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Coronavirus Therapy Update (Remdesivir and Tocilizumab)

Let’s circle back to remdesivir. We already have the results of the remdesivir Phase II trial that led to its Emergency Use Authorization by the FDA. But now come the first Phase III results, and it’s safe to say that they’re not making anyone happier. The news isn’t bad, but you can’t say it’s particularly good, either.

This was an open-label randomized trial comparing a 5-day course of the drug with a 10-day course. It’s important to note up front that there was no control standard-of-care group, which makes interpretation of efficacy impossible – it pretty much always makes such interpretation impossible (with real-world effect sizes, anyway), which is why you probably shouldn’t run uncontrolled trials unless there seems to be no good alternative. And in this case, the trial was run (earlier this year) in this fashion partly because there were no matched placebo vials available and because getting people out of the hospital and making space for new patients was a priority. There are no viral load figures available, either, because of the variability in the testing (and testing capacity) across the different trial sites at the time.

Using data from about 200 patients in each group, there appeared to be no statistically significant difference in outcomes between 5-day and 10-day treatment. These outcomes include relatively easier-to-measure things like time to improvement, clinical status at day 14 after treatment, recovery and hospital discharge, death, and so on. If you want to talk nonsignificant trends, then the 5-day course of treatment actually looked a bit better, but there are possible reasons for that: more males in the 10-day group and more patients on the more severe end of the disease. So I wouldn’t say that 5-day treatment is superior, but this study does point to 10-day treatment not being superior.

This means that (to date) we have only two controlled clinical studies of the drug (The early “compassionate use” report was uncontrolled and at this point really adds nothing to our understanding). There’s the one in China that was stopped early due to declining enrollment, and that one did not show any difference between the treatment and placebo groups. But the problem is, given the number of patients it ended up with, it wasn’t even powered to show such a difference. Then there’s the NIAID study, the first link in the first paragraph above, which found that 10-day treatment was superior to placebo when you measure for time-to-recovery. The authors of this new paper suggest that their results could mean that a 5-day treatment might then show the same thing (which would have the side benefit of not using up so much remdesivir).

But this work just underscores something that I wish that the general public would take on board: remdesivir is not a cure. Not even close. We don’t have a cure for this disease yet. Remdesivir appears to be better than nothing – if I or someone I knew were in the hospital with the coronavirus, I would expect it as standard of care, and be glad that it was available, but I would not expect it to do anything dramatic. It appears to get people out of the hospital faster – a bit faster – compared to people who don’t get it. No bad thing, not at all, but not what we all want from a therapy, either. I would also definitely consider famotidine. It’s not that we have a lot of solid efficacy data yet, but there is some reason to believe that it helps, and it has an excellent safety profile so on balance I’d say go ahead. You take what you can get, and right now I think that’s pretty much what we can get.

Just this morning, though, comes word of another potential therapy for patients who are in trouble with the “cytokine storm” immune response. In late April we had some early data from France that the anti IL-6 antibody tocilizumab might help with that situation, but now there are some more solid numbers. This is from the University of Michigan system, a controlled observational study with 154 intubated patients, 78 of whom received tocilizumab. It has to be said that the treatment group was slightly younger and slightly less likely to have underlying pulmonary disease, so the results should probably be trimmed down a bit. But the results were good: 45% lower likelihood of death (the preprint’s Figure 2). The secondary endpoint of the trial was assessment on a 6-point disease severity scale, and the treatment group looks better on that one, too (the preprint’s Figure 3A)

There are other things to keep in mind, of course. Knocking down IL-6 activity would be expected to increase the risk of infection in general, and so it proved: the treatment group was twice as likely to develop a further lung infection, generally bacterial pneumonia due to S. aureus. That’s not good, but the time to discharge and fatality rates did not really differ between those who came down with this superinfection versus those who didn’t (and for that we can thank modern antibiotics – since I experienced bacterial pneumonia personally a few years ago, I am very mindful of them!) So this course of therapy is not without complications, but in the end, it definitely appears to have a real benefit.

The hope, then, is that early remdesivir treatment might decrease a patient’s chances of ending up in such bad shape to start with, and that tocilizumab might be the thing to give if things head that way. As with all these bimodal treatment regimes, figuring out when to switch gears will be crucial. But it’s very good to see that there’s something we can do about the cytokine storm, and I look forward to more studies of this kind reading out.

Looking for something even better, are you? Who isn’t? In the next post (probably tomorrow) we’ll look at the latest news on the things that are really going to get us out of this mess: antibodies and vaccines.

37 comments on “Coronavirus Therapy Update (Remdesivir and Tocilizumab)”

  1. spellcheck says:

    @Derek typo in first sentence just FYI:

    “Let’s circule back to remdesivir.”

  2. steve says:

    Remdesivir is like Tamiflu – small but real effect and needs to be used early in the course of the disease. Given that it’s delivered IV that is problematic. Anyone know what’s going on with favipiravir or camostat? We need an oral antiviral like one of those that can be used early by people without needing hospitalization.

    1. David Young MD says:

      Just what I have been saying for the past 6 weeks (and not just me). There is every reason to believe that Remdesivir, when started within a couple days of the onset of symptoms would make a remarkable difference in the outcomes of Covid19 patients. In a sense, it seems remarkable that there would be any difference in these studies where they are waiting 6 or 7 days to start Remdesivir.

      And then there is Favirpiravir (and to a lesser extent EIDD-2801). There are precious few studies on Favirpiravir, but Stanford has one open (and a few other places). It seems to be highly logical to combine Remdesivir and Favirpiravir for early disease. Give Remdesivir 200 mg on day one and 100 mg on days 2 and 3. Start Favi on day 1 or 2 and extend this oral drug for 8 days. The combination may be clean, safe and highly effective. But will it be tested in comparison to placebo?

      I have emailed Gilead twice now, begging them to consider his combination. It is not the sort of thing that a pharmaceutical company would consider, or even think of. For the NIH, I think that they are incapable of thinking of a combination like that. But the combination could be very effective.

      If anyone else feels the same, you can email Gilead. Here is one address:

      GileadClinicalTrials@Gilead.com

      You will get a response from someone who screens the emails. I just hope that my missive will arrive on the computer of a person who can understand.

    2. wubbles says:

      Then go out, find the infected, bring them into hospital, and start them on the drug. It’s hard, but it’s the best we can do to avoid them dying.

  3. JasonP says:

    Great stuff as always Derek! Really appreciate your trained eye and skilled translation of the deeply technical stuff so I don’t have to wander deep into the weeds! Much appreciated!!!

    Now as to this paragraph…..

    >>>>But this work just underscores something that I wish that the general public would take on board: remdesivir is not a cure. Not even close. We don’t have a cure for this disease yet. Remdesivir appears to be better than nothing – if I or someone I knew were in the hospital with the coronavirus, I would expect it as standard of care, and be glad that it was available, but I would not expect it to do anything dramatic. It appears to get people out of the hospital faster – a bit faster – compared to people who don’t get it. No bad thing, not at all, but not what we all want from a therapy, either. I would also definitely consider famotidine. It’s not that we have a lot of solid efficacy data yet, but there is some reason to believe that it helps, and it has an excellent safety profile so on balance I’d say go ahead. You take what you can get, and right now I think that’s pretty much what we can get.<<<<

    I agree, remdesivir is not a cure. But I appreciate the acknowledgement that, given at the right time, it has some efficacy or helps a bit. Sans a cure, I think Docs are using any tool in the tool box to help. So remdesivir gives a bit of help here, famotidine a bit of help there. Perhaps the third rail of this blog a bit of help too? Seems like each tool has a place or time where it can help, not cure the disease, but lessen the effects or shorten the time frame. From this chair, that is a good thing.

    But that creates a push-pull doesn't it? Pure research scientist are going to push back that because of no Gold Standard, statistically significant result, it isn't a cure. Ok, it isn't. Then there seems to be a line of thought that anything that is not a "cure" is a waste of resources or unethical or side effects ( what doesn't have side effects?) or whatever and thus should be discarded. So it is refreshing to see this blog pivot and agree that something "helps" and going in that direction, until we have a cure, immunity, etc. is a good thing.

    I am a bit saddened with what appears to be a"toss the baby out with the bath water" view opined my more than a few here. I get that we can't hold remdesivir (or others) up as a cure. But to bash them as totally ineffective? Look in a war, you can take orders from the book learned generals (researchers) or one can learn from the sergeants on the front line (Hospitalists. Docs). The best example is Col Hackworth and how he ran essentially "root cause analysis" with his troops after a battle. By doing that he adapted and adjusted to the realities in the field and greatly reduced his fatality ratio. So why not the same approach here in this "war" with SARS-COV-2? Why isn't adjusting and adapting even if it is
    "anecdotal" or retrospective studies. It is the best we have and probably more efficacy than standard of care. Maybe this thinking gets ingrained with years of shooting for the blockbuster? Something only has a partial effect, Bah! (But hey how did 2 drugs get approved for ALZ treatment when they aren't "a cure?")

    Oh and while I'm on the soapbox….for those who deride retrospective studies, do they have the same disdain for the whole field of epidemiology?

    Anyway, thanks Derek for the post, for tolerating those of us without the advanced knowledge, but still interested and wanting to learn!

    1. zero says:

      You’re making somewhat vague references to a stance and then attacking it, which looks like a classic strawman approach. You’re following up with allegories or parallels from an unrelated field which includes a subtle jab at researchers. It would be easy to categorize your comments as rhetoric that pattern-matches politicized news sources like Fox and dismiss them (and you) as irrelevant.

      Why not say “The evidence does not support statements made by marketing departments or a certain strident French researcher, but it does support the decision to use these compounds as the current standard of care”?

      This isn’t a ‘both sides’ situation, this is a group of people (doctors, researchers) communicating in technical terms that another group of people (publicists, commentators, journalists, the general public) misrepresent or misinterpret, intentionally or otherwise.

      These drugs are only *almost* totally ineffective. Which is better than nothing, but do patients really understand the risks they’re taking for the chance that they might be one of the lucky one in 20 (or 300 or 1000) who benefits significantly?

      “But hey how did 2 drugs get approved for ALZ treatment when they aren’t “a cure?””
      Because it was a political decision with a lot of money involved, not to mention astroturfing by industry-supported patient advocate groups (much like DMD). It is difficult to overstate the influence the current administration holds over anything that could be spun into positive press. The drugs in question aren’t causing serious cardiac side effects and generally seem not to do much at all (whether positive or negative), so it’s a low-risk decision by the FDA even if it wasn’t the best decision for patients.

  4. SaneAnalysis says:

    The really quite nominal value of Remdesivir that can be inferred so far would not pass muster for approval in normal times.

    And, honestly, if I had a loved one with Coronavirus, I’d opt for HCQ/Zn/antibiotic over Remdesivir. Validation data for that regimen is also flawed, but those using it in the field, at least, asset greater effect and the components are better qualified for safety in humans. (Not to mention it’s all effectively free).

    (NB: The Lancet article is in dispute, and the Veteran’s data was based on late-stage patients not treated with Zn).

  5. steve says:

    “…those using it in the field…” Hence the need for clinical trials, which so far have shown the toxicity far outweighs the efficacy. Medical history is littered with “those in the field” who were convinced they were doing good only to find out they were doing harm, starting way back to blood letting to hormone replacement (countless breast cancers induced), to high dose chemo with BMT (thousands of women injured and killed with no benefit) all the way forward to today. You can always tell when a hypothesis like HCQ is BS. First HCQ is a wonder drug for COVID, then it has to be used in combination with azithromycin, then never mind it’s really zinc, etc, etc. Citing anecdotal and anonymous evidence from “those using it in the field” just doesn’t cut it.

    1. JasonP says:

      Oh my the old “blood letting” counter-argument. Sigh.

      So I’ll toss it right back at you…. SOURCES for the toxiticity?

      So what is your suggested treatment regime or do we just hold patients hands and hope they get better?

      No one is saying remdesivir is a wonder drug, a cure and the same for HCQ. Just that they appear to have some effect, use at the right time and with the right patients.

      But you are correct, a CURE, needs to be proven by CTs. In the mean time….

  6. SteveM says:

    Russia has approved an anti-influenza drug, Avifavir, to treat Covid-19 and will start delivering it to hospitals this month:

    https://www.cnbc.com/2020/06/01/russia-approves-drug-to-treat-covid-19-hospitals-to-use-in-june.html

    Suggest watching the embedded video for more details from the developer.

    I am dispassionately reporting the status of this clinical research. Unfortunately, the politicization of science has become so pathological, the now normative Russia Hate will probably deep six reporting on this work no matter how beneficial or legitimate.

    1. steve says:

      According to the article it’s a favipavir knock-off. Why not go with favipavir itself which has already been approved and therefore we know its safety profile?

    2. Nat says:

      Pro tip: ending your comment with self-pitying drivel about “the sheeple will never accept this” or “I’ll probably get modded down for this” is a good way to make the rest of us ignore whatever else you have to say, whether or not we agreed with any of it. Don’t want science to be politicized? Then stop politicizing everything.

    3. cynical1 says:

      According to Wikipedia, it’s not a favirpiravir knock-off. It IS favirpiravir.

  7. David Young MD says:

    By the way, Gilead is going to get into the idea of treating Covid19 patients early. They are considering an nebulized form of Remdesivir, which obviates the need for an intravenous line. That study may be a few weeks off, or a few months.

    I still think they should consider a combination with Favirpiravir.

    Or, if Merck can accelerate the development of Emory’s / Ridgeback’s investigational drug EIDD-2801 then maybe a combination there (since it is also oral).

    The one nice thing about Tocilizumab is that it is on the market. So are two other anti-IL6 monoclonal antibodies. No need for FDA approval. You get your shot in the hospital and the payment all goes under a DRG. FDA approval does not help the hospital one bit in terms of the cost. (for out patient… well, that’s a whole other story).

    The hospitals, of course, are going to lose big here.

    1. Philip says:

      Mannkind’s Technosphere as a delivery mechanism?

  8. Nebul says:

    Gilead is studying how its existing IV formulation of remdesivir can be diluted for use with a nebulizer – a drug delivery device used to administer medication in the form of a mist inhaled into the lungs.

  9. Philip says:

    I would really like to see a study of remdesivir given very early. The only place I know to find test subjects would be places where testing is done daily, or almost daily. I am thinking the White House, meat packing facilities, some health care facilities and a few factories. I don’t care too much for antiviral studies where the viral load is already decreasing.

    Why tocilizumab over siltuximab? Same result, but different mechanisms. I would like to see a comparative study.

    Now I am going way over my head. Would a drug like ozanimod or fingolimod be effective at calming the adaptive immune system that would work for COVID-19? If so their shorter half life may be an advantage?

    1. David Young MD says:

      What would you say, Philip… limited participants to within 2 days of onset of symptoms, or 3 days? I could see including those within 3 days. It would be important to start therapy (or placebo) right away. Even the same day that the consent is signed, I mean… the very day that they come in to get tested. That might allow the antivirals to work the best.

      1. Philip says:

        I would want to start an antiviral no later than the day after they first test positive. I am looking to see if given the best chance of working, if the antiviral really does work. If the placebo controlled, double blind study shows that the antiviral works, do an open label study to see how soon you have to give the drug and base that on testing and onset of symptoms.

      2. Thomas says:

        But it would make a rather unusable drug, given the symptoms and how treatment is usually started.
        And also make the test hard, because you need those early-tested people to sign up for the controlled trial.

        1. Philip says:

          Not an unusable drug, a not yet proven usable drug. I am not an expert at drug study design, but that is not going to stop me at this time. Those with more experience, please step in to correct my mistakes and make suggestions.

          All studies should have a question they are trying to answer. For this placebo controlled double blind study, the question is does remdesivir or any antiviral work if given very early in the infection. The hypothesis being that in COVID-19, as with other virus caused dieases, for an antiviral to be effective it must be given early. If an antiviral given early is not effective, there is no reason to continue with any testing. If it is effective more testing is warranted.

          To answer the question the subjects would have to be in a place where very frequent testing was ongoing. As stated in an earlier post, the White House, meat packing facilities, some health care facilities and a few factories would meet this criteria. You would sign up those being frequently tested before they test positive. When a person turns positive they would be randomly placed in a control arm or a drug arm of the study (to be more efficient, multiple drug arms could use the same control arm). The primary end point is the patient dies or goes 28 days without symptoms. A secondary measure would be the number of hospitalizations. If there is NOT a significant improvement in deaths, stop any further testing. Stopping ongoing studies is very important. It conserves resources, including study patients.

          If a drug is proven safe and effective, a second study can be set up to see how far after a positive test or onset of symptoms the drug is effective. Here is where I would take big short cut. Run an open label study where all patients receive the drug, but it is started at different times after a frequent tested person turns positive or some number of days after symptom onset. If the first study was a “game changer”, you would should not delay treatment, the delays would have to occur from the patient not trying to get treatment earlier.

          If a safe and effective drug is found, TETRIS would need to be ramped up to be sufficient to catch most people in time for the treatment to work. That is how flattening can be used to reduce the area under the curve without a vaccine.

  10. Todd says:

    Remdesivir and tocilizumab are not cures, but they are tools that combined with Pepcid and anti-coagulants which can piece things along until we get the antibodies and vaccines together. Considering where we were in March, if this isn’t an improvement, I don’t know what is. Throw in the public health efforts with test and trace, and we’re getting somewhere. That will also encourage the powers that be to get things right with the vaccines and antibodies before getting it to the public. Not an ideal solution, but definitive progress.

    1. Philip says:

      Flattening the curve may have reduced the area under the curve, even without a vaccine. We are getting better at treatments. As more studies are completed, we should improve treatments.

      For remdesivir to be effective we are going to need a lot more TETRIS*. If we can do that, we could really reduce the area under the curve, and not have to kill the economy in the process.

      So lets get TETRIS going and the economy open and save a bunch of lives.

      * TETRIS is TEsting, TRacing and ISolation, thanks TWiV

  11. steve says:

    But they didn’t add azithromycin! No zinc! They forgot to include the kitchen sink! Maybe they need to try it at a different latitude than Minnesota! I’m sure we’ll hear all of that to explain today’s results from UMinn showing yet again that HCQ does squat for COVID. https://tinyurl.com/y8n4dlxr

    1. Edward R says:

      Steve,

      Did you read the NEJM study you linked above?

      They self-administered 1400mg of HCQ within the first 8 hours then took a further 600mg per day over the next 4 days.

      According to the study the successful internet applicants then self-reported any common covid symptoms back over the following days. If two or more SYMPTOMS were reported (ie. headache and diahrea) then the study concluded they had covid.

      My problem with this particular study is that those 2 above symptoms are also known and extremely common side effects of merely taking HCQ.

      How can we know the difference?

      1. OC says:

        Exactly. PCR Positive test result or the study is WORTHLESS given confounders on self reported symptoms. Also what about asymptomatic infections which are VERY common in young people (circa 50% according to the result from the USS Theodore Roosevelt?

        I find it truly depressing that the richest, most powerful nation on earth can’t figure out how to test all healthcare workers who 1) have had exposure to COVID-19 AND 2) report symptoms of COVID-19 AND 3) ARE IN A CLINICAL TRIAL TO DETERMINE THE EFFICACY OF HCQ AS A PROPHYLACTIC AGAINST COVID-19!

  12. dearieme says:

    May I suggest a topic, Derek?

    How does one test tests? In other words, when someone says his test is 99% accurate, or whatever, how does he know? I ask not so much in general but in the context of the present pandemic.

  13. Walter Sobchak says:

    “Coronavirus: Ibuprofen tested as a treatment” By Michelle Roberts Health editor, BBC News online | 3 June 2020 | https://www.bbc.com/news/health-52894638

    “Scientists are running a trial to see if ibuprofen can help hospital patients who are sick with coronavirus. The team from London’s Guy’s and St Thomas’ hospital and King’s College believe the drug, which is an anti-inflammatory as well as a painkiller, could treat breathing difficulties. They hope the low-cost treatment can keep patients off ventilators.

    “In the trial, called Liberate, half of the patients will receive ibuprofen in addition to usual care. The trial will use a special formulation of ibuprofen rather than the regular tablets that people might usually buy. Some people already take this lipid capsule form of the drug for conditions like arthritis.

    “Studies in animals suggest it might treat acute respiratory distress syndrome – one of the complications of severe coronavirus.

    “Prof Mitul Mehta, one of the team at King’s College London, said: “We need to do a trial to show that the evidence actually matches what we expect to happen.”

    1. Charles H. says:

      And as a added benefit, ibuprofen is a blood thinner. Not a strong one, admittedly, but strong enough that I was asked to discontinue use a week before surgery.

      1. Walter Sobchak says:

        My brother, the retired pulmonologist, tells me his colleagues who are treating COVID patients are using blood thinners early and often. They have observed many COVID patients have suffered from problems related to blood clots in their lungs.

  14. RA says:

    Thanks for a great post!

    My guess is that any antiviral will not make a huge difference, but I agree with many commenters that it would be better to study any potential anti-viral as early in the course of the illness as possible.

    But even though Remdesivir is an IV med, why is it only being considered in the hospital environment? Many nursing homes can give IV meds. Outpatient infusion centers can give IV meds. Even home care companies can do IV infusions in the home. If Remdesivir only needs to be dosed once a day and doesn’t have a particularly bad side effect profile, wondering if there are other options besides hospital settings to study/give it to patients?

    1. Diane says:

      I work in an oncology infusion center and before that a mixed oncology/non-onc infusion center. Both places were/are full and we have chronic staffing shortages.

      Just about everyone receiving an infusion is immunocompromised.

      So, no extra chairs/nurses for additional patients in the numbers we would could expect, plus we would be exposing the current (Immunocompromised) patients to a highly contagious disease.

      The logistics of early-infection administration of IV Remdesivir would be a a lot, including getting people who feel only mildly unwell to think of calling their doctor.

      1. RA says:

        Good point…you definitely would not want to mix the immunocompromised (or any non-infected patients in the with covid patients) in the same indoor space…but we could have COVID only infusion centers…there is a ton of outpatient medical real estate currently sitting dormant that could be repurposed….doing an IV infusion doesn’t take a ton of equipment.

        If society can figure out a way to have mobile vans that go around giving IV infusions to paying customers with hangovers after a night of hard drinking, we can figure out a way to give Remdesivir outside the hospital setting…at first for a research study, and then if effective, on a more widespread basis.

        The mild symptoms issue is important…good research would help us figure out who could benefit from this the most…I would think those who are at the highest risk…the elderly, those with chronic conditions, etc would be the most likely patients for whom the hassle would be worth it.

  15. loupgarous says:

    The jungle telegraph is madly efficient today – famotidine, either brand-name (Pepcid) or generic, is gone from the dollar store shelves today in our sleepy little coast town.

    Fortunately, our Walgreens has plenty. I’ve been advised to go over to Pepcid because it doesn’t interfere with the action of my new chemo drugs as much as pantoprazole. This isn’t a panic move to something that may have worked well out in Wuhan for COVID-19.

  16. Carla Ellingsen says:

    Tocilizumab helped my father greatly (70 years old man). He received 3 doses around 3 am, and 30 hours after he was out of intensive care. It was a real miracle for our family.

  17. SALEH says:

    Etude Pirnay (Pirnay trial) HCQ-AZITHRO old and very old patients

    https://reader.elsevier.com/reader/sd/pii/S2211104220300771?token=FD28A2440C4E215A86D60545A4427765BAE945753C4135DAFE5073867AA0EE2BB0F8887FA56C14A7197E0E8403DBE02F

    Interesting new observational French trial of old and very old persons living in nursing home (the first of its kind).
    The trial includes 68 residents with a medium age of 86 years, early treated with HCQ –Azithro within 2.5 days of onset of symptoms (Raoult protocol)
    Cardiac tolerance : 2 QTC prolongation (treatement stopped)
    Only 7 (10.3%) died within the experimental periode (same as median mortality for the same periode in 2019, 2018)
    By comparison the median « above everage » over- mortality in old peaple homes in France during the same periode due to COVID is 20-30% . The real delta here is then around 10 versus 30-40%.
    Even if it is not an RCT, still this delta is still amasing
    It is the first trial of its kind

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