outcomes measures for the trial were changed (as noted by Walid Gellad on Twitter). That primary endpoint of the trial mentioned above, time to recovery? It was originally an 8-point severity scale (death, on ventilator, hospitalized with oxygen, all the way down to discharged with no limits on activity). A similar ordinal scale measure is still in the secondary endpoints, as it was before, but we have no numbers for that yet, of course. But it’s clear that the primary endpoint was changed at some point in April.

The other piece of news is this paper in The Lancet describing a randomized, double-blind, placebo-controlled trial in China with 237 patients – in fact, the very one that was halted suddenly. This one enrolled patients that had 12 days or fewer of symptoms, confirmed viral infection, and involvement of the lungs as well (<94% oxygen saturation on room air and confirmed viral pneumonia on X-ray). The dosing of remdesivir was the same as in the NIH trial. But in this one, the use of the drug was not associated with a shorter time to clinical improvement. A subgroup analysis showed a trend (not statistically significant) towards shorter duration in the patients who overall showed symptoms for ten days or less, though. Mortality was identical between the two groups, although there was again a trend (not significant) towards less mortality on remdesivir in the shorter-duration patients, and thus a trend towards higher mortality in the others. The viral load was checked in both the upper and lower respiratory tracts of the patients, and remdesivir had no effect whatsoever on it compared to placebo, in any group.

So that paper’s results are not very impressive, frankly, and if you’d seen that one first then the NIAID results would have been even more surprising. I very much look forward to seeing the viral load numbers from that one, since that was one of the more striking misses in the Lancet paper. Remember, the mechanism of action of remdesivir, as a nucleoside mimic, is to interfere with viral replication. So if viral load isn’t be affected, you have to wonder what’s going on.

It’s possible that the drug’s efficacy, such as it is, is most apparent when the drug is given earlier in the disease course or to patients with are getting severe disease in general (those two categories probably have substantial overlap, and early in the infection you probably can’t tell the difference). Many people yesterday were saying that sure, the Chinese patients in the Lancet paper were in worse shape than the ones in the NIAID study, but looking at the inclusion criteria, I really don’t think that they were that different. The authors of this study note that their patient population was actually less ill than the ones reported in Gilead’s earlier NEJM paper, and that they had hoped, based on this, to have seen more of an effect than they did.

Taken together, the picture that’s emerging is that remdesivir may be of some help in less-severe cases. It is not a cure; a cure would have shown up in the trials we’ve run already, and cures are mighty thin on the ground for viral diseases. We can hope that the time-to-recovery is actually a useful measure and that the drug might get people out of hospitals a bit earlier, and hope a bit harder that there really is a mortality difference that will turn out to be real as we go into larger and larger numbers of patients. But working against that is the possibility that wider use of the drug will obscure the effect rather than make it more obvious.

To forestall some questions that I know will come up: what do I think about this versus hydroxychloroquine? Well, we have more controlled data to work with on remdesivir, for one thing, so whatever benefits there are, are more obvious. The balance of what controlled data we have on HCQ is negative, and here we’re at least more mixed. There is also (to the best of my knowledge) no particular safety signal for remdesivir, as opposed to HCQ (particularly the HCQ/azithromycin combination). So while I’m not bowled over, I’m more optimistic than I am about hydroxychloroquine.

That said, I continue to think that we do not yet have any treatment regimes that are making a big difference, unfortunately. I saw a tweet from Nate Silver, no fool, wondering about the possible effects of having some combination of drugs by this fall, things that could be widely administered so that anyone who needs them could get them, that reduces mortality by a significant amount (he mentioned 30%, 50%, or more). He started out by saying “Non-rhetorical question”, so taking that non-rhetorically, all I can say is that I don’t see it happening. Speculation about it seems a waste of mental effort. Remdesivir was honestly one of the better shots, and at best it might have decreased mortality from about 11% to about 8%. I don’t see any combination of repurposed drugs adding up to the numbers that Silver is wondering about. The only new (non-repurposed) therapy that could do it in that time frame is, I think, a monoclonal antibody. Having that widely available by the fall would really be pushing it, since it looks like the first patients will be dosed in June for the very fastest-running efforts. “Widely available” is the key phrase: I certainly think an effective mAb can be found, and the number of companies working on finding one makes it more likely than ever that we’ll get a good one. But proving that it’s good and (most importantly) getting it produced and distributed – well, “fall” to me starts in September, and that would be quite an accomplishment. Note that I have not even talked about cost. (This is a good point to mention that even remdesivir production is not a straightforward process, either).

Until we have such a mAb, and until the advent of a vaccine later on, I do not see any game-changers on the horizon. I will look forward to being wrong about how quickly these things will appear – that would be great – but I don’t think I’m wrong about those being the main things that will knock down the virus.

122 comments on “About Remdesivir and About “Game-Changers””

  1. luysii says:

    Well, the USA is about to embark on a series of non-randomized, non-controlled social experiments on relaxing the restrictions on activity. This will be accomplished many different ways, in many different locales (which is good, because if there ever was a country where one size does not fit all, it is the USA). But beware of what you read about the effects. There are people who will be proved very wrong either way — if nothing happens, or if cases and deaths skyrocket.

    It’s good to see that people are being explicit about their predictions. What are your own? Time to commit yourself before the data rolls in. Here are two rather emphatic predictions, both of which can’t be right

    https://www.theatlantic.com/health/archive/2020/04/why-georgia-reopening-coronavirus-pandemic/610882/ — Here’s how it begins —

    Georgia’s Experiment in Human Sacrifice

    The state is about to find out how many people need to lose their lives to shore up the economy.

    So beware breathless reports of spikes in incidence, hospitalization, deaths occurring in the first few days after the restrictions are lifted. Remember the mean incubation period is 5 days with a range of up to 11 days.

    On the other hand

    https://www.theepochtimes.com/as-ccp-virus-brings-a-taste-of-fascism-trump-needs-to-end-us-overreaction_3330804.html

    As CCP Virus Brings a Taste of Fascism, Trump Needs to End US Overreaction

    Also beware of breathless reports of nothing happening in the first few days confirming that it was OK to lift restrictions, again because new cases will take a while to show up, and new deaths from the disease will take even longer.

    1. intercostal says:

      As someone who lives in one of the states that is reopening (TX), I think the results will be somewhere in between, but closer to optimistic than pessimistic. (Though I definitely don’t agree with the politicization of this!)

      I expect to see some increase, at least in some of the states that are being less careful (e.g. GA) and have relatively dense populations, but not disastrous results. Both because of population density and transit differences (NYC is not at all typical of the US), and because people won’t go totally back to pre-COVID activity patterns immediately. Weather/outdoor activity patterns may make a difference also.

      I’m not going to make numerical predictions, though; far too much uncertainty.

    2. David says:

      The Atlantic is a reputable source of long-form journalism which general falls in the middle of political debates. The Epoch Times is a right-wing propaganda organ, funded by the Falun Gong, which often promotes radical ideas and conspiracy theories.

      As you write, both of them can’t be right.

      1. anon the II says:

        David is exactly right. luysii has given us a false dichotomy. Beware.

        1. luysii says:

          I could have given you the following from the Sunday NYT — How The Republicans became the Party of Death , which certainly matches anything Falun Gong has come up with, but I found it rather embarrassing. https://www.nytimes.com/2020/04/24/opinion/republicans-coronavirus.html

        2. Anon says:

          Leave the old man alone. He is just happy that he can say “merry Christmas” again thanks to the great new administration.

          1. JA says:

            ^ this was unnecessary. No need to be a jerk.

      2. intercostal says:

        I certainly agree that one source is more politically extreme/fringe.

        But there are very different experiences with this pandemic between the Northeast (NY, NJ, Massachusetts) and the big Great Lakes cities (Detroit, Chicago).

        From here in TX, I do think there is a degree of unintentional bias toward the New York/New Jersey experience in much of the nationwide reporting.

        Harris County – Houston, TX – has over 1/2 the population of NYC and less than 1% of the deaths. Many of the interior plains states like South Dakota might be better off because they got the virus later (and therefore might be hit hard in the future) – but I don’t think that applies to Texas, Florida, etc.

        1. Hap says:

          Harris County has 2700 people/sq. mi, while NYC has 29000 people/sq. mi. You’d expect transmission and infection to be increased where densities are higher (and where most forms of transit involve lots of people (subways, buses) as opposed to cars (with fewer people). That might help the outcomes in TX in the same way, but might also explain (in part) the problems in places like NYC.

          1. intercostal says:

            Yep. I think the cars vs mass transit thing is probably critical.

            The question will be:
            – does it just slow down the spread, but ultimately ends up comparable barring social-distancing differences?
            – or does it reduce “viral dose” and thus make a smaller percentage of infections serious/critical/fatal?

            Florida and Texas have fewer confirmed cases than New York, but also fewer deaths per thousand cases. Is that just a testing difference or do the transmission conditions actually affect how dangerous it is? Or some kind of sunlight effect (vitamin D)?

            Disclaimer: I am no expert nor any kind of doctor, just watching and trying to make sense of the data.

    3. Tom A says:

      If you’ve seen the ads for the Epoch Times on Youtube you’d know they’re a joke masquerading as a “newspaper”. They’ve got to step up their game in the PR department. It’s laughable. But I’m sure they have a loyal following subscribing to the epistemic closure that’s offered.
      My apologies going off topic. Wish it was Things I Would Rather Not Work With.

      1. luysii says:

        Apologies about epoch times. I’d never heard of it. I do read real clear politics, and they appear to be equally balanced between left and right (which is where I picked up the epoch times. Try this one from Bloomberg on for a view in favor of opening things up — it quotes Ioannidis of Stanford

    4. Chris Phoenix says:

      https://www.ledger-enquirer.com/news/coronavirus/article242371976.html
      …has stats of Georgia counties, for known cases, hospitalizations, and deaths.

      Scatter-plotting hospitalizations vs. deaths shows a lot of un-correlation – counties with too few deaths. This tells me that a lot of Georgia counties are just starting up the curve – it’s been less than 40 days since cases really started to explode.

      Scatter-plotting cases vs. deaths also shows a lot of un-correlation. That tells me their testing is completely inadequate in many counties.

      This looks like exactly the wrong time to ease restrictions. I expect they will learn that 40 days from now (about how long it takes from infection to death).

      1. luysii says:

        We should know a lot sooner than 40 days , if the Georgia counties report cases of infection (e.g. finding viral genomes) as well as deaths as they do here in Massachusetts. There is a large ego investment on the side stating that loosening the restrictions will very wrong — see the article by the always excellent Matt Taibbi (certainly not a right winger) — https://taibbi.substack.com/p/temporary-coronavirus-censorship

    5. Robert Carnegie says:

      Snopes.com reports one protester in Tennessee did indeed have a sign that appeared on television, “Sacrifice The Weak, Re-Open TN”.

      https://www.snopes.com/fact-check/sacrifice-the-weak-sign-real/

      This appeared on 2 different telelvision channels so presumably was not brought by one of them to add je ne sais quoi to the occasion, and no one seems to have asked the protester himself whether he really meant that (at least one of the journalists was asked about it), and whether the TV camera was pointed at the protester, or the protester came over to stand in front of the TV camera, is not known.

      But unlike a lot of protest sign photographs that reach Snopes, this was really there.

  2. myst_05 says:

    Wouldn’t mass scale convalescent plasma injections count as a game changer? Or are they impossible to scale up to the right level?

    1. Todd says:

      It’s too hard to scale up. It is definitely useful in severe cases, but it won’t be the leading therapy by a long shot.

      1. Anon says:

        Companies like Grifols and CSL Behring already have a vast diffuse network of blood/plasma fractionation centers. They might just be able to pull it off if this is the only viable quick response in the short term. Hope someone is looking at all this.

  3. psoun says:

    Excellent post as always. What about EIDD-2801? That seems to have some legs to it?

    1. Stephen says:

      EIDD-2801 is pre-clinical. While all the mouse data looks fantastic, there still needs to be tox and the phased clinical trials.
      On the upside, after reading the patent, it doesn’t seem that difficult to scale up.

      1. The Fine Print says:

        Well it’s going to have to be easy to scale, the efficacious dose in mice is 500 mg/kg

        1. milkshake says:

          Dose in mice is typically much higher than the human dose but 500mg/kg is quite a lot

          1. anon the II says:

            We recently went through this calculation using the guidelines in an FDA document and it works out to about 1/12 going from mouse to human, if I remember that correctly. So average human (not US) weighs 62 kg. 500/12 * 62 = 2.6 gm. That’s a lot of drug. Seems like some of the early HIV drugs were given on this scale. I don’t know if that’s still true.

          2. Ian Malone says:

            That’s not a drug, that’s a condiment.

  4. Churlish says:

    In the 2nd to last paragraph describing remdesivir’s potential impacts on mortality, I think “8%” and “11%” should be swapped.

    Thanks for all your articles! This blog has been such a wonderful source of knowledge for me, both pre-pandemic and now.

  5. KRL says:

    Thank you for the concise summary. I suggest two minor corrections: remdesivir is a nucleotide analog, not a nucleoside analog and “… decreased mortality form about 8% to about 11%” – should read from about 11% to about 8%.

  6. KRL says:

    Thank you for the concise summary. Remdesivir is a nucleotide analog, not a nucleoside analog as you wrote.

  7. A Nonny Mouse says:

    From your link

    …..Remdesivir as a compound is not particularly difficult to synthesize, experts said……..

    Who are these “experts”? Looks pretty tough to me after 40+ years in the business.

    1. anon the II says:

      Having also been in the business about 40 years, any compound synthesis is easy as long someone else is doing the work.

    2. milkshake says:

      If you had a good team of say six process development chemist- and later another six for the analytic support and for operating the pilot scale reactors (before you build a dedicated plant), then a start to finish from medchem route to a fully documented GMP kilo scale run would take at least one year, for a molecule of this complexity, if you get lucky. There are several unpleasant steps that would require careful optimization

    3. Some idiot says:

      Not kidding…! When my wife and I heard the news over breakfast (presented in a _very_ positive fashion in the news), when they named the drug, my first response was “ouch… Upscaling’s gonna be tough…” Whilst I don’t have 40+ years behind me as a process chemist (respect!!! (-: ), I do have enough to be able to see that it isn’t something you “just” scale up…!

    4. David Young MD says:

      Not as easy as Lisinopril or Aspirin, to be sure. But then again, not as difficult as Paclitaxel or Bryostatin A. So, I guess it is all relative.

      Yeah, I think that making Remdesivir in a stable formulation is probably a little labor intensive and trick. But they are doing it.

      1. CMCGuy says:

        Relatively complex synthesis, particularly dealing with chirality, and stable formulation issues aside if a prodrug with the true active species/metabolite being the nucleoside portion I have to wonder if one potential longer term approach to securing a substantial supply of a compound that appears to be partly effective is to create a simpler analog. Of course unless Gilead or others have a closely related compound with significant tox and other preclinical data this would not be of immediate usefulness and practical development would be required and there is also the possibility of better drugs/therapies coming out.

      2. anon the II says:

        I don’t think anyone is making Paclitaxel or Bryostatin A from scratch. Paclitaxel is made by from some almost final compound that’s grown in some bug which has the yew genes inserted, or something vaguely like that. Bryostatin A’s structure was discovered (x-ray) in our lab when I was in grad school. I’m pretty sure nobody is making it either for a full scale clinical application. Maybe a mg or two here or there. So not an apt comparison.

  8. Christophe Verlinde says:

    By the time patients arrive in the hospital the interleukin-6 fueled immune-storm is already going full blast, damaging lung tissue like a blowtorch. Administration of Remdesivir stops the creation of new virus particles, the original cause of the immune-storm but such storms don’t die overnight, they are more similar to the self-fueled firestorm that destroyed Dresden in WWII. Therefore, Remdesivir is likely too late on the scene to make an enormous difference. Earlier administration of the compound, when the patients are suffering from bearable symptoms would logically make more sense (a quick PCR confirmation would be required). That would be my next clinical trial.

    1. psoun says:

      That’s probably true about HCQ and other options too. The problem is that any properly matched cohort clinical trial for something dosed immediately at positive confirmation (when such options probably should be dosed) is likely to show modest effects statistically at best given that most will recover without, so isolating out that smaller subset that progress to full cytokine storm is tricky business, unless there are specific metrics of efficacy that could be teased out (beyond duration, mortality, etc. which would be noisy).

  9. coronadose says:

    Has the in vitro EC50 of COVID19 replication inhibition been reported for remdesivir or the parent nucleoside of remdesivir (not the prodrug)?

  10. Anon says:

    As described in the Lancet paper, patients in the Remdesivir arm had more comorbidities (hypertension, diabetes, coronary artery disease) than in the placebo arm.

  11. JN says:

    Thank you again for another informative post.

    What about the use of synthetic ACE II as a decoy to target the virus? This study is currently in phase II clinical trials in Europe and China. I haven’t seen any discussion of this approach but may have missed it: https://www.thepharmaletter.com/article/apeiron-biologics-moves-forward-with-apn01-for-treatment-of-covid-19

    Would be really interested in the views of those with a much better knowledge of the subject than I.

  12. Anon says:

    Are you pessimistic about the combination of an antiviral and an anti-IL6? Would love to understand better why. Just because most things fail (which seems a reasonable prior) or is there more to it than that?

    1. Anon says:

      He’s just a pessimistic individual. That way, when things fail (as they normally do), he can say: I told you so! and come across as full of wisdom.

      1. Derek Lowe says:

        Hah – but wouldn’t a pessimistic person assume even a higher failure rate than the real one?

      2. loupgarous says:

        In an industry where only one out of every ten new drug candidates wins marketing approval, pessimism shows you’re paying attention.

        Just because we badly need a “game changer” hasn’t meant we’ve gotten one or are about to. The current dismal success of clinical trials for HCQ and remdesivir in Covid-19 treatment follow a longstanding pattern.

  13. David Young MD says:

    I have been begging, begging, begging for a trial of Remdesivir against placebo in very early disease. Enroll 1,000 patients at the onset of symptoms (within 3 or 4 days of symptoms) and give 2/3rd Remdes and 1/3 placebo infusion. Yes, there are some obstacles, mostly logistic obstacles to such a trial, but it can be done. It should be done.

    I also have hoped that some in vitro studies would have been done by now on combination. can you get a somewhat (even mild) synergy when using Remdesivir and Favipiravir together in the lab? Can you safely give iv Remdes and oral Favi to patients? Is there enough synergism where you could use 80 percent the dose of Remdes and 80 percent the dose of Favi (maybe a moot point since vial size is immutable).

    One could conceive of a large multi-arm study with 1/5 of the early disease enrollees on placebo and having the other four arms represented by straight RemDes, strait Favi and two combinations of the two drugs.

    I just can’t understand why, in the past 6 weeks, we don’t have an ongoing study on testing these drugs in patients with early disease. Prevent hospitalization and the cost of hospitalization. Prevent over use of hospital resources. Lessen spread in mild cases. Prevent death and disability. Looks, there are all kinds of reasons to treat the early patient.

    1. psoun says:

      Totally agree David. But from a design standpoint (I’m an economist that does work in health so looking at this from the impact standpoint), it’s going to be tricky to get statistically significant results for something like Covid (compared to say, Ebola) where the overwhelming majority of cases recover and where giving anything like remdesvir, HCQ, etc. is going to have modest (or negligible) impacts on that large cohort that doesn’t need more than Tylenol and fluids. You’d need a massive trial to get there.

      Are there more subtle metrics beyond obvious ones like duration of disease or mortality that could be measured that could show a difference?

      I do have to note that while I realize this is a pandemic and we’re in battle mode, I have never seen so many design fails for these clinical trials. The Brazil HCQ is my favorite for WTF were they thinking.

      So yes, early trials please but can we have some broader range of outcomes to measure “success”?

      1. cynical1 says:

        Your point is well-taken but I would suggest that you could start with a trial in a smaller set of patients in the hospital setting and measure viral load clearance versus placebo knowing that much of the illness at that juncture is immune system mediated. You may not get the improvement that you are wanting. However, if a drug like Favipiravir or Remdesivir (or the combination) were to accelerate viral clearance versus placebo, I think that you could make a stronger argument for larger trials in recently diagnosed infection with the expectation of improved overall outcomes. In fact, there was a post on this very blog on March 19 with a link to a paper comparing Favipiravir to lopinavir where Favipiravir very clearly showed increased viral clearance versus lopinavir. (You can basically assume lopinavir/RTV is a placebo because using that drug is just plain dumb).

        Of course, everyone knows that we shouldn’t look at clinical data like viral clearance and instead look at the antiviral activity in Vero-6 cells. Who cares about increased viral clearance in humans, right? Why would you think early treatment might work? (Yes, read sarcasm.). Let’s wait until they are all on ventilators to start our study and then scratch our heads.

        1. psoun says:

          That’s all very sensible. There is a real missed opportunity where I am based (Senegal) to do early trials of candidate treatments. Here, everyone that tests positive is immediately hospitalized and contacts quarantined (and tested) so in principle (with proper consent) you’d have a captive audience to administer early treatment options. In practice, it seems to be the case that everyone that can take it gets HCQ automatically and to be fair recovery rates have been pretty good here (up above 60% of total cases at one point before a recent spike in outbreaks), but obviously not set up against placebo etc. to see if it’s that or something else. Where you have strict protocols to test, isolate, and quarantine, doing these early trials might be possible. That obviously isn’t the USA right now.

          1. Cynical1 says:

            Well, if I was in charge of the world we’d be doing some trials in Senegal. Your system is set up pretty nicely. It’s very frustrating to see so many lost opportunities when so many people are dying.

          2. milkshake says:

            The local outbreak is followed by a rapid increase in reported mortalities after about 3 week delay. Look at the data from Czech republic and Germany. Senegal is still too early to guess what the spread will be like

          3. Forte Shadesof says:

            I checked deaths per million by day on ourworldindata. Senegal looked to be about .1. France is 10. Algeria about 1. Algeria Was tracking France until they introduced hcq seems to have bent the curve. Is hcq the reason. What is your view on hcq in Senegal.

      2. David Young MD says:

        That’s right. So an outpatient study would have to be restricted to a cohort of people who are more prone to having a hard time with Covid19. Say, anyone over the age of 60, or anyone from 40 to 60 who has diabetes requiring medication, those with COPD or Asthma, those with hypertension. It would not be too difficult to look at actuarial data to come up with a filter that would estimate that at least 30 percent of infected people would require hospitalization. You would expect then that the control group would have about 30 percent hospitalization. Then you could require a drop in that number by… say half (to 15 percent)…. to judge that outpatient administration of Remdesivir is economically worthwhile. I don’t know the numbers but I think that one could come up with the numbers. I would hope, of course, that early use of Remdesivir would drop the hospitalization rate to only 10 percent (from 30 percent) and decrease the death rate from, say 8 percent to perhaps 2 percent. I just hope that they do the study… and soon!

        And I hope that they consider combination studies. Well, if Remdesivir gets approved in Japan, which is rumored to happen very soon, then perhaps the Japanese would consider the merit of testing combinations of Favipiravir with Remdesivir in early disease.

        1. psoun says:

          Milkshake – Senegal’s first outbreak was 3rd March, so timeline is not that far behind Europe. Currently at nine deaths for over 1,000 cases, and about half of those over the past week (there’s been a doubling of cases as tests have been ramped up considerably since the 20th of April or so). Demographics are different to be sure, but treatment facilities will be considerably less sophisticated than Europe/USA, so those effects wash out at least. Effectively, Senegal is doing a universal HCQ trial without a matched (domestic) cohort.

          1. Forte Shadesof says:

            Algeria seems to have already done this. Per our world in data it tracked France almost exactly until they introduced hcq. Now deaths per million is .2. France is 10. https://twitter.com/shanejhayes/status/1256229354360750081?s=21

          2. Forte Shadesof says:

            Algeria already did this. Per our world in data it was tracking France exactly. Introduced Hcq and deaths per million is 1 versus France at 10. I Would link to a graph but it gets stripped out. You can literally see the curve being bent.

          3. psoun says:

            @Forte – short answer on Senegal is I don’t know. A lot of causation but scientifically that’s not really good enough. What I see from the data I track:
            * Before 20 Apr, Senegal was testing ~200/day and catching 10-ish cases per day and falling. The proportion of community cases was increasing but generally 1-3/day. Mitigation is mainly test/trace/isolate + hospitalize all cases. No lockdowns here but an 8pm-6am curfew, inter-region movement restrictions, and school closures.
            * Net active cases were falling – down to just over 100 in mid-April and recovered rates ~60% of total. Only a handful of deaths (I don’t have my data in front of me but 60 years old and a majority of cases <40 (see https://cartosantesen.maps.arcgis.com/apps/opsdashboard/index.html#/260c7842a77a48c191bf51c8b0a1d3f6). But beyond basic supportive care, if one needed a lot of ventilator or more high tech support, I think you'd be SOL. Having spent a few days in Dakar's best private clinic a couple years ago, beyond basic care gets a bit dicey.
            * I would like to see more data on this – the Ministry does a good job on general comms and an excellent job on tracing/isolating, but there are nuances that could inform a great deal, not just here but elsewhere. Might see if I can leverage some friend of a friend contacts to see what is possible.

          4. psoun says:

            One of my notes was deleted in pasting: cases have accelerated here in the past 10 days, now at just over 1000 with 9 deaths. Testing has ramped up 4-5x to over 1000 test per day. So they are finding and isolating a lot more.

      3. Matt says:

        What if you do the study on early stage elderly patients? The mortality rate is so much higher maybe you could get a significant result with early stage patients.

    2. Druid says:

      It is understandable to want to treat patients in hospital as they are are great risk of dying. Also, hospital patients are on hand, and very willing to participate. The patients you want to treat will not present at hospital. Until patients are ill enough to require hospitalization, they don’t even find it easy to get tested for virus, and they are told to isolate. So, these are some of the logistical difficulties. Who is going to run the trial? How are they going to “recruit” patients? Would you treat them as in-patients? In isolation wards or can you leave them to go home when you know they have virus? And because the patients are not already in hospital, everything has to be funded. It might not be easy to recruit patients with early, not serious, symptoms, who think they are going to beat this infection without assistance, to stay in isolation with other definitely ill people for at least 2 weeks, and may be given a placebo for their troubles. I think you would have to recruit 100,000 healthy volunteers and wait for 1% of them to get infected, with regular testing for virus. It can be done, but everyone is looking for the quick and easy fix instead of planning for the hard work. All the while, seriously ill patients are dying in hospital.

    3. Alan Goldhammer says:

      @David Young MD – the problem is NIH, FDA and everyone else was too slow to react. They needed to have a centralized clinical trial platform. It’s a crime that all these hydroxychlorquine trials are going on and there is little opportunity to bring new or repurposed drugs in the system. The Scripps and Mt. Sinai teams have identified maybe a dozen other investigational drugs that have Phase 1 data but it’s doubtful they will enter trials. I address the problem here: https://agoldhammer.com/covid_19/ in the Clinical Trials in a Pandemic paper. There was a big failure in imagination.

      1. David Young MD says:

        I agree!!

        1. David Young MD says:

          Everyone must agree… putting only 0.5 percent of patients on trial is an embarrassingly low percent!

  14. Eric says:

    Nice review Derek, although I do have one quibble about your response to Nate Silver’s tweet. If we assume the data presented by Fauci is real and translatable to clinical use, then we are already seeing approximately a 25% reduction in fatalities (11-8=3; 3/11=0.27). If IL-6 inhibition were to have even a small benefit then it seems very plausible we could get to a 30+% reduction in fatalities in the fall with a combo of remdesivir and IL-6 inhibition. It’s still not a cure, but reducing the worldwide death toll by 30% isn’t insignificant.

    1. Not Joseph Conrad says:

      I agree with this.

      I’d also like to lodge my (perpetual) gripe against describing results as “significant” or “not significant.” As reported, the reduction in mortality was significant at p = 0.059. Obviously p = 0.050 would make us more confident that this result is a true drug effect. But only a bit more! We need to educate the world that p value significance isn’t a binary on-off but a spectrum of confidence. (Derek Lowe 100% knows this, which is why I was a bit surprised to see this phrasing in his article)

      1. Derek Lowe says:

        You have a point there, of course. I think it’s a reaction on my part – an overreaction? – to the headlines that breeze past the issue entirely.

        1. Not Joseph Conrad says:

          I completely understand. The reporting *has* been frustrating. And your commentary has in general been tremendous (not that you need the compliment, but it’s true). P value interpretation is just a particular obsession of mine…

        2. pessimist says:

          Another point in favor of Remdesivir is that both the Chinese and the NIH study do show a trend toward lower mortality when given < 10 days after symptoms. Each individually is not "statistically significant" given the magic 0.05 but surely these effects can be combined? I am surprised no meta-analysis is being done.

          Fully agreed that this is not a game-changer, but even ~25% mortality reduction is quite a decent result.

      2. Adam Zweifach says:

        If p>0.05, then it’s pretty much certain that the 95% confidence of the effect size includes 0, so at this point there’s no reason whatsoever to believe there is any effect on mortality.

        1. intercostal says:

          I think the idea is that there’s nothing inherently special about the 95% confidence interval, vs. say a 99% or 90% confidence interval – it’s just standard practice.

          Wouldn’t p = 0.059 give you more confidence that it is real than p = 0.45, just as p = 0.001 would give you more confidence than p = 0.04?

          1. Not Joseph Conrad says:

            Intercostal’s analysis is precisely correct. p = 0.05 means there’s a 1 in 20 chance you get these data if the null hypothesis is true. p = 0.06 means there a 1 in 17 chance that you get these data if the null hypothesis is true. That’s it. Obviously, the lower the p value the better. But if you feel you have reason to believe X based on your priors if p = 0.05, then you probably should feel not too different at p = 0.06 (maybe 15% worse!)

          2. JasonP says:

            I wonder if this ‘debate’ over statistical significance is an artifact of the way we train scientists and it becomes a bright-line way of thinking? Certainly no one defending a dissertation or thesis is going to hang their hat on any statement that doesn’t have a 95% confidence level. So isn’t there a tendency to toss the baby out with the bathwater when, as similar to this case, the confidence level is only 94%? Certainly one doesn’t want to waste resources or do harm, but as a society, in the middle of a crisis, are we willing to adjust, adapt or bend from the strict 95% confidence level? When can scientists adjust the line?

            I listened to Dr. Fauci in the news conference the other day. Two things stuck out: 1) He said this would be the new standard of care and 2) Fauci compared this ‘break through’ to ATZ for HIV/AIDS.

            I’ll be interested to see Derek’s and the group analysis of the data when the paper goes to pre-print. We do need the scrutiny, especially if this is to be the new standard of care.

            Should I be concerned with the comparison to ATZ?

          3. Ian Malone says:

            Sort of, five percent was introduced originally as a kind of rule of thumb. But it’s actually quite generous, a compromise between wanting certainty and the limitations of (in particular) biological studies (in particle physics they prefer to measure p by order of magnitude). Wanting to revise it upwards is always a temptation. Meta analysis as already mentioned is a good answer, if multiple independent studies are giving you p bordering on 0.05 then you may well have built good evidence for a much smaller p (or for publication bias of course).

          4. Hap says:

            This is a paper discussing the interpretation of the p-value that’s come up here before: https://royalsocietypublishing.org/doi/full/10.1098/rsos.140216 It implies that p=.05 is not as helpful as people think it is – that the likelihood of a result being by chance with a p=.05 is much higher than .05.

      3. matt says:

        That’s fair. But the physics perspective is you are already being ruinously lax by accepting 0.05 as the threshold. That’s a “indicates there might be something there” and if you want to really establish you have seen something, or publish, your data better go to 5 sigma. So relaxing the standard a bit to say, well, that’s close enough, when the standard was already set low, is a recipe for not having a standard at all.

    2. Derek Lowe says:

      That would be most excellent, I have to say.

  15. Adrian Bunk says:

    A mortality reduction from 11.6% to 8% would actually be a 30% reduction.

    And a substantial reduction in mortality might be possible even without antiviral drugs.

    Better handling of the symptoms as we learn more about the (often surprising) aspects of this disease:
    You already mentioned immune modulation in an earlier post.
    There are anecdotal reports that the blood clotting problem is so bad that even asymptomatic COVID-19 might be causing strokes in people in their 30s.
    How much reduction in mortality might happen just by doctors stopping to put patients on ventilation solely based on oxygen saturation? Initial assumptions regarding how early to put patients on ventilators, and about the benefits of ventilators, seem to not be correct for COVID-19.

    When hospitals are overloaded they are sending patients home who might in normal times have been monitored in an ICU just to be on the safe side.
    The situation of people with COVID-19 can deteriorate quickly.

    There are even non-medical ways to reduce mortality:
    In many places in the world up to half the deaths are in retirement homes.
    Testing and proper hygiene can help a lot.

    1. nobody says:

      Are there any trials looking at using blood thinners to tackle the clotting problem?

      If effective, warfarin could be ramped up fairly readily–with some degree of reduction in quality control–given that it’s widely produced for non-medicinal purposes.

      (I’m not stating the obvious for the sake of anyone out there who might be dumb enough to take it unsupervised….)

      1. Adrian Bunk says:

        For people in hospital due to COVID-19 the clotting problem was already recognized in Wuhan, and there are trials with substances like heparin or tPA.

        It is a fairly recent observation that a symptom of a COVID-19 infection might be a stroke or heart attack, some patients have no other symptoms. I used the word “anecdotal” since I am not sure how much of that is 100% established (or how widespread it is), and how much are just observations reported from small numbers of patients.

        My point was that there is still a steep learning curve regarding COVID-19, and the result will be better treatment of symptoms with standard medication. To me it sounds plausible that we might end up with a > 30% reduction in mortality in September 2020 (compared to March 2020) just by better treatment of symptoms.

        1. JasonP says:

          I have been watching the MedCram videos (updates 61 & 63). It looks like SARS-Cov-2 attacks the ACE2 receptors in the epithelium, leading to inflammation and the release of clotting factor leading to thrombus.

          Interesting how some are managing things in the clinic.

          https://youtu.be/22Bn8jsGI54
          https://youtu.be/Aj2vB_VITXQ

      2. Murph says:

        Dr. Daniel Griffin at NY Presbyterian-Columbia has said they are using Heparin and the like to address the high clotting they are seeing in their COVID patients. He said they are also dosing at levels higher than normally proscribed because the recommended dose is insufficient and are tailoring it to each patient based on the follow-up blood work.
        He has been contributing a weekly update on what’s going on in the clinic to This Week in Virology (https://www.microbe.tv/twiv/twiv-606/). I highly recommend listening to the show and its sibling podcasts for informative discussions on COVID-19 and microbiology more widely from researchers and doctors who specialize in microbiology, virology and infectious diseases. .

        1. psoun says:

          Not to hijack this back to HCQ, but doesn’t HCQ have anti-clotting properties? I’ve seen a couple of papers on this but they’re a bit out of my comfort zone to interpret. If so, in principle, if you gave this early, one of the protective effects might be fewer strokes/clotting incidents (irrespective of what it does from an anti-viral standpoint)?

    2. intercostal says:

      As someone (not a doctor) who is early-30s and so far was seeing myself as low-risk, how solid actually is the asymptomatic-stroke information? I know blood clotting problems are known from very severe COVID cases (eg in ICU), but asymptomatic is a very different matter.

      I saw one case report with 5 strokes between 30-50 at a NY hospital, two asymptomatic… but do we know that COVID was the cause of the strokes? NY’s government serology studies have suggested 25% of NYC has had the virus, so could the presence of the virus be coincidental? 30-50 is young for strokes though…

      1. It seems that there’s enough clotting to cause skin problems in a lot of otherwise asymptomatic young people. (WaPo URL on my name with lots of description and some photos.) A web search for “covid frostbite” will find several articles.

        1. intercostal says:

          Huh. Weird. I’d seen the headlines about COVID ‘rashes’, but wasn’t sure if that was true (I’m not really trusting anything from a “generic” media source – vs medical-oriented – anymore!) and had no idea that it had anything to do with clotting.

          What does that mean about the strokes? More likely to be a real causation even if (otherwise) asymptomatic?

          1. Chris Phoenix says:

            https://www.livescience.com/frostbite-toes-covid-19.html

            It has a couple of actual medical links; I’m posting that one rather than load down this comment with several links and get it held for moderation.

            I have no idea what it means about strokes. It seems to be common sense that clots in the legs implies the possibility of clots in the brain – but medicine often doesn’t make as much sense as non-experts expect it to.

    3. Jim Palmer says:

      A mortality reduction from 11.6 to 8% is a 3.6% absolute reduction. All reductions in risk and endpoints should be quoted as both relative reductions and absolute reductions lest inaccurate pictures be presented (or inferred). Still, a 3.6% absolute reduction translates to an NNT of about 27-28 (meaning that for every 27/28 people treated, one will survive). That’s not very good, really, but it’s better than nothing. What would be more encouraging is if this NNT value could be improved by earlier administration of the drug, but that would require earlier diagnosis and intravenous infusion of patients who weren’t necessarily hospitalized. That presents a logistical issue, to say the least.

  16. Eric says:

    I think it is important to note that the DSMB stopped the trial for efficacy based on an interim analysis. Despite the early termination for efficacy, the sample size was nearly 4 times larger than the China trial and thus more believable than the underpowered China study.

  17. JeffC says:

    I think all of the data released from the remdesivir studies makes sense. We know for almost all acute viral infections, especially respiratory ones, that you need to get in early, preferably before peak viral load. I have yet to see a study where patients have had their viral load consistently measured (my lack of seeing it doesn’t mean it’s not bee done) so we’re still not sure how viral load measures up disease progression/severity.

    Another thing to point out if that measuring viral load here is not as straightforward as you might think. The virus is replicating inside cells and sampling in the lungs does not always give a good picture of what is happening. The sample is of what is in the lung cavity, not inside the cells of lungs. Nasal swabs are even harder to interpret (and tough to do consistently from person to person). It’s way easier for viruses that show up in the blood (like HIV or HCV) but the lungs are tricky. You’ve got to do lung biopsies which are not pleasant and may not even be possible in these patients (it does not appear that they did this from clnicaltrials.gov).

    So this is hard stuff all round. But my bet is still that once they start using remdesivir more broadly in less sick patients we’ll see even better results

    1. loupgarous says:

      That links to a press release by the manufacturer of that drug reprinted by Yahoo! Finance from Globe Newswire.. Most of what we’ve seen about leronlimab online is statements by its manufacturer, either directly or through sites like Yahoo!Finance and Globe Newswire..

      So what about leronlimab? The only people in the business who are talking about it are CytoDyn’s PR people, so far.

      1. KatLuna says:

        It does have a sound MOA though

      2. Just their PR people, their paid stock promoters, and this letter ( https://www.nejm.org/doi/full/10.1056/NEJMc2011117?query=featured_coronavirus )in the NEJM….which you won’t see the company talking about….basically Cytodyn’s ancient, yet still unapproved, one time AIDS drug, leronlimab, has no effect on real-world outcome for these Coronavirus patients.

  18. Ghyu says:

    Is it possible that remdesivir stops immune cells from proliferating, thereby preventing damage to the lungs from excessive inflammation or even a cytokine storm?

  19. Scott Stewart says:

    Thank you for all the information. My wife asked me about the headlines yesterday and I told her her I didn’t know much until I either read the article or ITP had a post on it. This is the only place on the internet I get smarter after reading the comments.

    1. Science Mechanic says:

      Hear! Hear!

    2. Know-Something Party Organizer says:

      Re: Scott Stewart’s quip that this is the only place on the Internet he “get’s smarter after reading the comments”, is yet another positive result for the efficacy of this blog. Not only does the high signal to noise ratio eradicate rogue viral theories, it engenders a robust response among a diverse community of clear thinkers that amplify its benefits.

  20. ghost of q.mensch says:

    Chris Martenson compares NIAAD and Lancet (China) remdesivir (REM) studies side-by-side (also note from Derek’s link the detailed Lancet supplemental data pdf) :

    Starts from ~minute 4:00 https://www.youtube.com/watch?v=VscMiksyfW4

    -I think Fauci’s rather exuberant remarks to the press yesterday and this morning regarding the NIAAD study conclusions did not address at all the much more somber Lancet study findings.

    -Question regarding REM manufacturing scale-up for those familiar with US pharmas’ API supply chain: Is there existing remdesivir (and structurally comparable nucleotide (ie where does Gilead source its sofosbuvir now?) and nucleoside antiviral/ anticancer agents) gmp level manufacturing capacity still based within the US?

    Or are these gmp grade REM APIs sourced largely from China and India nowadays, and need to remains so for the foreseeable future ?

  21. Mark says:

    As always, thanks for your clear eyed calm approach, Derek!
    What would people consider as a “game changer”? Oseltamivir is approved for flu with a therapeutic effect so small that the Brits excluded it from their formulary for a long time. I hope that this stuff is great, but I fear an anchoring effect where some compound with a modest impact becomes the king of the hill to the exclusion of more worthwhile compounds. Once some treatment becomes the standard, it takes a lot to overturn. Everyone is anxious for some benefit, and this stuff may get crowned in our haste fueled by fear and politics. Fear and politics are motives that lead to dangerous steps.

  22. Rubidium says:

    Can Remdesivir be formulated for oral administration? asking for a friend

    1. David Young MD says:

      Probably not. Remdesivir is a “prodrug” that is activated into the active agent. If taken orally, it is probably broken down in other ways to make it useless.

      1. PS says:

        There are several prodrugs (of nucleosides/nucleotides/NNRTI’s) formulated as solid dosage forms. Many HIV drugs made by Gilead and others are formulated as capsules/tablets etc.

        An advantage of IV is it gives near 100% bioavailability while solid dosage forms gives much lower bioavailability. This means you can treat more patients with limited amounts of the drug. On the other hand solid dosage forms have many other obvious advantages.

        PS

  23. Giannis says:

    “Remember, the mechanism of action of remdesivir, as a nucleoside mimic, is to interfere with viral replication. So if viral load isn’t be affected, you have to wonder what’s going on.”

    It seems they only did qRT-PCR. That doesn’t count live viruses. You need to see plaque assays.

    For example in the first figure of this paper the “viral load” (which in reality was just RT-PCR) was about the same beteween remdesivir and placebo. But when the researchers measured “live” virus with TCID50 the results were completely different and remdesivir had reduced “live” viruses by 2 orders of magnitude. In reality most of the RNA isn’t even in functional particles. It’s either free or in damaged particles.

    https://www.biorxiv.org/content/10.1101/2020.04.15.043166v2

  24. Gd says:

    I was wondering about the differences between Remdesivir and Sofosbuvir. Both are nucleotide prodrugs, based on adenosine and uridine respectively. Otherwise the chemical structures are very similar. Why has Sofosbuvir, which is even an oral drug, not been testedA? Scientific or strategy/marketing considerations?

    1. Alan Goldhammer says:

      there is evidence from a preprint that sofosbuvir has no activity against this virus. https://www.biorxiv.org/content/10.1101/2020.04.29.067983v1 The FDA scientists looked at several other antivirals and other than remdesivir none of them showed activity.

      1. Gd says:

        Thanks, hadn’t seen that new paper.

      2. cynical1 says:

        You should be very careful about extrapolating antiviral effects in any cell line that hasn’t been shown to cleanly translate to in vivo efficacy. Yes, you can infect Vero cells with an RNA virus. It’s true.

        Yeah. You can grow HPV in Vero cells as well. Yeah. What does that mean? How many antiviral HPV drugs are out there? Last count: zero.

        In the antiviral world, activity in Vero cells is what you call a “warm fuzzy”. It makes you feel good but you probably shouldn’t believe it much either. I worked on those projects with the “warm fuzzies” in Vero cells. They didn’t go far.

    2. David Young MD says:

      Don’t forget about the Japanese drug, Favirpiravir, which seems to have activity against Coronavirus. Favirpiravir is an oral medications. It has been on the market for several years in Japan to treat Influenza. It has a remarkably safe profile. We don’t know yet just how well Favi works against Coronavirus. Studies are in progress.

      And there is EIDD-2801, an investigational agent made by RidgeBACK biotherapeutics in Miami. Another drug that works in the same or similar fashion as Remdes and Favi. It is being investigated at Emory and a few other southeastern universities, now entering clinical trials. EIDD-2801 is an oral medication.

      And as I have stated many times, there should be studies combining these drugs, to see if there is at least additive effects, if no synergism.

  25. Academic Med Chemist says:

    Well I’m taking Pepcid. Not because I think it will prevent coronavirus, but rather because a lifetime of chemistry has left me with pretty bad heartburn.

  26. steve says:

    I think the commentators on this thread are all missing the point. Sure, the data on Remdesivir have been hyped. Have you ever looked at a picture of Tony Fauci standing next to Trump? Trump could swallow him whole and still eat half a dozen Big Macs and still be hungry. So yeah, Fauci probably feels intimidated. But I digress. The real advantage of Remdesivir will only be seen as a COMBINATION drug. That’s why NIH is immediately segueing from this recent trial to one looking at the combination of i.v. Remdesivir, oral sodium hypochlorite and rectal UV light. Guaranteed to work.

    1. Some idiot says:

      Very good point. This marks the beginning of the beginning. I saw a very good interview last night with a (Danish) virologist, who is involved with the trials. Although he was very happy with the results, he said (a) this is no cure by itself, but (b) experience from the antiviral world shows that you typically need more than one tool to get an infection down, and now we have the first one, and (c) they will start their next set of trials next week looking at combinations with other drugs, to see how they can convert this “useful finding” into a “treatment.” He also said very clearly that the whole procedure was going to take time; lots of time. Very balanced and sober. And with a refreshingly high signal-to-noise ratio, as opposed to the actual news item!

  27. anon says:

    Does this mean we can go outside again?

  28. MMDN says:

    There are reports that the virus itself – not only the cytokine storm – causes damages to vital organs such as liver, kidneys, heart, lungs, maybe brain,…
    So blocking virus replication – even in later stages – could prevent organ damage to reach the point where the organ will shutting down.
    If Remdesivir does that, then I could see that it would provide a modest benefit in lowering patient mortality.

  29. An Old Chemist says:

    Register for this webinar, on May 6, by Derek Lowe and other Experts:

    Can old drugs take down a new coronavirus? The state of COVID-19 drug repurposing efforts

    https://connect.acspubs.org/CENWebinar_Wuxi_5_6_20?partnerref=CENFB

  30. Rick Rude says:

    It seems Turkey is getting good results with hydroxychloroquine. They are giving it to every patient who tests positive, and they have a low mortality rate. Here doctors are being forbidden from giving it to patients.
    And now I see the media singing the praises of remdesivir.
    It’s corruption. Follow the money.
    Perhaps the ends justify the means, I don’t know.

    1. psoun says:

      FWIW, some results reported from Senegal today. Seems some pseudo controls. Like to see this written up/peer reviewed.
      https://www.dakaractu.com/Pr-Moussa-Seydi-%C2%A0Les-patients-traites-avec-l-hydroxychloroquine-associee-a-l-azithromycine-ont-une-duree-d_a187651.html

    2. David Young MD says:

      “Here doctors are forbidden to give it to patients”. Are you kidding me? Practically every patient hospitalized with covid19 has been given Hydroxychloroquine. At the hospital I work at Hydroxychloroquine has been the standard treatment for the past 6 weeks. Hydroxychloroquine is part of the pre-approved admission orders on the electronic medical records. As the admitting physician you have to go out of your way to NOT give them Hydroxychloroquine. And think of the rest of the hospitals in the country. Someone gets admitted for Covid19 and they DON’T get Hydroxychloroquine? Are you kidding me? Can you imagine the anger that the son, daughter, niece, nephew, brother, sister will have at that? They will explode with rage! Explode at the nurses, explode at the doctors. Explode at the administration,. They will also do something that strikes the fear of God in every hospital CEO’s heart. They will get on the internet and tell everyone, I mean everyone, how terrible that hospital is. You bet they are all given Hydroxychloroquine. And contrary to general physicians, all of these hospitals had first access to obtaining Hydroxychloroquine from suppliers. So, why do we still have coronavirus deaths? Huh?

      Better think again Rick Rude. Or are you one of those conspiracy theorist who believes that the medical profession would risk the lives of their small children, parents, spouse and grandparents just to make more money? Every doctor keeps this wonderful secret about how Hydroxychlorquine is the best, but just won’t use it because if they used it, they would make less money.

  31. Daniel Barkalow says:

    I think it would be worth doing a trial of remdesivir for people who are contacts of someone who tested positive (primary endpoint: lower portion of these contacts subsequently test positive). Obviously would take a lot more remdesivir as a treatment, and you’d have to be more sure of the safety, but it could help a lot to limit outbreaks if it worked. And it would give people a personal benefit to participating in contact tracing.

    1. Grigoriy says:

      Yes, it is really strange, that the drug is not considered to be used along the lines of chemoprophylaxis. It could protect most vulnerable contacts, like relatives of infected persons, and also, e.g., healthcare providers in ICU units/EDs. Is it worse, than moAbs/passive immunization? Why? Very short duration of protection? But seems still cheaper to mass produce, and in any case already available.

  32. Toni says:

    Maybe a potential “gamechanger”: RNAi
    Strangely enough, little attention is paid to this technique in the context of COVID19 , at least when compared to the last major Ebola epidemic, during which Tekmira Pharmaceuticals in particular was the focus of attention for several weeks.

    So far, not many companies have come up with an RNAi project for COVID19.
    A certain “disinterest” could also be related to the fact that RNAi is not exactly predestined for the lungs. However, the question is whether it will not be possible to transport RNA to the site of action by inhalation. In fact, as early as the SARS outbreak, a company (Sirnaomics) published results on the effectiveness of RNAi in a monkey model of the SARS coronavirus. Unfortunately, the results were not so exhilarating at the time.

    In the meantime, however, RNAi therapeutics are much more advanced and an approach using inhalable nucleic acids seems to actually work well in some models. (e.g. Arrowhead’s cyctic fibrosis Project)
    Here is an announcement from Alnylam: https://www.pharmashots.com/32498/vir-and-alnylam-anticipate-the-initi…..-year-end/

  33. Bill B says:

    I don’t think I’ve seen a mention here of Derek’s appearance on WNYC’s “On the Media” podcast titled “Waiting For a Game-Changer”, a segment about remdesivir :
    https://www.wnycstudios.org/podcasts/otm/episodes/finding-covid-panacea-easier-said-done-on-the-media

  34. Joe B says:

    I’m not a chemist or a doctor, but I applaud the information in this blog as well as the scientific conversation in these comments, it leaves one feeling more educated than the political nonsense, lacking data or having bias that’s readily available throughout the media and internet.
    I’m curious to the doctors and medical researchers who may read this, are the clinical trials coming to combine drugs for true efficacy?
    From the data and evidence I’ve come across personally it seems like the multi drug approach with existing compounds is the key.
    It’s already becoming widely regarded as a life saving measure to use supplemental oxygen and prone positioning to increase lung capacity and bring blood oxygen levels back up sharply in order to avoid potentially lethal intubation.
    It’s interesting to see how a couple of anti-virals are showing decent efficacy at reducing viral load and clearing the virus independently, the two most notable in my opinion are Remdesivir and avigan. Also notably that inflammatory immune response through IL-6 is causing cytokine storms and damaging lungs and other organs further progressing patients toward death.
    What would the potential outcome be of combining prone positioning and supplemental oxygen to support respiratory function, while using a 3 legged approach to drug therapy, combining Remdesivir and avigan to reduce and clear the virus, while also adding in IL-6 blocking actemra to reduce the cytokine storm and get the overactive immune response in check?
    I know I’d like to see not only a clinical trial using this combination of technique and drug therapy, but would also be extremely curious of the “anecdotal” evidence that could come on a case by case basis using these combinations on the absolute effect of preventing death vs intubation or one drug therapeutic efforts.

  35. Joe Psycho says:

    I thought remdesivir was the best candidate for treatment and/or prophylaxis in February and it is still what I would recommend more research on it especially in combination with low dose hydroxychloroquine (400mg/day total max) and/or favipravir

    And I also think that bioavailability studies should be done with remdesivir to see if intramuscular or subcutaneous administration is possible for treatment.
    If anyone has data related to remdesivir bioavailability studies it would be extremely helpful if you could share the results in a reply to this comment.

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