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Covid-19

The Order of Battle

Among the many drug-discovery lessons that this pandemic is highlighting is the difficulty of meeting the challenges of a new target, a new pathogen, a new disease, or a new mechanism of action. When you look at the history of the drug industry, the typical time for an effective therapy to be developed from a standing start is somewhere around ten years. Once in a while it’s shorter, and it can be a lot longer. You can see this when a new virus appears (such as HIV), or when a new disease process is discovered (either a particular biochemical pathway or the gene for a genetically-driven condition), because those have a definite starting pistol that goes off. For other things, well. . .try this example: thanks to Gilead’s combination therapy (and the work of many other companies along the way!) we can now flat-out cure hepatitis C. For how many decades had people been trying to treat hepatitis C before that was realized? At the far end of the scale, for how long have we been trying to treat (say) Alzheimer’s, with basically nothing being realized at all? Drug discovery is hard. We keep on saying that, sure, but that’s because it keeps on being true.

Now, in the pandemic era, we get to see the process work under time pressure. I’ve talked about this topic in passing in other posts, but I thought it might be good to break it out by itself. The list, in order of rapid deployment, looks something like this:

1. Existing drugs. We don’t really have anything approved against coronavirus infections, so all of these are going to have to be repurposed, and you have to hope that something works. Don’t expect cures – the odds of something working that well when it was developed for some other use entirely are extremely small. Wandering through the shelves of the auto-parts store and throwing things out into the parking lot at random is unlikely to fix your broken lawnmower, for similar reasons. If you’re very lucky, you might find something that can be jammed on with a hammer and aligned with duct tape, and that’s pretty much what drug repurposing is like even at its best. But the good part is that if you find something, it can be deployed more or less immediately, especially as compared to the next options. This is where remdesivir, hydroxychloroquine, azithromycin, falapirivir, ivermectin, basically every single one of the drug ideas you’ve heard about come from – they’re all attempts at repurposing things that weren’t developed with a coronavirus in mind. I’ll have more to say on the general topic of drug repurposing in a post in the next few days.

2. Monoclonal antibodies. These take months (in theory) to years (in practice, so far), and only when you have an absolutely clear shot at a particular protein that you know you want to shut down. That’s what mAbs are good for: they will stick to a protein and jam up its function but good. And that’s the tough part, because all too often we don’t quite know what protein we should be zapping in order to fix a disease. There might be no good candidates, or there might be too many to choose from with no real standouts, or you have strong reasons to believe that blasting your target protein out of the sky will do lots of other things you don’t want, or the only protein targets that we’re certain of are things whose activity we would want to increase, not wipe out, and so on.

The good news for us versus the coronavirus is that we have such a target (the viral Spike protein or some part of it) that we have strong reason to believe would shut things down, and the mAb folks (Regeneron and others) are going at it hammer and tongs as we speak. They’re trying to set the new speed record, so we’ll see how that goes. Keep in mind, a mAb therapy would not confer lasting active immunity (via antibodies of your own), but it would be something targeted and effective that could be given to you if you have a bad nCoV-19 infection, and we don’t have anything of the sort right now. I’ll be doing a post on this stuff soon.

3. Vaccines. I’ve done a couple of whopper blog posts on these recently, so I’ll just refer everyone to those. The current speed record is about five years, for the Ebola vaccine, and as you can see from those earlier post, everyone is pulling out the stops to break that by a wide margin. I have no idea if that will work; vaccines typically have the same sorts of fearsome attrition rates in the clinic that the rest of the industry has. The hope is that if we have a lot of people taking shots at this from a lot of different directions, then something will get through. The number of people trying to develop a vaccine might cancel out the uncertainties. We all get to see if that’s true, lucky us! If everything goes perfectly for someone, first time through, then we might be ready for an emergency use authorization early next year at the very earliest possible date. Beyond that, there’s literally no way of knowing.

The great thing about a truly effective vaccine is that it makes the disease go away. Smallpox went away. Polio has gone away, except in a few places that are in such bad shape, politically, physically, and/or mentally, that the vaccination campaign hasn’t quite made it through. In the developed world, things like rubella, measles, diphtheria and whooping cough have largely gone away, and would pretty much go away forever if everyone got vaccinated, which is why anti-vaccine activism makes so many of us in the business want to scream and kick things. And a solid coronavirus vaccine could do the same: we’ll have to see if such a thing can be developed, because you’ll notice that there no one could ever get that to work against (say) hepatitis C or tuberculosis.

4. New bespoke therapies. As mentioned, not every pathogen can be dealt with by a vaccine (although I have every expectation that this coronavirus can be, really). And not every disease, needless to say, can be solved by raising or injecting antibodies to some protein. So for those occasions, we’re back to good ol’ small molecule drugs or engineered proteins, Huey Lewis “I Want A New Drug” territory, and this is the longest timetable of all. Bringing up such things from scratch is fraught with uncertainty. You have to find a target, and then hope that your target is something that you can find potent chemical matter against, and hope that said chemical matter doesn’t do a bunch of other horrible stuff to people at the same time, and can be dosed in a reasonable fashion at a reasonable interval, all the classic worries of classic drug development. And then you get to go to the clinic and hope that you picked the right flippin’ target in the first place. If you’re lucky, there’s a good enough animal model to help you defuse that question before you go to the massive trouble and expense of clinical trials, and the good news in infectious disease is that such animal models are more likely to exist than they are in most other therapeutic areas.

The bad news is that all these development steps take time, and some of them are pretty incompressible. Finding a good compound takes the time it takes, however long that is, and you have no way of knowing beforehand what that will be. Safety testing takes the time it takes, and although you have a much better idea of how that is, you can’t shorten it and you generally can’t go into humans until it’s done. And so on. The upshot is that this is the longest option of all; getting it all done in five or six years would be extremely impressive. As mentioned above, the standard is more like ten. If we absolutely have to do this for the coronavirus, it’s because the mAbs and the vaccines have failed us. We will be Breaking Glass in Case of Emergency, and that will not be a good thing.

But I really don’t think we’ll end up there. I think the chances for useful recombinant antibody therapies are very good (although manufacturing them on scale will be nontrivial, as we like to say), and I think that the chances for a useful vaccine are also good, especially with as many organizations hammering away on the problem as we have. We may in fact end up with the luxury of arguing over which vaccine is more appropriate, and that’ll be just fine.

112 comments on “The Order of Battle”

  1. Barry says:

    Passive gamma-globulin therapy is not fashionable, is hard to scale up, hard to patent, hard to monetize, and has not yet been proven efficacious against this novel virus. But it remains a very good bet in the relatively short-term.

    1. Process scale-up is not difficult (good old Cohn- I worked in one of the UK’s few plasma fractionation centres many years ago before segueing into the Transfusion Service), identification of appropriate donors and logistics of collection are the bigger challenge.

      As the recipient of many hyperimmune anti-hepatitis B shots (IM, hefty volume- it hurts…) in pre-vaccine days, I can testify to the effectiveness of the concept.

      1. FoodScientist says:

        Collection of anti Covid-19 serum seems like it would be REALLY REALLY easy…
        Roughly 25 million people are jobless because of covid. You can sell plasma and the stigma would be reduced because it would be very directly saving lives.

    2. Barry says:

      But even if passive gamma-globulin therapy were to wholly eliminate virus in the plasma compartment and in plasma-exposed tissues, it might miss the critical lumen of the lungs (accessible to mucosal defenses only) and the testes?

      1. Giannis says:

        The injected Influenza vaccine elicits primarily IgG antibodies. From studies from mice we are pretty sure that IgG antibodies can neutralize the virus replicating in the lung.

        1. Mo Shoreibah says:

          True but we have to keep making new flu vaccines every damn year. What about IgAs? No-one pays much attention to them. Isn’t mucosal immunity paramount to defend against a virus that attacks alveolar type 2 cells among others? IgGs may work but where they intervene in the infection cycle is an open question. With Covid-19 I would urge a closer look at IgAs conferring protective immunity instead of only IgGs and IgMs.

    3. Barry says:

      https://www.jci.org/articles/view/138003

      The convalescent sera option for containing COVID-19
      Arturo Casadevall1 and Liise-anne Pirofski2
      First published March 13, 2020 – More info

  2. JasonP says:

    Thank you for a well written, clear & concise post and your continued efforts to educate!

    A couple of side comments if I might be so bold:

    1. Have seen several anecdotal reports of plasma transfusion for the antibodies those carry. does that fit in the larger antibody discussion?

    2. I find the Daily Corona Virus Task Force briefings to be both interesting & frustrating. The frustration comes from the apparent lack of much scientific knowledge or acumen on the part of those asking the questions. Setting any kind of politics aside, it is sad that these are at the forefront of the 4th Estate and where check & balances begin, as well as dissemination to many Americans. Wish there was a “fix” for that.

    Keep up the good work Derek!

    1. Derek Lowe says:

      Plasma transfusion should indeed work – it’s been used for a long time, and is basically an injection of human-made polyclonal antibodies. Problem is, it doesn’t scale well: one person’s donation is about enough to for dosing one other person, most of the time, and it takes some labor along the way to prepared the plasma.

    2. luysii says:

      The lack of scientific acumen and knowledge of the press is fine and absolutely typical of the sort of thing that docs deal with every day. This isn’t a seminar for the cognoscenti, but for the general public. Trump fits right in with this, asking ‘dumb’ questions of the experts present.

      1. Chris Phoenix says:

        I hope you were being sarcastic.

        These briefings are supposed to be informative – to give the general public useful and relevant information about COVID.

        Instead, yesterday on live TV the President proposed to his own medical experts that it might be a good idea to literally inject disinfectant – probably chlorine dioxide, since quacks pushing that substance had gotten a letter in front of him a few days before.

        Today, a Maryland emergency hotline reported that they had received over 100 calls about this idea, and felt compelled to publish a statement that one should never do this.

        Also today, our President lied about who he had been asking that question of yesterday.

        This is not about politics. This is about worse-than-useless medical misinformation being uncritically spread on national TV by the top leadership that we happen to have in office. Every sane person, regardless of politics, should condemn this and try to shut it down.

        1. Ogamol says:

          My only reason for NOT shutting Trump up is political. Almost every time he opens his mouth or shows off his typing skills, he also “stuffs a limb in his mouth” in public. Prior to this crisis, I was flabbergasted that Democrats wanted this self-destructive maniac silenced so that they would not have constant reminders of his, and his cohort’s, idiocy.

          As of this crisis, I’m torn. The political fallout of his blatantly projected idiocy is priceless. The health fallout of his idiocy is (borrowing from NM Law)on the “depraved mind”-level of criminal. So, I’ll abide his being shut up, for the sake of my idiot neighbors. (“My brother’s keeper”, etc.)

          I just won’t like it.

          1. luysii says:

            Calling Trump’s cohort idiots is probably not an effective strategy for electing his opponent. They hear you loud and clear.

          2. Hap says:

            At this point, convincing Trump’s supporters appears unlikely (being immune to data sort of seals that deal). On the other hand, being unkind to them is unnecessary – like in books, you let their actions and words tell the tale to people who might not yet be immune to data. If that doesn’t work, well, you’re screwed anyway – freedom depends on your ability to respond to data and consequences, and if we have neither, then we won’t be around for long.

        2. chiz says:

          Wait until someone asks Trump about 5G.

          1. David says:

            5G is one better than IVG.

            sorry

        3. x says:

          Democracies get the government they deserve – so do non-democracies, if you are of the radical “liberty or death/kill your masters” school.

          And before anyone supposes this is a veiled dig at Trump voters, let me note that the Democrats appear to be doing their damnedest to lose to Trump in a close race. It’s better for fundraising off of frightened liberals, I suspect; painting an upcoming election as an unprecedented existential crisis never seems to stop working no matter how many times it’s reused.

          In any case, I’ve completely lost faith in the idea that a small activist minority can do anything to stave off widespread suffering and needless death – or scientific illiteracy. Perhaps when enough millions finally die, the survivors will get their shit together.

  3. TPO says:

    One small correction. Monoclonal antibodies can indeed provide immunity — immunologists do this kind of experiment all the time while investigating mechanism of protection, and it’s called passive immunity. The downside is that it’s limited by the half-lives of the injected antibodies, and the need for repeated dosing gets expensive. It would be damn hard to scale across the general population, but might be good for targeted populations like health care workers and Dr. Strangelove.

    1. Derek Lowe says:

      Just clarified that – thanks!

    2. eub says:

      If we did scale up a mAb’s production to the billions of doses, how much would it cost to produce?

      I know palivizumab is $$$$ (have done the indication dance for insurance coverage…) but what is the actual marginal cost of a dose, and what does that asymptote to at scale?

      1. Giannis says:

        MoAbs cost around $100 per gram. Most of the cost is surprisingly purification and not the protein production in the bioreactor. If the neutralizing antibody has low picomolar affinity to SARS-CoV-2 RBD then if it has the new high affinity FcRn mutations it could be cost effective. A single 100 mg injection should protect a person for a couple of months.

        1. eub says:

          Thanks, Giannis! If it can be $10 a dose, that would be a “shut up and take my money” situation for sure. Leaving only the questions like how to build the production capacity to get the volume in reasonable time.

  4. Tony Scahrf says:

    I just want to personally thank you for these posts. In an age when it seems every other news source I have is spreading nothing but fear, you are ‘doing the lords work’ and giving people information as accurate as you possibly can, without either sensationalizing nor sugar coating the situation. That is something some of us really need right now. Thank you.

    1. dearieme says:

      Seconded.

    2. loupgarous says:

      Amen!

    3. Martin (still not Shkreli) says:

      ditto, I cannot say how much it helps understand what is going on.
      And the quality of the explanations and of the writing allows us readers to forward the information to other laypeople.
      You are doing the general (and international: I see readers here from UK, GER, FRA, CHN, JAP, IND, etc…) public a great favor.

  5. Brian says:

    5. zinc + zinc ionophore

    1. colintd says:

      Don’t forget:

      6) Leeches (with or without zinc)
      7) IV Bleach

      1. r66 says:

        I wonder if he can top that … on the other hand, actually, I wonder not.

        1. JN says:

          Zinc nanorobots armed with uv light and lysol.

          1. AS says:

            I would like to see a SWOT analysis of that approach.

          2. DrivingBy says:

            Zinc-pated nanorobots with lasers, frickin’ lasers!

          3. Annonned says:

            Try zinc plated specially bred nano labradoodles with UV-laser eyes.

        2. Milkshake says:

          Did you see the report that three days befote musing about disinfectant into lungs a group of religious nuts promoting chlorine dioxide as Natural mineral cure 99 per cent effective in curing coronavirus went inti the White House to brief Trump about their breakthrough??

      2. chiz says:

        (8) Intravenous bullshit.

        Animal shit is used in ayurvedic medicine. So, there must be something to it!! And everyone knows that medicine is better if you inject it rather than imbibe it!!

        1. DrOcto says:

          ”Sir, would you please swallow this animal feces”

          ”Um…. what’s option B?”

          1. MagicChicken says:

            Suppository?

  6. JoeB says:

    Derek my friend, I assume have you seen that I Tweeted

    https://stm.sciencemag.org/content/early/2020/04/03/scitranslmed.abb5883

    The 5′-isobutyrate ester of hydroxycytidine is orally active against viruses—this looks as promising as anything I have seen in the last two whirlwind months. A very simply nucleoside analogue that gets metabolized to the triphosphate and causes mutation catastrophe—would be very simple to make and could be administered mostly anytime during infection, I would think.

    Keep sending those updates and doing a fantastic job with this blog!

    1. Pyro says:

      My question about something like that would be along the lines of safety. Assuming I’m right in the impression I get of how it works – I’m guessing it gets taken up by an infected cell, used in place of a nucleoside when the viral RNA is being assembled, and the resulting virus is able to infect a cell, but not replicate within it properly because the compound got used instead of a proper nucleoside and doesn’t transcribe properly, so instead of components for a protein capsid, it gets unusable garbage instead.

      But how would it affect a human cell in its replication cycle? Would the bogus nucleoside be taken up by the mechanisms duplicating the DNA to go into the daughter cells and hopelessly corrupt it? Because if so, that seems like it would be a potent carcinogen. Which would be a significant safety hurdle, I think.

      1. Paul says:

        A small amount might get incorporated but our repair systems are good at removing ribonucleotides from DNA so I expect the toxicity and mutagenesis would not be that bad.

      2. Ian Malone says:

        Since we’re now into DNA modification, I can’t help but think CRISPR and mAb.

        What could possibly go wrong?

    2. ex-Glaxoid says:

      This is β-D-N4-hydroxycytidine (NHC, EIDD-1931), which UNC is testing currently. It does have the ability to make it through a few routes, some of which are pretty scalable, and appears to have some utility in the few papers on it. Even I could likely make this material, unlike Gilead’s drug, which is pretty tough to scale. So it might be a good anti-viral, but thats not known yet in human use.

  7. Sanjay says:

    Surely one cannot take such a list seriously if it fails to include all-over treatment with massive UV — like from a laser! Yeah! — or vigorous inhalation of household cleansers. I mean, I personally am betting on “Formula 409,” because it’s fricking _prime_ and that should be good for something.

    1. heteromeles says:

      Hey, my elderly mother uses 409! How dare you encourage people to hoard her favorite cleanser! 😀 They should use 30% hydrogen peroxide like the real nutjobs.*

      Derek, thanks for your coverage. This is one of my go-to pages for keeping track of what’s going on.

      *Yes, I’m being sarcastic. Please use social distancing, masks, and handwashing with soap against Covid-19. And save the 30%+ peroxide for the homebrew rocket fuel boffins and people doing soil particle size analysis.

      1. Redox says:

        Google intravenous hydrogen peroxide treatment.

        1. heteromeles says:

          What?

          (googles)

          Oh yuck. Thanks….I guess. No, I didn’t think anybody would do that. I’m sadly naive.

    2. Micha Elyi says:

      “…all-over treatment with massive UV…”

      Is somebody remembering the xenon flash scene in the movie Andromeda Strain?

      1. Yup, rewatched this not long before the world went pear-shaped. Big flash, and body hair and superficial epidermis reduced to a fine, sterile ash. I suspect Mr Trump’s concept is more, uh, endoscopic in nature, perhaps involving a large halogen bulb.

      2. cthulhu says:

        At least nobody has mentioned kalocin.

        1. loupgarous says:

          Or buried study facilities complete with nuclear weapon destructs you have to be single to disarm….

  8. RespDoc says:

    the Mab Lessons of Palivizumab are instructive…..dose, regimen and cost of goods. Partially effective only….probably 50-60% effective. But RSV is seasonal and COGs just about work out because RSV is a disease of babies. It’s hard to see how anyone going to find SARS CoV2 Mab that can be given year round in adult doses at a sustainable cost across the adult population……
    RSV teaches us that entry inhibitors have no role in treatment and SARS CoV2 is no different. Respiratory antivirals have little benefit once viral cytopathology has occurred. That’s why Remdesevir China data completely expected. Unless you get therapeutic antiviral levels in respiratory epithelium early, it’s game over. From a small molecule antiviral perspective, best option is to go via inhaled delivery…get high local exposures at multiples of the IC90.

    1. eub says:

      Even something expensive and meh like palivizumab could be of use within a ring-‘vaccination’ approach? Detect cases, dose all their contacts with the mAb — even if it’s only 50% effective, that would knock an Rt of 2.4 down to 1.2, and if most of the contacts can self-isolate that can take it below the 1.0 threshold.

      Of course, this assumes the damn testing capacity to detect the damn cases in the first place.

    2. Giannis says:

      You are so correct. Maybe an inhaled version of remdesivir would require far less drug than the IV form.

  9. Ned says:

    Crazy to me that I happened to start reading your blog because I liked your articles about which laboratory chemicals have the most unpleasant smells and it’s now become my most trusted scientific news source for the biggest thing to happen in my lifetime.

    1. Athaic says:

      Similar experience here. Came for the weird chemical stuff, stayed for the insights about pharma industry. And now, that.

    2. Margot Otway says:

      I did the same. I found this blog a decade ago because of one “Stuff I Won’t Work With” post, and have been reading it ever since. Now I see friends discovering it and passing the word around.

      1. Simon Auclair the Great and Terrible says:

        Me too-came for tiww.

        Love the comments too and the whole no bs attitude.

  10. r66 says:

    Thanks a lot for your almost daily updates with well-written and founded posts. My first comment here although I read you since about almost 10 years now.

  11. James Donovan says:

    Thanks for the great post.
    You mentioned you have every expectation that this can be dealt with by a vaccine. What differences from HIV, HCV etc are there that provide this confidence?

    1. Derek Lowe says:

      That’s worth a whole new post! I’ll work one up and talk about the SARS vaccine experience, too.

      1. Giannis says:

        Please mention the attenuated SARS vaccine, that is also hypersensitive to remdesivir and ribavirin since the attenuated strain is exo-. I know that classic attenuated vaccines (like the measles and polio vaccines) are out of fashion but if an attenuated SARS2 vaccine kills one in a million people it might be worth it since many people are suffering (and dying) because of lockdowns and economic collapse.

        https://jvi.asm.org/content/92/17/e00710-18

  12. Al says:

    If vaccines don’t work or not for a while, billions of folks will need anti-viral treatments in developing countries. The TPP for other diseases of the developing world pay significant heed to stability and cost-of-goods. Biologics are probably non-starters.

    1. Derek Lowe says:

      The distribution of mAbs is definitely a potential problem, as compared to antiviral small molecule pills. But one way or another I think we’re going to have a vaccine first. Two years away? Vaccine. Four years away? Vaccine, etc.

      1. johnnyboy says:

        Yup. Vaccine is really the only way to properly deal with this. Antivirals are a red herring. Mabs may be useful if and only if they reduce the induction of cytokine release (ie. the bad cases), but producing enough to give to all hospitalised patients throughout the world does not seem economically viable, apart from the richest countries – and it does nothing to stem the transmission.

      2. Frank17 says:

        Shouldn’t (early) therapy of the risk groups be considered in order to gain time? It could be some time before a really effective, safe vaccine is available. Perhaps research could be done to find out whether inhalation delivery systems for drugs, such as liposomes filled with HCQ/camostat or ivermectin, could be used early in the course of the disease. Side effects such as QT prolongation in case of HCQ or hyperkalemia in case of camostat could possibly be reduced. Clathrin-mediated uptake into the cellular lysosome has been demonstrated for numerous substances. Could an effective IC 50 be achieved in the affected cells of the respiratory tract?
        In the case of chloroquine derivatives, I am not sure whether this could reduce the risk of haemolysis due to glucose-6-phosphate dehydrogenase deficiency ?

        1. metaphysician says:

          That would first require real evidence that any of these molecules actually do anything at all against Covid-19.

  13. Oudeis says:

    Derek,

    What are the explanations for why some diseases are so hard to vaccinate against? I know about mutation rate for flu, but what’s the issue with TB, etc.?

    Thanks for the informative work.

    1. Barry says:

      The simple answer is that a pathogen that provokes a vigorous immune response (fever, congestion, aches, diarrhea…) is an excellent candidate for a vaccine. The immune system recognizes it as a threat.Think smallpox, or influenza. A disease that doesn’t provoke such a response (TB, AIDS…) is a poor candidate.

      1. Oudeis says:

        Makes sense. Much appreciated.

        By that standard, it seems there’s reason to be optimistic about a coronavirus vaccine.

  14. Ian Malone says:

    Speaking of hepatitis, when all this is over it’d be interesting to see a post on hepatitis D and satellite viruses, that’s a bizarre area, even for biology.

  15. Tom Boyer says:

    Great post. As others have noted,while there may be no drug that has antiviral effect by itself, combinations might work. Anti-viral cocktails is the approach that, after a lot of skepticism, finally worked for AIDS (and keep in mind we are STILL without an AIDS vaccine after more than 3 decades of effort.)

    I would encourage Derek Lowe to talk about what would be needed to accelerate — greatly accelerate — the pace of research. We should be testing not just drugs but combinations of drugs. If you consider the thousands of approved drugs and OTC drugs and minerals (like zinc) and supplements — there simply HAVE to be combinations of things that would help. How do we find them? We don’t have decades to wait.

    Really it would require an effort on the scale of the Manhattan Project. But we don’t seem to have the leadership capability in Washington to do this right now. Hyperpartisanship has crippled our ability to rise to a challenge. Where’s FDR when you need him?

    1. DrivingBy says:

      “There HAVE to be combinations”

      Nature has no obligation to give you a desired result using the tools you have, including throwing the entire toolbox, kitchen sink, junk drawer and basement lab into the wishing well.

      1. Charles H. says:

        There’s no guarantee that there’s a correct approach, but if you don’t look, you won’t find it. So it’s best to assume that a cure is out there.

        That said, it could well be something that requires more than a single drug (whether vaccine or other). In fact it might require something weird, like warfarin combined with lowering the body temperature a couple of degrees combined with ?. And in that case it might exist, but not be found. At least not until there’s a really detailed model of human immunology (aka don’t hold your breath). But even then there are likely to be many “not quite as good” answers, and if enough people look in enough different places, probably one of those will be found.

  16. steve says:

    The issue with vaccines and monoclonals is potential immune enhancement. This happened with the first SARS vaccine. It also happened with Dengvaxia, a vaccine against Dengue that had a horrible result in the Philippines a few years ago. Safety has to come first and cutting corners could be as dangerous as taking medical advice from the orange fool in the white house.

  17. sgcox says:

    One approach not mentioned: solube ACE2 as a decoy, for example
    https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf
    The big plus may be that the virus can not mutate out of this as it will stop binding to endogenius receptor too.
    Fusing with Fc will basically mimic entracept for RA

    1. theg9 says:

      How strong of a binding would there be between the viruses and these soluble ACE2 receptors? If the binding isn’t highly favorable in terms of energy, then couldn’t the viruses just detach and be free to infect cells again?

      Also, it seems that a primary concern for treatment is managing an overactive immune response in some patients. Injecting these ACE2 proteins could potentially lead to even more of a heightened immune sensitivity due to the body being flooded by all these foreign proteins.

      Still, it’s an interesting approach.

      1. Giannis says:

        The ace2-Fc fusion protein is extremely effective at stoping SARS2. Much better than SARS1. A enzyme dead has exactly the same activity. The EC90 is less than 1mg/L. That is on par with monoclonal antibodies.

        https://www.biorxiv.org/content/10.1101/2020.02.01.929976v2.full.pdf

    2. Barry says:

      But that hypothetical decoy soluble ACE2 would have to be applied (aerosol?) to the lung surface, not set free in the plasma compartment

  18. sgcox says:

    Etanercept of course, sorry.

  19. Pete says:

    Tom Boyer – one of the main things that slows all this stuff down is not producing something which works, but testing it to find that it works. It is very very likely that there is a working vaccine right now in existence for this coronavirus; actually there are probably several. What we do not know is: which ones are they, and which of the ones that work do so without side-effects that are too serious to consider for vaccination.

    Suppose you have a medicine M for disease X. You need to know how effective M is against X. You also need to know what side effects M has. How much you care about these things depends on what X is, and how you want to administer M.

    If X is something really nasty, like say Ebola or an aggressive cancer, and M is supposed to treat someone who has symptoms of X, then you do not care too much about side-effects. More or less anything will be tolerable, because without M, X is very likely to kill the patient in an unpleasant way. You really only care that M is effective, and that’s something you can probably measure relatively easily if X is prevalent; you’ll have no trouble finding people willing to take anything that might work.

    If X is something not very nasty by comparison, like this coronavirus, you care much more about side-effects. If your M against coronavirus kills 0.5% of people who take it, then it had better be amazingly effective (in the way that, say, antibiotics are against scarlet fever, which is really an exception), otherwise you’ll end up killing more people not less.

    If X is something trivial, like the common cold, then it’s not clear you should even try to develop a medicine: you will need to be very sure that it is both very effective and very safe (or give it only to very-high-risk groups after they become seriously ill – but at this point most medicines won’t be effective). The numbers simply are not on your side for doing overall good.

    What if M is a vaccine? Then you are giving M to people who do not have X yet; maybe most of them would never have X, and that is especially true if you think that a better vaccine might come along. Your tolerance for side-effects is very, very low. And you had better be sure that your vaccine is more effective, even against these kinds of bad numbers. Putting some figures: if X is this coronavirus, and it has a 1% fatality rate, and you think 10% of the world might eventually catch it (this is low-ball if you think there will never be a vaccine, but if you have in mind the possibility – which is likely – that there will be a good vaccine soon, it’s high-ball), then you definitely cannot tolerate more than a 0.1% fatality rate for your vaccine – otherwise giving everyone the vaccine will kill more than X. In fact, you want your vaccine to have a much lower than 0.1% fatality rate, otherwise you’re at far too much risk of doing more harm than good – especially if you do not actually know how much good you are doing; how effective is the vaccine, and how long does protection last? It will not be 100% and forever!

    If you don’t know that your medicine is effective, on the other hand, then you can tolerate no side effects at all. But that is unrealistic; whatever medicine you look at, it has killed someone – maybe someone with a weird allergy unique to them in the entire human population, maybe someone who you happened to catch right at a critical moment in their fighting another disease, whatever. The measles vaccine, for example, has about a 1 in a million fatality rate, which is pretty good (and way better than no vaccine), but not zero.

    But even if we only look at fatality numbers, it’s going to take quite some testing to be confident that a vaccine doesn’t kill significant numbers of people, and that it actually works well enough. And that testing takes time.

    What makes things even more complicated is that of course fatality is not the only measure. There will be people who survive coronavirus but who have lasting serious health issues; how much weight should we give to that, and what is the rate it happens at? There will be people who suffer from whatever medicine M we develop (for example G-B syndrome); how much weight should we give to that and what’s the rate? In fact, we have some economic value already established for fatality and for most any side effect, so what is left (which needs testing and time) is to determine what the rates are for our M.

    1. Jim Hartley says:

      Clearly written and very informative, Pete. Thank you.

  20. RespDoc says:

    Synergy data here –
    https://www.sciencedirect.com/science/article/pii/S016635422030200X
    ideally, you would want to maintain emetine in respiratory cells at 5x EC50 (generic antiviral rule of thumb). It should be amenable to inhaled delivery by standard nebulization and would avoid systemic liability.
    Remdesivir is prodrug needing conversion to nucleoside triphosphate but is active in human respiratory epithelial cultures (0.07 uM EC50) so amenable to direct delivery.

    There are a bunch of unknowns – e.g. local irritancy but these could be rapidly assessed and addressed.

  21. Walter L Wilson says:

    Mother’s little helper…what are Einav’s drugs are?
    The Quest for a Pandemic PillThe Quest for a Pandemic Pill

    Einav’s collaborators are now testing these drugs on the new coronavirus. She’s hopeful, given that they’ve also shown promise against the virus that causes sars. But she notes that they didn’t work for DNA viruses. An infinitely broad-spectrum antiviral, she acknowledged, may be out of the question: “I don’t think it’s one for all, but it might be one for many.”

  22. VALERIE BRANYAN says:

    I am going to ask this again since no one had a comment the first time. I use NasalCrom for allergies. It is cromolyn sodium nasal spray. Why isn’t cromolyn an option for ARDs? It says it it a mast cell stabilizer. Do you think it could be protective or perhaps bad to use during this pandemic?

    1. johnnyboy says:

      It’s unlikely that mast cells play any significant role in the pulmonary lesion of COVID19. Mast cells induce an inflammatory reaction when antigens or allergens bind to IgE on their surface. The pulmonary lesion of COVID is most likely due to increased release of cytokines from lymphocytes, macrophages and dendritic cells, which wouldn’t be inhibited by cromolyn.

  23. Milkshake says:

    Sorry for nitpicking, you mentioned TBC as a disease for which an effective vaccine was not developed. This is not correct – in fact the BCG vaccine use in the Czechoslovakia after WWIi led to complete eradication of TBC. The commie regime was quite good at mass vaccination. It also did a thorough cull of TB infected cattle quite easily after confiscating all cattle (and land and machinery) from farmers.

    Many western countries chose not to adopt TB vaccination because it was deemed not effective enough and the immune reaction produced obscured an inexpensive skin test for TB. But the version of BCG used in the West was safer and probably less effective than the stuff in the Eastern Bloc

    1. baldrick says:

      By the way, people are looking into the use of the BCG vaccine against COVID-19:

      https://www.statnews.com/2020/04/14/decades-old-tb-vaccine-attracts-attention-and-skepticism-as-a-potential-weapon-against-covid-19/

      “Suddenly everybody and their brother has found the atlas and then taken their Covid data from the WHO or from Johns Hopkins University or wherever, overlaid the two and run regression models and [said] ‘Oh, look here. BCG works,’” Pai said.

  24. Anon says:

    Any reason why anti-IL-6 drugs aren’t mentioned here?

    More generally, I would love to understand why oseltamivir is only effective when given early on in the infection. Is that because the later stages of the illness are mainly immune responses rather than the direct impact of the virus. Is this likely to be true for other antivirals? Is it possible that remdesivir alone might be ineffective but might be more effective when combined with an IL-6 drug to help an immune response? I saw the Rhesus monkey study was with early administration of remdesivir.

    Just a physicist trying to learn here and maybe grasp at a few straws.

    Also was curious if anyone has looked at cross immunity from other human coronaviruses. I’m sure that full immunity is too much to hope for, but is it possible that it could lead to milder symptoms? Or is this silly?

    Thanx.

    1. Derek Lowe says:

      Those aren’t antivirals per se, which is what this post is concentrating on. But if people really are being killed by the immune response, this sort of things is important, for sure. The anti0IL-6 don’t “help” the immune response, though, they’re actually turning it down, so you wouldn’t want to do that in the early stages of infection, presumably.

      1. Giannis says:

        We need to give antivirals AND immune suppressors. Otherwise immunosuppression might allow the virus to continue multiplying and killing the host.

    2. Anon says:

      Just saw this

      https://www.medrxiv.org/content/10.1101/2020.04.17.20061440v1

      with respect to cross-immunity from other HCoVs. I wonder if you could do a retrospective study looking at parents with young kids in daycare to try to get a handle on any potential effect.

  25. Anon says:

    Yeah. I was thinking a combination of antivirals and anti-IL-6 for later stage patients, but I know nothing so I have no idea if that even makes sense. But if it does make some sense, I assume there’s a clinical trial out there? I hope?

  26. Anon2 says:

    Another item that should be mentioned is reimbursement.
    The public at large feels that the treatments/vaccines should be incredibly cheap, if not free. Pharma/science hasn’t taken the gloves off because our academics will still want to focus on their current grants and pharma will want to focus on what will actually be reimbursed. We are seeing now how basic symptom management at hospitals is putting millions (if not billions) into provider’s (hospitals/physicians) pockets. Literally very basic IV drips, NSAID, antibiotic protocols, etc that is not novel at all.

    It is interesting to think about how the market values this as well because with good/bad news recently we have seen a 5-10% jump/drop in market cap for companies like Gilead, related to their corona therapeutic news, yet the market as a whole is moving by trillions across all sectors based on this same news.

    How is it that drugs, which are actually doing the work, account for 10% of healthcare costs? Who is collecting that other 90%?
    I am seeing many companies and scientists stay out of this fight because they are not being given incentives like those on the service side, bonuses, overtime, govt grants (100 billion to providers alone via CARES Act)

    1. ab says:

      Who told you pharma isn’t working on COVID-19? This is on-another-planet wrong.

    2. Jack Reardon says:

      Anon –
      I wholeheartedly share your confusion regarding the healthcare price public discussion only covering drugs, which only account for 10% of healthcare costs.
      Physicians and hospitals get a pass, but they account for far more of the total price tag. Why is this?

  27. Guest1 says:

    Compare the market cap loss/gain on a Gilead stock when data is released versus the overall market. A company that shows negative data drops by a billion in market cap and the market at large drops by a trillion. It really is a case for how underprice pharma stocks are, and how little of a very well defined value proposition will ever be realized.
    Drugs are one of best bangs for your buck of any product made.

  28. Earl Killian says:

    I am curious if there is a mab that binds to the spike protein, which attaches to ACE2 receptors, will this mab also bind to ACE signalling molecules, and therefore screw up blood pressure regulation?

    1. Derek Lowe says:

      If it’s “raised” to the spike protein itself, it will very likely be covering up the parts of it that recognize ACE2. That will leave the virus with a large new protein stuck to those area, and its outer surface should have no chance of being something that binds to ACE2 at all.

      1. Earl Killian says:

        I think you misunderstood my question. It wasn’t whether it would bind to the virus. I assumed that much (otherwise it would be discarded by pharma). It was if it binds to the virus, will it also bind to ACE created by the body, preventing the body’s ACE getting to the ACE receptors on the body’s cells, and thereby interfering with, among other things, blood pressure regulation.

        1. Derek Lowe says:

          Ah, we’re still misunderstanding each other – I though you were asking if the antibody would bind to ACE2. But no, if the anti-spike-protein antibody binds to the virus, it will not also bind to the ACE protein or to the ACE2 enzyme. It’s binding to and covering the part of the virus that recognizes ACE2, so the virus will no longer be able to bind to ACE2. Meanwhile, there’s no reason for the antibody to bind to the ACE protein, either, either before or after it binds to the coronavirus.

          I think you’re wondering if the antibody is acting as a mimic of the ACE2 protein and that’s how it binds to the spike protein, and that would make it capable of binding to ACE. But antibodies to a given target have very different binding modes than the natural ligands to that target – an antibody to the spike protein can bind to it all sorts of ways without having to be a copy of ACE2.

          1. Greetjamlyu says:

            Well, if you are worried about that, than forget it……there are a infinite possibilities but mab binding to the ” signaling molecules ” are the least of our concerns. That is the problem with ” I think something so its correct”. Read up before you post.

        2. chiz says:

          Derek – Earl Killian appears to be under the impression that ACE2 is a receptor for something called ACE. His thinking, presumably, is that if the spike protein binds to “ACE2R” then any antibody against the spike protein will also bind to any other ligand for “ACE2R”, such as this “ACE”, since all ligands for this supposed receptor will have similar shapes.

          I’m guessing he has only just found this blog and doesn’t know you posted some background on this back in mid-March.

  29. Adrian says:

    “Serum Institute of India to Start production of Oxford’s Covid-19 Vaccine in 2 Weeks, Launch in October if Trials Succeed”

    Is this just a completely crazy/desperate attempt that would end up being a phase 3 trial with 50 million people, or is there a realistic chance that this might just be faster than anyone had expected?

    I am not expecting a yes/no answer, my hope would be for a blog post assessing this schedule.

  30. RespDoc says:

    Just out – screened a collection of 5632 compounds including 3488 compounds (marketed drugs, phases 1 -3) across 600 indications.

    https://www.researchsquare.com/article/rs-23951/v1

  31. David Cockburn says:

    Maybe another approach worth discussing is to repurpose drugs to ameliorate the worst effects of Covid19. In this way, while many people would become sick we could ensure that they got only mild disease. I’m thinking particularly of drugs to control the cytokine storm which is apparently the cause of death in the worst cases.

  32. Oliver says:

    Derek: I just wanted to get your opinion whether two existing vaccines (TB – BCG and Polio – OPV) are simply grasping at straws or have a reasonable chance at decreasing the severity of COVID cases, should the vaccinated person become infected after administration.

    These are easy to test, because they already exist and the trials can start at Phase III. And it makes sense to try anything at this point, especially if the vaccines have been shown to be safe and are already in widespread use. And there is some evidence, perhaps not ironclad, that these do boost children’s immune systems to partially protect them from other pathogens for some period after immunization.

    Do you think these have promise?

  33. Toni says:

    I have noted here before that it turns out that COVID is not a typical lung disease, but affects the vessels (not only in the lungs) in particular. Meanwhile, there are more and more reports from doctors, who report above all on disturbed hemostasis (also in children; Kawasaki like symptoms). I now believe that we could reduce the mortality rate dramatically once we have a better understanding of the underlyingmechanisms.

    Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19 :
    https://www.sciencedirect.com/science/article/pii/S0735109720352189
    No significant differences in mortality were found in the overall collective of patients. However, the 395 patients on mechanical ventilation showed showed remarkable differences: a mortality rate of 29.1% compared to 62.7% in the nonanticoagulated group.

    See also Kawasaki disease: https://www.medpagetoday.com/infectiousdisease/covid19/86393
    https://www.medscape.com/viewarticle/930180

    1. Toni says:

      https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31041-2/fulltext :
      Before their admission to ICU, we detected low antithrombin III concentrations (26–62% [reference >70%]), severe hypalbuminaemia (serum albumin concentration of 1·4–1·9 mg/dL [reference 3·4–5·0 mg/dL]), and urine samples positive for blood, albumin, and leukocytes.

      If we could get results from studies testing the impact of anticoagulant therapy, we would have a simple test and possibly a prophylaxis that could significantly reduce death rates.
      I believe this point is important in light of what we are learning every day about COVID.
      My hope for such therapies that bring the disease into a controllable state is greater in the short term of this battle than a vaccination.

  34. Rob says:

    Any comment on the Hong Kong combination therapy trial reported in The Lancet? Small, open-label, but the results were quite good.

  35. Toni says:

    Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19 :
    https://www.sciencedirect.com/science/article/pii/S0735109720352189
    No significant differences in mortality were found in the overall collective of patients. However, the 395 patients on mechanical ventilation showed showed remarkable differences: a mortality rate of 29.1% compared to 62.7% in the nonanticoagulated group.

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