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Clinical Trials

The Latest Repurposing News (Two Parter: IL-6 and Apilimod)

As everyone knows, there have been a lot of attempts to repurpose existing therapies for the coronavirus pandemic. I’ve covered several of these along the way, but it’s time for some updates. The work that’s been going on not only adds to our knowledge about treatment for infected patients, but it should – ideally – also show what clinical research is like and why we have to do all these trials. Getting solid answers is a lot harder than it appears to be.

Antibodies Against IL-6 Activity

Case in point: the IL-6 story. Interleukin-6 is well-characterized as a pro-inflammatory cytokine signal, especially in the acute phase of the response, and that made this pathway a natural target for study after people realized that the “cytokine storm” immune reponse was getting coronavirus patients into trouble. Back in April, we had some numbers on the Roche/Genentech monoclonal antibody against the IL-6 receptor (Actemra, tocilizumab) that suggested that it might be beneficial – in fact, the French team conducting the study said that deaths were “substantially reduced” in the treatment group. But at the same time, another antibody against IL-6R, Sanofi and Regeneron’s Kevzara (sarilumab) looked like it wasn’t working. That was puzzling at the time, and investigations on both of these continued.

Well, earlier this month sarilumab failed to reach its endpoints in a trial adding it to standard-of-care for hospitalized coronavirus patients, and that pretty well took care of it idea of using Kevzara as a therapy. Meanwhile, tocilizumab had failed to help patients a bit earlier in the disease progression in a study in Italy, which was disappointing after the French results, but there was still some hope that it could help the most severely affected patients. But just today, Roche announced that no, Actemra had no effect on clinical status or mortality. So much for that.

This is instructive on several levels, especially for folks who have been looking in on drug development from outside during the pandemic. The IL-6 hypothesis was a perfectly reasonable one, a solid idea from what we know about inflammation and about what was going wrong with patients who were being put on ventilation. But it’s wrong. A lot of perfectly reasonable medical hypotheses are wrong; this happens all the time and it’s why we have to run controlled trials rather than just running with what looks like it should work. And to go further, that first trial of tocilizumab looked like it worked, didn’t it? Deaths were “substantially reduced”, and how can you argue with that, right? But it was a small trial and it was only one trial, at that. (Update: thanks to AndyBiotech on Twitter, I find that it’s even worse than that. Turns out that the trial’s safety data monitoring committee resigned in May over strong disagreements about how the readout of the trial was characterized. So there’s that!) Real treatments work again when you test them again, and they continue to work when you test them under more controlled and more statistically powerful conditions. Other results evaporate when you do that, and that’s what happened here. Those hopeful results early on were almost certainly an illusion, and this happens all the time. It’s why we run more than one trial, and why we make the later ones larger and more powerful.

You may be able to think of other high-profile therapeutic ideas that have had a similar course during the pandemic: promising early results in small trials followed by an inability to replicate them on a more robust scale. When such things don’t follow up, it’s not a conspiracy and it’s not malevolence and it’s not incompetence. Not usually. Because, and I cannot emphasize this enough, such things happen all the time. If you follow drug discovery and development, you’re used to it, because you’ve seen it happen over and over in all different disease areas. If you’re just tuning in, though, it can be hard to come to terms with.


There are plenty of other candidates out there. One that’s been getting attention is apilimod, a small molecule that’s been kicking around for some years now. It was originally investigated for its ability to lower IL-12 and IL-23 levels, a cytokine activity profile that looked like it could be useful in arthritis, psoriasis, and autoimmune diseases in general. If from that numbering you take away the idea that there are an awful lot of interleukins and that these cytokine signaling pathways must be rather a tangle, you are most extremely correct. The number of interactions in such systems (and with finer and finer distinctions of individual immune-responsive cell populations, too) is absolutely eye-watering.

But like many another small molecule, apilimod’s activity profile is a longer story than it first appears. It was identified in 2007 from a cell-based screen looking for modulators of interleukin activity. For some years, the only thing known about its mechanism was that it seemed to inhibit the activity of a transcription factor called c-Rel, preventing it from getting into the nucleus, and c-Rel was known to be essential for production of IL-12 and IL-23. But in 2017, a cell-based antiproliferative screen identified it further as an inhibitor of the enzyme phosphatidylinositol-3-phosphate 5-kinase (known as PIKfyve), and had just been found out (via other small-molecule PIKfyve inhibitors) that PIKfyve is essential for c-Rel activity, clearing up the mechanism a bit and giving apilimod a solid target and pathway to explain its actions. Apilimod has been suggested as an anticancer compound on the basis of such results.

So as for the pandemic, we’re back to inhibiting cytokine storms, right, this time by lowering IL-12 and IL-23 with this PIKfyve inhibitor compound, right? Maybe not! A recent paper in Nature (from a very large multicenter team) details another large-scale drug repurposing screen, this one done by looking for compounds that actually inhibit wild-type SARS-Cov2 virus infection of Vero-6 cells, a commonly used cell model from monkeys. Now, this is an in vitro screen, of course, but it’s a hard-core in vitro screen, because the team didn’t use a model for the virus itself (a pseudovirus or something of that sort), but rather went right to the real virus, which takes some serious screening facilities because of the serious containment needed. They followed up their best hits in human-derived cells and even in human lung tissue, so the results are quite solid.

And apilimod showed up as the best of the bunch, the only one to make it all the way through to good activity in the lung tissue assay. Not only did it inhibit viral replication strongly across all the whole screening cascade, but it also showed strong activity against the Ebola, Lassa, and Marburg viruses. (Told you that this was a hellacious containment facility, right? What a lineup.)  That’s very interesting indeed, suggesting that this almost certainly has to be a host target involved in general viral infection mechanisms and not some specific protease or nonstructural protein of the pathogens themselves. Those viruses are all over the map phylogenetically; they really shouldn’t have much in common past their common use of an RNA genetic payload.

Indeed, PIKfyve has been shown to be an important regulator of endosome activity, particularly early endosome formation. That means that it could be right up there at the beginning stage of viral infection, because endosomes are how many viruses actually deliver their genetic material into a host cell. The data in this new Nature paper strongly suggest the apilimod be tested as a preventative of coronavirus infection and in patients who already have the disease.

But there’s more to the story – I haven’t seen this highlighted, but PIKfyve has also been shown (by the van den Bogaart and Bertozzi groups) to be a key part of the process whereby antigens are presented to the surfaces of dendritic cells (for T cells to then come along and recognize them). That is an absolutely crucial part of the immune response to new antigens, and that paper (which came out in January of last year) showed that apilimod and other PIKfive inhibitors do indeed impair immune function and T-cell activation. That’s just what you don’t want in a viral infection!

So clinical trials of apilimod are going to be rather interesting. Will it protect from viral entry, but make other (nonviral) infections more likely? The balancing act between the viral entry inhibition and immune system impairment is something that can only be evaluated for sure in human patients. It’s one of those little biochemistry jokes – there are several of these – that the relentless evolutionary repurposing of enzymes and mechanisms should come along and complicate the attempt to repurpose a drug when it’s needed the most.

91 comments on “The Latest Repurposing News (Two Parter: IL-6 and Apilimod)”

  1. Philip says:

    Well tocilizumab not working is a bummer. Not shocking after sarilumab failed.

    Even with the IL-6 receptor blockers failing, I would like to see ongoing trials for siltuximab continue. Siltuximab has a different method of inhibiting IL-6 than tocilizumab and sarilumab. Siltuximab binds to IL-6 and prevents it from binding to cells. The other drugs attach to the cell’s receptor to prevent binding.* At this time I am not nearly as hopeful that siltuximab will work as the last time I posted about it (months ago I think). I still think that it is worth a shot.

    * I am a computer programmer. If I have this wrong, please correct me.

    1. Daren Austin says:

      Sarilumab binds IL-6. Tocilizumab binds IL-6R. Siltuximab looks like sarilumab. The safety of the IL-6 pathway (dislipidaemia) has driven maximum doses, and those maximum doses (in chronic indications) limit COVID options. Sarilumab was tested at 200 and 400 mg, compared with 150 and 200 mg in RA. Two-fold increases are barely above pharmacological assay noise. Come back with 2000 mg perhaps? Unlikely, even for acute treatment. So the plug has been pulled.

      1. Philip says:

        From the Kevzara website: KEVZARA (sarilumab) is an injectable prescription medicine called an interleukin-6 (IL-6) receptor blocker. So sarilumab, like tocilizumab, is a receptor blocker.

        I think there is little hope for siltuximab to work for COVID-19, but it is not zero. With the need for any drug that helps, even a bit, being great, I would continue current studies. I would not start new studies.

  2. cynical1 says:

    “The data in this new Nature paper strongly suggest the apilimod be tested as a preventative of coronavirus infection ” and inhibition of PIKfyve interferes with MHC Class II presentation of antigens.

    What could go wrong?

  3. Giannis says:

    Any news on eidd-2801/NHC?

    1. David E. Young, MD says:

      Only that Merck is taking it very seriously. There should be a clinical trial on it for early Covid fairly soon.

      1. Erik Dienemann says:

        Very, very seriously with Phase II ongoing. Biggest new project in the Company right now (I retired from there late last year – was in process R&D, so would’ve been my group’s project had I stayed – but still do some consulting for them), as it has promise to be better than remdesivir as an antiviral, based on animal studies, and it’s available in pill form, which is huge.

  4. sgcox says:

    I think every pharma chemist in the world are looking at the marvellous N-N=C and think oh yes, that is exactly the part I must have in my next drug candidate.

    1. Tom says:

      It may be a shocker of a drug molecule, but it looks like a great host for metal-binding!

      1. Obligatory Zinc Post says:

        But did they try it in combination with Zinc?!

      2. partial agonist says:

        yep, like most hydrazones… it ought to hold onto Zn like crazy I’d think

  5. Marko says:

    Takeda hyperimmune globulin trial ready to begin , if US regulators ever come back from lunch:

  6. Marko says:

    JHU says 20,000 patients have been treated with convalescent plasma over the past few months. How many were part of a RCT ? None , or nearly so , apparently. This sounds like hydroxychloroquine all over again :

    1. David E. Young, MD says:

      Monoclonal antibodies seems much more sensible to me. You can make them in large amounts and you don’t need to phoresis thousands of people. And the monoclonal antibodies are pure anti-Covid, where-as convolescent plasma is a diversity of antibodies including those against Covid. Not that convolescent plasma doesn’t work,…. it might. But if a monoclonal antibody is shown to work, it seems so much better and easier to use.

      1. Barry says:

        If by “monoclonal antibodies” you mean IgG, I’d want at least a hand-waving rationale that the infection is happening on a plasma-exposed surface. The surface of the respiratory tract is beyond IgG’s jurisdiction.

        1. Marko says:

          “The surface of the respiratory tract is beyond IgG’s jurisdiction.”

          Not entirely. There exists an IgG transport mechanism similar to the one for IgA , though it’s much less efficient , by orders of magnitude , perhaps. Still , low levels of specific IgG in the mucosa might have a significant effect.

          Transport is mediated by the neonatal Fc receptor ( FcRn ) , the same receptor responsible for transfer of maternal antibodies across the placenta.

          1. Barry says:

            And neonates aren’t dying from Covid19. But if we are to treat adults with mAbs, they should be mAbs with the right pharmacokinetics. That’s IgA, not IgG to the best of my understanding

          2. Marko says:

            FcRn functions throughout life , not just in neonates.

          3. Barry says:

            Immunoglobulin ‘A’ deficiency or absence is not lethal in humans, but IgG cannot whole replace its function. IgG provokes an inflammatory cascade that IgA does not. And in the lung, that can prove fatal.

          4. Marko says:

            “IgG provokes an inflammatory cascade that IgA does not. And in the lung, that can prove fatal.”

            Haha. Boy , you’ve changed your tune. From saying IgA is the only antibody of consequence in the respiratory mucosa to claiming that IgG poses a deadly threat there.

            Look , I’m as interested as anybody in seeing some vaccine candidates that are administered via the nasal or oral routes and that promote a strong secretory IgA response. I just object when people make broad statements that they can’t back up. We don’t know what the correlates of immune protection are for this virus yet , whether from natural infection or by vaccine.

            IgA is not the only antibody class that’s important in the mucosal space , full stop. In the vaginal mucosa , for example , IgG is the dominant class , and plays an important antiviral role there.

            Read a little about FcRn. For that matter , read about passive transfer of antibodies into the mucosa. Then you can pontificate about “IgG’s jurisdiction” or it’s requirement for a “plasma exposed surface”.

          5. Barry says:

            Yes,. IgG can be detected in the mucosa
   No, that doesn’t mean that It’s competent to mediate there needed response.

          6. Barry says:

            I asked for a hand-waving rationale that mAbs might work for Covid 19, and you have educated us. I for one was not aware that the neonatal secretory component is expressed throughout life. For this, I’m in your debt. But BCG has taught us that merely eliciting IgG in the plasma compartment–even though it does protect from miliary TB–does not protect from infection on the surface of the respiratory tract. Is there a reason that exogenous (mAb) IgG should do what endogenous IgG (elicited by a vaccine) cannot?

          7. Marko says:

            I have no basis to declare that mucosal IgG will be the critical factor in the COVID-19 immune response , whether it gets there by systemically-administered MAbs or convalescent plasma or as the result of a vaccination. My point is only that you can’t rule it out , because some IgG will invariably get there , via FcRn.

            The closest thing we have to a correlate of protection right now is neutralizing titer in the serum, mainly because that’s the easy thing to look for. It’s like looking for your lost car keys under the streetlamp because the lighting is better there. I wish we had more data on mucosal antibody correlates , but we just aren’t there yet.

            The importance of mucosal IgG may not be limited to neutralization by blocking the virus/ACE2 interaction. It may also involve the known role played by FcRn–mediated translocation of Ab/Ag complexes in Ag presentation to dendritic cells and the subsequent T-cell response , for example. Unlike the secretory IgA transport mechanism , which is unidirectional , FcRn transports Ab ( and complexes ) in both directions.


          8. Marko says:

            Well , this is timely :


            “…We developed enzyme linked immunosorbent assays to detect IgA and IgG antibodies to the SARS-CoV-2 spike protein (full length trimer) and its receptor binding domain (RBD) in serum (n=496) and saliva (n=90) of acute and convalescent patients with laboratory-diagnosed COVID-19 ranging from 3-115 days post-symptom onset (PSO), compared to negative controls. Anti-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16-30 days PSO. Whereas anti-CoV-2 IgA antibodies rapidly decayed, IgG antibodies remained relatively stable up to 115 days PSO in both biofluids. Importantly, IgG responses in saliva and serum were correlated, suggesting that antibodies in the saliva may serve as a surrogate measure of systemic immunity.”

            “….In conclusion, our study provides evidence that the IgG response to SARS-CoV-2 spike
            persists in the saliva and the serum, and that this response can be correlated between the two
            biofluids. Given that SARS-CoV-2 initially replicates in the oro- and nasopharyngeal tracts, in
            the future it will be critical to characterize the nature and kinetics of salivary antibodies at the
            earliest time points post-infection in contact-traced individuals in order to determine if there are correlates of protection that impact viral setpoint and COVID-19 disease progression. “

      2. Barry says:

        convalescent plasma therapy has had good results. But convalescent plasma is not just IgG
        “From the Spanish influenza to the current pandemic caused by SARS-Cov-2, it has been observed that the use of CP significantly reduces the case fatality rates. That is the case of Influenza A (H1N1) pdm09, Spanish Influenza A (H1N1), and SARS-CoV infections in which the use of CP was associated to reduction in fatality rates, mortality (Table 1 ) [5,[34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45],111], and mild adverse events (Table 2 ) [25,[46], [47], [48], [49]]. Furthermore, the use of CP in other coronaviruses such as SARS-CoV, reduced days of hospital stay in critically ill patients [42,50]. In relation to the use of mechanical ventilation, in Influenza A (H1N1) pdm09, and avian influenza A (H5N1), administration of CP reduced the duration of invasive ventilation [47,51]. In addition, it has been described that the use of CP in SARS-CoV and avian influenza A (H5N1) decreased the viral load in the respiratory tract [46,49]. Currently, CP used in patients with COVID-19 demonstrated to reduce viral load and improve clinical condition [38,39]….IgG and IgM are the main isotypes, although IgA may be also important, particularly in mucosal viral infections.”

    2. Daren Austin says:

      UK NHS Recovery trial is testing in A RCT . Presumably now against dexamethasone.

      1. Marko says:

        Good to know , thanks. I don’t necessarily think dex would be the SOC , given that dex is given later to sicker patients. I would think dex should be used in both arms of the trial as indicated , and the comparison would then be SOC +/– dex vs CP +/– dex.

        Based on the results of this meta analysis, we may be getting those Recovery results fairly soon. It suggests an effect size of ~50% reduction in mortality , which would only require a RCT of hundreds , rather than thousands , to demonstrate. I’m assuming the Recovery trial will be plenty big enough to do the job :

  7. tooearly says:

    The immune system seems such a good teacher for us that our linear reductive paradigms are badly in need of a good dose of complexity theory.

  8. loupgarous says:

    This interesting open access paper in Nature, “Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2” suggests that instead of targeting viral protein structure that is subject to change after successful therapy, it might be useful to identify host cellular pathways triggered by SARS that won’t change after evolutionary pressure from drug therapy. It’s something we might think about when repurposing drugs for COVID-19.

    1. loupgarous says:

      Derek, I realize your post is nothing but targeting host pathways (the interleukins), but I thought the Nature article was good general advice, even if most of the studies targeting interleukin receptors got skunked as treatments for COVID-19, so far.

      Changing the subject, any new news on camostat mesylate (apart from we’re learning that pairing it with HCQ isn’t a particularly good idea)?

      1. Tony says:

        Wait, is there a drug interaction between HCQ and camostat mesylate?

        1. loupgarous says:

          To be honest, I haven’t an idea. All the camostat mesylate trials I’m aware of, though are of camostat mesylate + HCQ vs standard of care.

          My best guess is that the study designers were hedging their bets, back before the bad news came in about HCQ efficacy..

    2. Toni says:

      In this context, a possible involvement of neutrophils, especially Neutrophil extracellular traps (NETosis), is also interesting. Targets aiming at the inhibition of these NETs are unfortunately not easy to identify or therapeutically use. To my knowledge PAD-4 is one of the few targets. There is also a DNAse (Pulmozyme for CF) which is tested in clinical studies.
      “Targeting potential drivers of COVID-19: Neutrophil extracellular traps”:

  9. MagickChicken says:

    Derek, I know you are tired about talking about HCQ, but do you have any thoughts on Risch from Yale still pushing it?

    1. David E. Young, MD says:

      “Fallacy of Authority” if you ask me. He quotes Zelenko, for example and I have a very hard time believing a family doc who says that he has treated 2,200 patients in 18 weeks. This would mean that if he worked 5 days a week for 18 weeks and saw each patient once, he would be seeing 25 to 30 Covid patients in his office each work day. He would have to see those patients 2, probably three more times if he was giving goo medical care which means that he would have to see 100 patients a day in his office and from day 1. That means that every other patient he sees (his diabetic, his hypertensives, his routine follow ups) would be told that they all have to wait for 6 months or more before he could see him. So, if Risch bases his data on guys like Zelenko it means nothing to me. And even famous people from Princeton can be poor investigators.

      1. loupgarous says:

        Even Nobel laureates can be, er, unreliable outside their field of competence. Luc Montagnier, for example. The strains on our credulity just keep on coming..

    2. Erik Dienemann says:

      The Zelenko study purported to show all these wonderful results from treating several hundred people who had COVID in a doctor’s office (not very sick yet if they weren’t going to the ER back in March/April), when he compared them to other people in NY who had far worse hospitalization/mortality outcomes. On the surface that sounds good.

      However, a simple read of the paper shows that the study was not randomized or controlled in any way, as the authors supplied zero information on the “control” population (those not treated with HCQ, supposedly) at all, with regard to demographics, underlying conditions, or severity of conditions at t=0 (patients going to see a family physician could have quite different severity from patients going to the ER).

      Nobody can know from this “study” whether the treatment is effective or not, which is why no reputable journal will ever publish this work. At a minimum we need the full data set on the control population to have any hope of determining efficacy, especially in a retrospective/observational study like this – at best, his results might suggest that we do a randomized, controlled, trial (RCT).

      Given all the other failed HCQ randomized/controlled trials, it’s doubtful this combo will be any better, but we won’t know for sure without an RCT on it, and we better not start giving another unproven treatment to mass numbers of patients. I’m sure Trump will now start pushing this as the new COVID gamechanger, as the authors are now firmly in his ear.

      1. ThePrimordialOrderedPair says:

        “and we better not start giving another unproven treatment to mass numbers of patients.”

        Marijuana has had absolutely no proof as being effective for anything, at all, and is even smoked by most people (which is known by anyone with a brain to be exceedingly harmful, contrary to left-wing claims that smoking pot does nothing to you) and yet it has been quickly brought into medical use for many states and even ranked up in “essential” services for the crazy Wuhan virus lockdowns.

        I don’t think most of the medical profession or political class care one bit about whether a “treatment” has any proof of efficacy behind it or how dangerous its application might be. That is abundantly clear from the whole medical marijuana scam.

        HCQ, at least, is not dangerous, so at worst it is ineffective. At worst.

    3. gippgig says:

  10. Lane Simonian says:

    Nuclear Factor kappa B is likely a better and earlier target in terms of supressing widespread inflammation than Il-6. Polyphenols deserve some consideration in this respect as NFkB inhibitors. Moreover, several (all?) flavanoids appear to bind to ACE2 in place of the coronavirus.

    There are a few ongoing trials using various flavanoids to treat this current coronavirus. Hopefully, some results may be available this Fall.

    1. pterin says:

      Aren’t flavenoids generally terrible drug candidates?

      1. anon the II says:


    2. Have you got a link outlining those trials’ protocols?

        1. anon the II says:

          It appears that you think that Artemisinin is a flavonoid. It’s not.

          1. Lane Simonian says:

            Right, artemisinin is not a flavonoid but some of the trials are either using flavonoids in combination with artemisinin or appear to be using other components from Artemisia annua (the first study should have been excluded).

      1. Lane Simonian says:

        I found a more general one for polyphenols.

        The flavonoid trials may appear here tomorrow.

        1. Thank you for the links, LS.

          1. Lane Simonian says:

            You are welcome, Rick.

    3. anon the II says:

      Unfortunately, scientists continue to rediscover great activities related to various coumarins, flavonoids and other polyphenols. Great effort goes into optimizing the structures for better activity and in almost all cases, med chemists are able to increase the activity by about 1.2 fold and no more. Having watched this sad dance over and over for over 35 years as a lead generation medicinal chemists, I have learned to not bother reading the articles and view the authors with scepticism in anything else they do. If you go back, you’ll find that I was one of the first ranting on this blog about the scam of the GSK Sirtris purchase. There’s too much that needs to be done to waste any more time with these molecules.

  11. ScientistSailor says:

    It’s Actemra, not Actema

  12. zero says:

    I’ve made an effort to explain this study outcome reversal to non-technical people before:

    We don’t have perfect studies. People make mistakes. Every result has a chance of being wrong. That doesn’t mean science is wrong, it just means we need to plan for some bad data in the mix.

    When we get an interesting result, we need to double check to be sure it’s not a false alarm or a mistake. That means a new study, hopefully one that measures the target in a different way so we’re less likely to make the same sort of mistakes the first team might have made.

    If the target is important then we need to do much more than two studies; many people with many perspectives cooperate to run multiple studies examining different parts of the target until we can be sure what we see is actually real.

    If you read it in a news headline you’ll only hear “good” or “bad” like it’s some kind of horse race; this is click-bait journalism. Most of the people writing those articles don’t actually know whether the results are real or meaningful; they are just passing on impressions, quotes and sometimes sales pitches from people with most of the context removed. Don’t be surprised when a “good” thing turns out to be a “bad” thing or vice versa; chances are the research was solid but the headlines were wrong. This happens all the time with diet advice and leaves people thinking that scientists have no idea what they’re doing, when the truth is that sensationalist journalism is shambling zombie-like from one clickbait headline to the next with complete disregard for the harm they do.

    1. Harvey 6'3.5" says:

      I find the XKCD green jelly bean cartoon can be helpful to explain why “significant” results may not really be significant.

      1. HTSguy says:


  13. one says:

    Looks like Verge Genomics ( has applied their AI-based platform to discover a therapy that works for ALS and for COVID-19!

    Just something to keep an eye on, given that this blog previously covered the company’s revolutionary approach.

    1. Derek Lowe says:

      Hello, Webmaster from Verge Genomics! You sure that you want to draw people’s attention back to that coverage?

    2. Anon says:

      Verge. Yeah, sure.

      What. A. Crock.

  14. Titos A says:

    Recovery trial yet continues with Tocilizumab
    “We are investigating the use of tocilizumab for sicker patients, whereas the Roche trial looked at patients with milder disease”
    Timing is important here like the cortocosteroids

  15. Luis says:

    Derek a bit off topic but what do you think of this? Do you think it could make a difference to fight covid19 if proven effective as it is claimed? Thank you

    1. loupgarous says:

      “If proven” is the critical phrase. A mask that inactivates coronavirus is an extraordinary claim. Such a claim requires extraordinary proof. Randomized, controlled trials are how we prove claims like that. When there are good randomized, controlled trials showing such masks work, we’re waiting for the proof.

      1. Luis says:

        Yes i agree with you,so far all the lab tests showed that is effective which is a good start…

        1. steve says:

          Just a point about Vero infectivity studies – they are not stringent, they are artifactual. They are what led to the chloroquine nonsense to begin with. It turns out that was an artifact of Vero cells not expressing TMPRSS. When you put that in all of a sudden chloroquine does squat to prevent infection. Also doesn’t work with human lung organoids.

          1. Stewart says:

            I was about to ask whether that paper implied that camostat mesylate was a potential treatment/prophylaxis for COVID-19, or whether I was leaping to an unjustified conclusion, but Wikipedia tells me that there is a trial or two in process.

  16. myst_05 says:

    At this point, what are the odds of an effective drug against COVID being found prior to a mass deployment of vaccines? Seems like we’re at most 6 months away from the successful completion of a Phase III vaccine trial (possibly 3 months, if we’re super lucky), so getting a drug to work becomes less and less important with each passing week.

    1. johnnyboy says:

      I agree. Antivirals, anti-inflammatory approaches were always something of a hail Mary. The possibility of finding not just a drug, but one for which we would have time to sort out the proper treatment regimen (what dosage, who to treat, when to start, when to stop, what to combine it with) and which could make more than a dent in survival for more than an anecdotal proportion of patients, was always close to zero in my mind. While no one is wrong for trying, the bulk of the effort should (and now seems to) be directed at vaccine work. Prevention is always preferable to trying to cure.

      1. confused says:

        Dexamethasone reduces mortality by ~a third for the sickest patients (those on ventilators), right? I’d say that’s better than anecdotal… though still not game-changing (we really need something that keeps people from getting that sick).

  17. Sebastián Ibáñez says:

    A superficial and disappointing comment by the editor. Industry studies of tocilizumab and sarilumab have had the clinical error of not knowing how to select patients. The inclusion criteria of Roche made it foresee, when including any patient with an altered image and requiring a little oxygen, that they would not find significant differences. Derek Lowe’s analysis is lacking in depth, too fast to rule out a mechanism of action that may serve well-selected patients

    1. Derek Lowe says:

      Don’t try to convince me – go try to convince Roche!

  18. Klaus says:

    There is another repurposing approach, that has not been mentioned so far (unless I have missed it): plitidepsin as antiviral therapy, PubChem ID 9812534. It was found to be active in vitro (more potent than remdesivir) and is now investigated in two clinical trials (in Spain and in Korea). Plitidepsin is thought to reduce viral replication due to its inhibition of the elongation factor eEF1a.
    I’d be curious to hear your (and your audience’s) views on this approach.

  19. Toni says:

    Regarding MHC-II blocking: Wouldn’t we expect presentation of antigens by MHC I to be more important in viral infections?
    Are there known associations between the disease course of COVID and certain HLA haplotypes, as is known from some autoimmune diseases. (e.g. HLA-DRB1*0401 and RA)?

  20. Nile says:

    An observation, for those who are writing about a ‘race’ between the arrival of an effective treatment, and the arrival of a vaccine: it’s not a race, and they are running on different tracks.

    The ‘treatment’ track is mostly about saving lives – there’s already one success, which reduces the death rate by 30%, in patients proceeding to intubation and ventilation – when they are seriously ill, in hospital.

    I expect to see more of those: significant, but not miraculous.

    But… Those patients aren’t walking out of hospital, they are wheeled out, and they will not return to full health for months; or maybe not ever.

    There is no prospect *whatsoever* of a pill like an antibiotic or the antivirals for a coldsore, in the next five years. There is no Tamiflu or Relenza for Coronavirus in the pipeline.

    I would love to be proven wrong there.

    That leaves the ‘race’ with a victory for the old, old lesson that prevention is better than cure.

    Long term, we’ll still need to treat a small but significant number of patients who get the disease: we’re not going to eradicate this strain of Coronavirus for a few years, if ever.

    Meanwhile, none of us will like having a mild or ‘moderate’ case of COVID-19: sick enough to be flat on your back and off work for weeks, like the real ‘flu, is no fun at all.

    But it’s better than a trip to hospital, whether you’re walked out, wheeled out, or depart in a refrigerated truck.

    Worst of all, if you have a conscience, is walking around after shaking off a bit of a sniffle or nothing at all, and finding out that you are a symptomless carrier, and have a share in the death toll in your community; I’m not cut out for walking out with an hourglass and a scythe, even if they are not in plain view, but I hear that some people are fine with that.

    1. Rob says:

      Each has their place. Even with a vaccine, there may be localized outbreaks. Not everyone gets vaccinated, the vaccine wears off, etc. You don’t want to have a hundred people turn up in the ER and not have a therapy. And don’t be too pessimistic about the prospects for a therapy. The monoclonal antibodies have promise; Regeneron’s should be generating results in a couple months or sooner, for example. Merck’s compound may turn out to be toxic, but it’s probably much more potent than remdesivir. Gilead has a compound that’s much better in vitro, as well. Plus these studies should yield fast results; these aren’t long-term studies of some chronic condition.

  21. SALEH says:

    The main problem is not the observed race to pick up the right horse , but rather the method used to compare them.
    RCTs are an expensive heavy duty method very difficult to conduct that have a problem yielding a convincing result , this method seems to me like a huge mountain that will give birth to a tiny mouse (dexamethasone)
    Still it’s the official gold standard, that is supposed to give robust results, but instead it seems more like a heavy dinosaur and looks more and more like a giant standing on feet made of clay.
    Are RCT still a relevant method in a crisis like this, where the ethical priority is to cure with the available knowledge relying on presumption of efficacy , I wonder

    1. Some idiot says:

      An interesting comment, but I flatly disagree. If anything, I would say the reverse. This pandemic has lead to many ideas and hypotheses for treatment (and most of those I have seen have been pretty reasonable). However, given the complexity of human biochemistry and all its myriad of possible cross-interactions, after some proof of principle has been shown in the lab, the only way of finding out for sure is to test it in humans.
      And history is littered with people using procedures to treat people with the very honest belief that it works, only to find out later, through more rigorous trials, that procedures that “everyone knew” were helpful, in fact turned out to be useless, or even worse, harmful. It is only through RCTs that we can get through to the “truth”, and even though the “truth” sometimes comes in pitifully small doses, this is at least beneficial to receiving false hope in extremely large doses.

      1. Daren Austin says:

        Every molecule I have ever taken into the clinic has passed those Translational Pharmacology tests with “promising results in the lab”. Even the ones that failed in RCTs (i.e., the vast majority). There are no examples of the reverse (no preclinical promising results but go anyway). The only exception to RCTs is conditional approvals in Oncology where the ethical concerns are slanted further towards early patient benefit with subsequent confirmation in First line therapy. Everyone who has ever worked on TARGET X has seen the diagram where TARGET X is at the centre of the picture, with lots of inputs and outputs and pointing to clinical response. Drugs don’t get to humans without this ascertainment bias. RCTs are the answer to refutation.

        1. Kamil says:

          Still that is a very drug-centric view. There are many reasons not to rely on RCTs because it is impractical, even though they are ALWAYS preferable. Surgical techniques or aging research come to mind (lifespan per se is rarely ever a reasonable main outcome).

          Regarding COVID, there are several examples. There are no – good, consistent and/or positive – RCTs for such varied public health measures like respiratory etiquette, hand washing, masks, social distancing of the “stay at home” kind (AFAIK) and no evidence that staying apart a certain distances is protective (and what distance). Nevertheless we have to do something based on prior plausibility and preferably in the meantime we’d run the RCTs.

          I think dexmethasone & remdesivir might have been used prior to RCTs on an empirical basis as well? Not sure whether that was wise or not though.

    2. Derek Lowe says:

      RCTs are, in fact, the most relevant thing possible in this situation. Otherwise we’re chasing shadows – and there are a lot of shadows out there.

    3. loupgarous says:

      Any therapeutic intervention taken without an effort to learn whether it is (a) safe and (b) effective – which means a randomized, controlled clinical study – cannot be considered science-based medicine. Any other approach is littered with sources of potential error and hazard to patients. Randomized, controlled clinical trials have evolved specifically to identify and exclude potential sources of error.

      1. En Passant says:

        Any therapeutic intervention taken without an effort to learn whether it is (a) safe and (b) effective – which means a randomized, controlled clinical study – cannot be considered science-based medicine.

        Was penicillin subjected to double-blind RCT before it hit the beaches at Normandy on D-Day?

        Has penicillin ever been subjected to a double-blind RCT?

        Has Ignaz Semmelweis’ hypothesis, that surgery should be done with aseptic instruments and physician’s hands, ever been subjected to double-blind RCT?

        Are both considered to be science-based medicine today?

        1. loupgarous says:

          “Was penicillin subjected to double-blind RCT before it hit the beaches at Normandy on D-Day? Has penicillin ever been subjected to a double-blind RCT? Has Ignaz Semmelweis’ hypothesis, that surgery should be done with aseptic instruments and physician’s hands, ever been subjected to double-blind RCT? Are both considered to be science-based medicine today?”

          Semmelweis’s original observation was that of the two free maternity clinics offered indigent patients in the hospital where Semmelweis worked, the “first clinic” offering care by medical school professors and their students was known widely by repute among patients to have much higher rates of death due to childbed fever, and avoided even at the cost of bearing children in the streets or at home compared to the “second clinic” in which midwives and not physicians or medical students delivered babies.
          Semmelweis found this a horrible discrepancy, but doggedly collected data from both clinics, finding 10% higher rates of death from childbed fever in the first clinic where physicians were trained,. delivering babies between dissections in the autopsy room. Eventually, one of Semmelweiz’s friends, another physician, was stuck by a medical student’s scalpel and died with symptoms much like those of childbed fever.

          Semmelweis’s impoverished, unwed mother patients were, as a group, better scientists than the professors at his medical school. They knew that their likelihood of coming home well from the first clinic staffed by medical students was much lower than coming home well either from births attended at the second clinic by midwives, or even with no medical intervention at all. The midwives, of course, had no occasion to visit the hospital’s autopsy room as medical students and professors had to.

          That Semmelweis’s ideas were received so badly had several causes – but he was the 19th century’s equivalent to a chief resident trying to convince the professors at his teaching hospitals that “cadaverous particles” brought from their autopsy rooms to their poor patients’ bedsides were killing those patients. Semmelweis may have had many intellectual gifts, but tact and humility were not among them – he wrote screeds accusing the teaching doctors of Vienna and Budapest of being murderers, and was eventually was committed to a lunatic asylum despite having virtually eliminated childbed fever when and where he was able to do so.

          You seem to be saying Semmelweis didn’t need randomized controlled trials, but that structure of proving new medical concepts might have proven his case even without Pasteur’s germ theory (which at that time didn’t exist). Without randomized, controlled trials, Ignaz Semmelweis was handicapped by not having a proven scientific theory which supported his observations. Semmelweis’s family involvement in the 1848 revolution sweeping Hapsburg Europe and his failures at hospital office politics doomed his ability to win converts to his theory of the cause of childbed fever – despite his success in ending that disease where and when he could.

          Penicillin was not a radically new concept, except that it was discovered as a by-product of fungal cultures, not from the effort to screen many derivatives of a lead compound chemically related to arsenic-based dyes – the first of many modern drugs specifically made to treat microbial disease . That drug’s nickname, “606”, referred to the hundreds of trials required to find it.

          The discovery of penicillin’s usefulness as a microbe-killing drug, by contrast, was almost entirely a fortunate accident. If Fleming’s first discovery had been more toxic than penicillin, and been a lead compound like arsanilic acid, it would never have spawned a useful drug for curing infectious disease in time to be useful in World War 2.

          You’re proposing we toss out a powerful tool proven again and again to work well in separating drugs that work well from drugs that don’t. If you have a specific reason for that, by all means, make your special plea.

  22. SALEH says:

    I thank you for your both comments

    I am only questioning the appropriatness of performing RCT in such a stressfull and deadly pandemic.
    I know that this is not an orthodox way to reason science today, but what I observe is that EBM has become a sort of absolute Faith and all those who try to to find their way outside this main stream are treated like heretics.
    The psychodrama surounding all this issue is very near what you would expect in a middle age war of religion where all means are admissible to silent the opponent
    I was looking recently to a scientifical series here about medical discoverys from the begining of last certury (Pasteur, Yersin, Koch) and I said to myself , how lucky they where at that time.
    RCT ok is today the gold standard to compare data but RCTs have their ouw flows and those flows are known of the prponent of this statistical method. External valididy and reproductibility is only some of these.
    For me trials are like preparing a kitchen recette (Derek seems to like kitchening) , the result will vary according to the quantity and quality of the ingredients (even one small ingredient like salt is sufficient to change the outcome) , not to mention the skill of the chef (to interpret the recette) and also the clients opinion and level of satisfaction.
    To approche trials from this example above, reproductibility of the outcome might vary from one day to another, this is true in both situations
    All in all!
    We fortunately are not a statistical unit yet , nor the clone of one another (for the time being at least)
    Truth is relative concept operationg in a specific contexte that might be corrected or contradicted by new findigs and nobody can pretend to have the monopoly of the truth.

    1. Ian Malone says:

      Every such comment starts from the supposition that we can somehow know a treatment works otherwise, and that a trial is just the red tape to prove it.

      This is wrong.

      We don’t know treatments work until they are seen to work. And we don’t know how people would have fared otherwise. Higher survival rate in your treatment group with no control? Persuade me you didn’t just recruit less seriously affected people, or that they didn’t simply get a better overall standard of care (as people in research often do).

      Every time you think you’ve found a solution “well we can just skip RCTs if”, ask yourself, “Am I basically assuming this treatment works, and works well enough that it will always be worth applying despite any potentially side-effects .” The answer will generally be “yes”.

  23. steve says:

    Infectivity on Vero cells is not a “robust assay’; in fact, it is prone to artifacts. This is what led to the whole HCQ fiasco. Chloroquine inhibits infectivity in the Vero assay only because those cells don’t express TMPRSS; once they do chloroquine fails to work. It also doesn’t work in human lung organoids.

  24. Alan Goldhammer says:

    There is a preprint from Cuba on there own version of an IL-6 mAb blocker (itolizumab) here: From the abstract: “Its effect is associated with a reduction and controlling IL-6 serum levels. Moreover, treated patients had a favorable clinical outcome, considering their poor prognosis. This treatment is associated significantly with a decrease the risk to be admitted in ICU and reduced 10 times the risk of death.”

    this was only a single site trial, uncontrolled on 19 patients. Not sure that it is all that credible.

  25. SALEH says:

    Steve , wwhy did’nt you include in your comment Fred’s and John Abeles reserved comments just below the article you mentioned

  26. SALEH says:

    Here is a very rencent in vitro yet study concerning TMPRSS2 saying in short that combining HCQ with Camostat (active on TMPRSS pathway) gnerate better HCQ activity (is that effective on lung cells ? not sure)
    Title : Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2
    Authors :Tianling Ou1, Huihui Mou1, Lizhou Zhang1, Amrita Ojha1, Hyeryun Choe1, Michael Farzan1* 1Department of Immunology and MicrobiologyThe Scripps Research Institute, Jupiter, FL 33458, USA

  27. SALEH says:

    Don’t misunderstand me, I never said that trials are not necessary but there is a lot of methods to “approach” evidence even if some of them are by far more robust to answer a (not the) question. But are RCT adapted to the difficult context of the current COVID.
    The problem with covid pathological characteristics is complexity, everyone knows by now that COVID-19 includes in fact two different phases or diseases (like a gift packing, you buy one the other is offered) which one are we treating ?. Most launched in a hurry RCT in a sense of emergency didn’t see that.
    One infectious disease Professor from Paris (opponent of HCQ) said that if it was today (with the better understanding) those RCT wouldn’t have been designed in the same way. Bur once the trains where launched it has become a challenge to stop them.
    I heard one Chinese proverb is saying (China again) , the main thing is not answering a question but posing the right question.
    The other problem with launched RCT is over simplicity (one tested product at a time for one disease ).
    Raoult team yesterday, aware of new pathway hindering HCQ efficacy in some cases is convinced that the answer is a combination of complementary products to face virus incredible ability to use our own immunity to penetrate the cells.
    Raoult thinks that research paradigms are to adapt to this double complexity and I quiet agree with that (even if I am not a researcher and less his disciple).
    Over all, I still believe that vaccine is the right answer to pandemics (I mentioned Pasteur, Yersin and Koch) but in the meanwhile different treatments have also to be explored , there is no contradiction between them and vaccine
    Maybe health authorities and WHO might be afraid that HCQ early adoption in many countries (this is a fact) might hinder vaccine diffusion seen here as the health priority but I don’t think that prohibition is the right answer.
    A truce and dialogue is needed so that doctors assume with serenity their role (it’s an appeal)
    I profit here to sincerely thank “the very tolerant” Lowe DEREK for the huge work he is doing to keep us informed

  28. Kate W. says:

    On the inconsistency in the Tocilizumab trials, it would be interesting to investigate Vitamin D deficiency as a possible confounder. While the RCTs of Vitamin D for COVID-19 are ongoing, there is associational data now showing that patients with severe COVID-19 are often Vitamin D deficient – even after adjusting for comorbid conditions. Since Vitamin D sufficiency reduces IL-6, this makes some sense. There is a recent trial of RA patients out of Korea showing that patients with sufficient Vitamin D responded better to tocilizumab than those with low Vitamin D.
    As others have said – metabolism is multi-factorial.
    Any thoughts on this appreciated.

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