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What Do the New Remdesivir Data Mean?

A report has come out in the NEJM on the experience with “compassionate use” (off-label or not yet approved) of the Gilead drug remdesivir in the Covid-19 epidemic. Here are the inclusion criteria:

Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.

Presented are data from 53 patients in the US, Canada, Europe, and Japan. They were in bad shape – 30 of them were on ventilators and 4 were receiving ECMO treatment (blood oxygenation outside the lungs). At the time of the manuscript’s preparation, 25 patients had been discharged from the hospital, and 7 had died (6 of whom had been on ventilation). Overall, clinical improvement was seen in 36 of the 53 patients.

That’s pretty much it – those are the numbers we have. The study did not even collect viral-load data, so we can’t say what that was like or if it correlated with clinical outcome. What do they tell us? Not much, because this (like so many others early in this epidemic) is not a controlled study. What if you had a list of patients of similar age and gender and pre-existing conditions in similar shape, and didn’t give them remdesivir, but just standard-of-care without it? We have just described an appropriate control group, and you can see why you’d want one in order to say anything useful. To be honest, those outcomes sound not unlike what you might expect from treatment without remdesivir, but who knows? Needless to say, you would also want to look at this in a lot more than 53 patients to be sure. It’s effect size again: no one expects remdesivir to have miraculous get-up-and-walk effects; what effects it does have are going to be more subtle. And that means you’re going to have to have a sufficiently powered (i.e. larger and well-controlled) study to see them.

The authors themselves know this well, of course, and they make no claims. Comparing the 28-day mortality in this study to others, it might be a bit better, but as the paper concludes, “Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy.” At the moment it is literally impossible to say. If you’d like more detailed reasons why this is so, I can recommend this analysis (hat tip to Bruce Booth on Twitter). I’m aware that that author’s last objection is that “big pharma” was involved, which (like Bruce) I’ll let slide for now, only noting that Big Pharma and Big Biotech and Big Whoever are going to be the only things that are going to provide new treatments for this disease at all, so get braced for that, is my advice.

And here is an open letter from Gilead’s CEO, Daniel O’Day. Some excerpts:

Remdesivir is an investigational treatment and has not been approved for use anywhere in the world. In the broader efforts to determine whether it is a safe and effective treatment, we have some way to go. . .In studying remdesivir, the question is not just whether it is safe and effective against COVID-19 but in which patients it shows activity, how long should they receive treatment and at what stage of their disease would treatment be most beneficial. Many answers are needed, which is why we need multiple types of studies involving many types of patients. Some of these answers will start to emerge in the coming weeks as we receive the first data from the various clinical trials underway.

It goes on to give brief details of seven of those trials, the first of which will read out preliminary data around the end of April. Note how there is nothing in there about how it would be somehow unethical not to give remdesivir to everyone, how there is nothing in there about how controlled trials are a waste of time, etc. I refer, of course, to the statements of Dr. Didier Raoult on his hydroxychloroquine/azithromycin combination. Put those claims next to O’Day’s for a quick lesson in what someone trustworthy says about an investigational drug.

Note: The next post this morning will take us back into the hydroxychloroquine world. . .

47 comments on “What Do the New Remdesivir Data Mean?”

  1. ghost of q.mensch says:

    “Put those claims next to O’Day’s for a quick lesson in what someone trustworthy says about an investigational drug.”

    I would trust the CEO of a company that markets a HepC drug for $1000/pill, $85K /treatment course about as far as i trust Martin Shkreli, who coincidentally also has lots of new ideas about Covid cures.
    https://thehill.com/policy/healthcare/491536-shkreli-seeks-prison-release-to-conduct-research-for-coronavirus-cure

    1. Derek Lowe says:

      The price of Gilead’s drugs means that their data are unreliable? That seems to be a non sequitar. . .

    2. Aleksei Besogonov says:

      There’s a reason Gilead can charge $85k for a treatment. It’s because it works.

      1. ghost of q.mensch says:

        Shkreli was a small-time pharma price gouger who bought the rights to pyrimethamine, an old antiparasitic drug with re-purposed applications in tx of AIDS pneumonia; and raised previous $14/pill cost–>$750/pill.
         
        Gilead is top 10 (annual rank varies btwn #7-15) pharma price gouger with an army of excellent lawyers who somehow secured original patents, based ion  preexisting active key  PROTIDE  (ie nucleoTIDE PROdrug) IP, (Cardiff Univ 1990’s https://en.wikipedia.org/wiki/Protide ) which they incorporate both in their  $1000-1750/pill sofosbuvir HepC products, ANDin  investigational remdesivir (REM) discussed here.
         
        Any guesses how much Gilead would be marketing a new lifesaving covid- REM pills for if they get ever get approvals based upon the combined creative efforts of their  50+ study design doctors  https://emcrit.org/pulmcrit/pulmcrit-eleven-reasons-the-nejm-paper-on-remdesivir-reveals-nothing/  ,lawyers and regulatory affairs departments?

        Putting aside the the rest of the world for the moment, how many in the US (average personal per capita income  <$45K/yr ) could  ever afford  any new Gilead pill for covid?

        Don't you think that is relevant?

        1. ghost of q.mensch says:

          Two Clarifications/additions:
          1.  Per pill retail sofosbuvir price estimates were based upon information cited in the “sofosbuvir” Wikipedia entry for proprietary forms in the USA.

          2. Gilead had applied for and had just received approval  from FDA this March  for  “orphan drug (ie RARE disease)”  status for Remdesivir in covid , which provides extended patent protections (my understanding that certain other countries’s drug regulatory agencies  also extend favorable tax treatments to ‘orphan drug’  awardees operating within their jurisdictions).

          https://www.biopharmadive.com/news/coronavirus-gilead-remdesivir-orphan-drug/574882/ 

          This is for a drug they already had ” in the can” for Ebola an Marburg,  with safety/Phase I+ studies done  in 2013-2016, with most costs  probably already supported/paid for by the DOD (and you and me).

          Evidently, the behind the scenes outrage erupting over Gilead applicant finagling/gaming a “rare disease” status for remdesivir/covid was sufficient to shame even Gilead top brass, so they quietly backed out from the award. 

        2. Retiarius says:

          McGuigan’s academic breakthroughs involving prodrug research date from 1992. If this was patented, a 20-year patent life brings that to 2012. Sobofusivir received FDA approval in 2013. Further, it’s clear that Professor Michael Sofia had something to do with Sofosbuvir as it was named after him. Academics do built upon the work of other academics, so there is nothing subversive about that.

          1. ghost of q.mensch says:

            Interesting that those excellent Gilead patent lawyers waited until the Cardiff IP protection had just expired…

            Quoting from https://en.wikipedia.org/wiki/Sofosbuvir entry once again:

            “Patent challenges
            In February 2015 it was reported[72] that Doctors of the World had submitted an objection to Gilead’s patent[73] at the European Patent Office claiming that the structure of sofosbuvir is based on already known molecules.[74] In particular, Doctors of the World argue that the Protide technology powering sofosbuvir has been previously invented by the McGuigan team at Cardiff University in the UK, and that the Gilead drug is not therefore inventive.[75][76] The group filed challenges in other developing world countries as well.[77]”

            Remdesivir (REM) uses the same PROTIDE IP. But according to the study reported by NEJM, REM was (must be?} administered by IV infusion to pts.

      2. cwp says:

        doesn’t matter if it works or not, there is never, EVER a reason for a drug to cost that much…ever

        1. Retiarius says:

          The cost of Gilead’s HCV treatment has always been far less than the cost of a liver transplant, which can be upwards of $500K. It was also competitive with the previous standard-of-care, interferon+ribavirin, which had worse efficacy and side effects. The $1000 a pill thing was bad optics, but what it really exposed was the horrid relative cost of hospitalization, the greed of the middlemen (pharmacy benefit managers), cashflow problems when a near-perfect cure happens suddenly, the shrillness of lobbyists for the competition and grandstanding politicians, etc.

      3. Retiarius says:

        The price of Gilead’s HCV treatment is now down to $24K, since they are competing with Abbott and even themselves. See: https://www.fiercepharma.com/pharma/gilead-s-authorized-hcv-generics-now-own-over-20-market
        Further, the cost of Gilead’s drugs have always been on a sliding scale on a country-by-country basis. Like many drug companies Gilead has programs to help subsidize treatment for the poor, even in the U.S.

      4. Jason> says:

        “There’s a reason Gilead can charge $85k for a treatment. It’s because it works.”

        Exactly! It sure beats the price of a liver transplant.

      5. Nota Bene says:

        “There’s a reason Gilead can charge $85k for a treatment. It’s because it works.”

        …just like remdesivir worked for ebola?

        1. Derek Lowe says:

          Non sequitar. Remdesivir was tested in trials for Ebola, and was not effective. Gilead’s Hep C combination was tested in trials, found to work extremely well, and was approved by the FDA. Insurance companies are willing to pay for it to forestall paying even more as the disease progresses.

    3. loupgarous says:

      ghost of q.mensch:

      “I would trust the CEO of a company that markets a HepC drug for $1000/pill, $85K /treatment course about as far as i trust Martin Shkreli, who coincidentally also has lots of new ideas about Covid cures.”

      Mr. O’Day’s statement made no extraordinary claims of therapeutic value for remdesivir at all. A reasonable observer would question his veracity only if he’d made claims for remdesivir based on questionable evidence. Nothing Mr. O’Day said could be taken as promotion of any product of his firm. He has stated repeatedly that more studies of remdesivir are needed before any decision can be made regarding its use.

      Mr. O’Day, unlike Martin Shkreli, is a free man and the CEO of a major pharmaceutical company with considerable experience in management of another major pharmaceutical company. No analogies can be drawn between the two men. His firm’s decision on pricing of their hepatitis cure reflects their assessment of its value on the pharmaceutical market. If it costs too much, a free market will drive that point home.

    4. Joe says:

      The data reported by the NEJM looks reasonably good. Patients so ill they require ventilation have a survival rate of less than 33%. In NYC, Gov. Cuomo claimed survival rates for patients on mechanical ventilators was only 20%. But here, we have 30 very ill patients on ventilators and 17 — or 57% – improved enough to be extubated. The full NEJM study says only 18% of the patients on ventilators or ECMO’s had died at the end of the study period, implying some were still alive and on ventilators when the study ended. Randomized trials still needed, but these results seem positive.

  2. Pricing aside Gilead’s science is usually pretty legit

  3. Kevin says:

    In defense of the PumlCrit commentary’s final point, he raised some reasonable points about how Gilead’s involvement could have impacted the study (although I think they do good science and have been responsible in the language they’ve used). It wasn’t just big pharma fear-mongering (and he didn’t say “Big Pharma”).

    In a situation like this, why is Gilead pushing out a paper like this when they have RCTs running and can’t meet demand for the drug already?

    1. Derek Lowe says:

      Not real happy about this being in the NEJM myself, but these are weird times.

      1. Dan says:

        They are in a tough situation. What if they didn’t publish this and it leaked out (which it would have)?

    2. Djhdd says:

      I personally don’t think Gilead is going after the PR and ‘stock price pump up’ with all this. For one they are under an intense microscope. If they hype and then don’t deliver they are going to be toast. Second I don’t think the risk/benefit of hyping this drug is all that great for them. They have a portfolio already and their strategy forward doesn’t pivot on this particular drug’s performance.

      So why are they releasing this case series? I think it’s genuinely information I think they wanted to share.

  4. charlie says:

    rumors that one of the Chinese trials was cancelled.

    1. Joe says:

      Canceling a trial is either very good or very bad. It is very good if the drug under investigation proved so efficacious that the trial was cancelled so everyone, including the placebo group, would now receive the drug – or it was so bad that the drug clearly provided no value at all and continuing the trial would be futile. The China trials have been ongoing for a while – so I would be disinclined to believe rumors of cancellation. In fact, readouts of both trials are due imminently.

  5. James Leroux says:

    Un-ironic use of the term “big pharma” gets you ignored and/or blocked in my book. Nothing good ever comes from interacting with people like that.

    1. Kevin says:

      To be clear he never actually said “Big Pharma” in the PulmCrit article.

  6. Tourettes of Chemistry says:

    The notion of ‘alchemical medicine’ was shared with some others earlier this week. The Booth pointer into the commentary literature is much appreciated along with the contextual summary here.

    This will allow some phenotypical characterization to be hung on that phrase.

  7. Daniel Wigger says:

    Your reasoning is all correct. Prof Simon Maxwell, Professor of Clinical Pharmacology, University of Edinburgh, even calls NEJM’s study unethical. I tell you what is unethical: If everyday 10 000 people die from Covid-19, we have a drug that most probably helps, and we do not apply it in patients. Let us continue to do studies. But we have to use Remdesivir here and now.

    1. Another Guy says:

      My view is that remdesivir “might” help patients, and “seems” to have a reasonably good safety profile under the circumstances, however we don’t know enough about it to start giving it to every COVID-19 infected patients right now. It is a physician’s judgement call to use it on a case-by-case basis. As Derek has stated many times in his blog over the years, there have been many examples of drugs that looked effective in case studies but failed to show any significant benefit in randomized controlled studies.

      Additionally, I think many of the Big Pharma/biotech companies are working hard to find effective treatments and preventative vaccines. Looking at the economic side, stock prices and profits will go up if we can all get back to work and doing the things we did before, so it is in Pharma’s best interest to find an effective treatment/vaccine, quickly and at an affordable price. What good is a high-priced COVID-19 treatment if the economy collapses and few can afford any medication of any kind? The cynics will never believe my next statement, but here it is: there are actually people in the industry that care about saving lives, we are not all of Shkrelie’s ilk.

  8. Daniel Wigger says:

    I appreciate all your arguments. But still I cannot understand. Yes, an unproved drug bears some risks. Yes, we don’t know if Remdesivir is safe or works (more or less) succesfully.
    I don’t care if Big Pharma, some corrupt government or any mean hedge fonds manager are trying to take profit. I just see that all signs for Remdesivir look positve, health risks seem to be low, so we have to ramp up and start giving it to terminate ill patients. In big scale and large proportions. It is so far our only hope until we have a vaccine.
    I admit, I own shares of Gilead (about 10 000$ of value). But i did it because I believe in this drug, because I hope that it will reduce the suffering of many human beings all over the world.

    1. Tom A says:

      Daniel: You didn’t mean “…..so we have to ramp up and start giving it to terminate ill patients.”

    2. Jdhdhdhhd says:

      It looks positive but you don’t really know if it works. Could be 1/3 possibilities: 1) kills you faster or makes your sickness worse 2) does nothing, in which case nobody should be taking it because you’re exposing yourself to tox for no benefit or 3) it helps.

      Right now there’s not enough information to know which one of these three is the case. So responsible thing to do is what’s happening now. Use it on a case by case basis.

    3. anonymous says:

      Daniel,
      Remdesivir is not a simple drug to manufacture and supply will be limited in 2020 under the best circumstances. Assume for a minute that Remdesivir actually has efficacy against SARS-CoV-2 infection. Which patients will benefit the most? Which patients should be dosed to do the most good? You might say that we should of course use it for the most critically ill patients. But what if it is too late in the course of the infection for these patients to be helped? And what if it turns out there is fabulous efficacy if the drug is given to a subset of patients who are early in the course of the illness, but who have a particular underlying condition, or have a particular biomarker? Might it be unethical to rush ahead and dose the critically ill patients who can’t benefit? The system of using controlled clinical trials is a result of a long evolution of practice. Yes, we should streamline trials as much as possible. But the situation with COVID is not fundamentally different from other disease situations, e.g. terminal cancers, where there are drug candidates and patients in desperate need of treatment, and we have learned that still we need to do controlled trials, or else patients end up worse off.

  9. Richard H says:

    Should NEJM have even published this?

  10. John P. says:

    “Big Pharma and Big Biotech and Big Whoever are going to be the only things that are going to provide new treatments for this disease at all”

    Cytodyn with their drug Leronlimab may disprove this. Entire drug cost for treatment should be $1,100 or less.

  11. Robert Monje says:

    1 word- Leronlimab!

    It’s working, it’s safe, and should be emergency approved by FDA bottom line! This should be about saving lives! It is saving lives and will continue too. Blows my mind FDA wants double blinded Placebo trials during this time. It freakin Works so why do that!

    1. metaphysician says:

      “It freakin Works”

      *citation needed*

      Or to put it bluntly: until we actually *do* a double blinded controlled trial, *we don’t actually know if it works.* Humans are terrible at assessing probability, that is why we have to do these rigorous studies in the first place. Doubly so in a situation where everyone is desperate for a quick solution, and so everyone is all the more susceptible to being fooled ( even by themselves ).

  12. Rick w says:

    O Day’s letter says they stopped the severe disease study in China because of stalled enrollment, which presumably means they no longer had any severe disease in by the end of February in Wuhan. Does that seem possible?

    1. loupgarous says:

      I wouldn’t bet on it. According to Bloomberg, who apparently still have good Chinese sources,

      “There are still a few or a dozen asymptomatic people every day,” an unidentified official at the Chinese Center for Disease Control and Prevention said in a Monday article by Caixin, referring to those who have the virus but don’t display any symptoms. “It can’t be determined whether transmission has been completely cut off in Wuhan,” the official said”.

      Bloomberg quotes an report by the South China Morning Post headlined:

      “A third of coronavirus cases may be ‘silent carriers’, classified Chinese data suggests. More than 43,000 people in China had tested positive without immediate symptoms by the end of February and were quarantined. It is still unclear what role asymptomatic transmission is playing in the global pandemic.

  13. Fiocruz, the main research center in Brazil, has indicated good news about the treatment of SARS Cov-2 with Atazanavir.

  14. loupgarous says:

    Point #11- “Massive Involvement of Pharma” in “PulmCrit – Eleven reasons the NEJM paper on remdesivir reveals nothing” is the weakest point of the indictment.

    The only people who pay for the time of co-investigators and study statisticians at study sites and statistical processing of data once collected on CRFs are the study sponsors (the people making the drug). By Pulm Crit’s standards, every study datum collected on Phase II and Phase III clinical trials of investigational new drugs in support of marketing approval for a new drug are also tainted by “Massive Involvement of Pharma”.

    All of Pulm Crit’s other points are valid and then some. I’ve been involved with randomized clinical trials where FDA granted compassionate use, but only after the data showing safety and efficacy were already in the hands of the FDA and there was a good case for safety and efficacy.

    That didn’t happen in this study of remdesivir. NEJM had higher standards when I dealt with them for my employers – we had a matched case study comparing intracoronary stents and atherectomy of the same category of coronary artery lesions and NEJM shot us down. We didn’t randomize that I can remember, it was a retrospective study, but done much better than this. Allowing Gilead to publish these data in anything but a letter to the Editor is puzzling.

    1. Derek Lowe says:

      Agreed – most of those points were completely solid, and I’m willing to overlook the last one for the sake of getting the word out on the others!

  15. Dohin says:

    I don’t want to spoil the little Remdesivir party you’ve got here, hope it works, but where is the risk/benefit data, where are the randomized controlled studies? All this excitement is not for few anecdotal cases, right? Especially when there are other options right now, like the 70yrs old H/QL – well known safety profile, cheaper and available, with some evidence in two randomized controlled studies.

    1. Derek Lowe says:

      You must have missed the part where I said that we need more trials to see if it’s actually useful. Just like HCQ!

  16. First, I must commend the writer for this great insight.

    However, I am of the strong view that the drug is well tested if possible on animals first to determine how far it can go to treating COVID-19 patients. This is because life is sacred and the utmost measure must be put in place to protect and safeguard it.

    1. James Millar says:

      Pretty sure you are just here to spread the junk link, but regardless –

      Gilead has been playing with this for a while now, years before the emergence of this particular virus. I imagine they already know as much as you’ll ever get from animal testing re safety, and it doesn’t seem probable that efficacy data can be gathered that way.

  17. KEVZARA SARILUMABE

    Kevzara is currently approved in several countries for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients with an inadequate response to, or intolerant to, one or more disease-modifying antirheumatic drugs. Kevzara was jointly developed by Sanofi and Regeneron under a global collaboration agreement. Kevzara is a fully human monoclonal antibody. It specifically binds to the IL-6 receptor and has been shown to inhibit IL-6 mediated signaling. IL-6 is a protein of the immune system, produced in increased amounts in patients with rheumatoid arthritis and has been associated with disease activity, joint destruction and other systemic problems. Kevzara is being investigated because of its ability to reduce the hyperactive inflammatory immune response associated with COVID-19, based on evidence of elevated levels of IL-6 in patients severely infected with coronavirus. I don’t know if REMDESIVIR will have full effect or half of what is expected. We cannot forget that Regeneron, already beat REMDESIVIR, in the treatment of EBOLA, with REGN-EB3. REGN-EB3 is an experimental biopharmaceutical treatment that comprises three monoclonal antibodies under development by Regeneron Pharmaceuticals to treat Ebola disease. In August 2019, Congolese health officials announced that REGN-EB3 and a similar treatment of monoclonal antibodies, mAb114, were more effective than two other treatments in use at the time, including REMDESIVIR.

  18. GerryL says:

    It is immoral and unethical to wait for results of stage 3 clinical trials. All patients with serious life threatening covid19 illness should be given access to this drug.
    Stage 3 clinical trials should be reserved for people with milder illness who are expected to recover to see if the drug shortens duration and severity of illness.
    FDA paper pushers and corporate profit motives should be set aside. The drug needs right now to be manufactured in large quantities for wide distribution.
    If it does not work we will have lost maybe a billion dollars, possibly less, but if it does work we will have saved tens of thousands of lives.

  19. tom hennessy says:

    They’ve tested iron binding drugs against virus’.

    Remdesivir is ‘kind of similar to acyclovir’, another antiviral, which, strongly binds iron.

    “Remdesivir is a nucleoside analog. It works through inhibiting viral replication through competitively inhibiting viral RNA polymerase, kind of similar to acyclovir and ganciclovir.”

    Acyclovir strongly binds iron.

    “acyclovir” “strongly binds Fe(2+) and Fe(3+)”

    Two other iron binders, Ciclopirox and Deferiprone, have been tested.

    “Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone,”

    “Chelation of intracellular iron with Ciclopirox”

    “Deferiprone is an oral iron chelator”

    So, does Remdesivir also strongly bind iron?

    They’ve recently proposed simple tetracyclines should work against COVID, and THEY are ‘iron binders’.

    “Therapeutic Potential for Tetracyclines in the Treatment of COVID‐19”

    “iron chelation plays a prominent role in the tetracycline management of African trypanosomosis”

    Are they NOT, targeting the iron .. ?

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