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Covid-19 Biologic Therapies Reviewed

Friday I looked over the small-molecule landscape in this post, which has been updated and will continue to be as more news comes along. Today let’s look at the biologics landscape. One thing that I want to emphasize up front, as I did in the earlier post, is that none of these things are available right now, and that it’s very likely that none of them will be available for many months even if things run as quickly and perfectly as possible.

The anti-corona biologics field divides into several smaller categories (we’ll get to those) and two large ones, antibodies and vaccines. The way to think of that is that the former would be dosing external antibodies that have already been targeted to some part of the coronavirus, while the latter would encourage your own immune system to raise such antibodies itself. There is an overview list here at BioCentury, open-access.

Where do you get such external antibodies? Takeda has an effort underway to isolate them from the plasma of people who have already developed immunity (immunoglobulin therapy). This program (TAK-888) would take around a year, give or take some months, to start treating high-risk patients. But how many? One recovered-patient’s worth of plasma might only be enough to treat one other person; we just don’t know. It might be a bit better; it could be worse. So this is going to be something for people who are in bad shape and need something immediate. This technique gets broken out during severe epidemics, and has already been tried on an emergency basis in China, but we really don’t have any well-controlled data to work with yet. The hope is that such a therapy could skip Phase I (immunoglobulin therapy has a long history of clinical use) and go straight into Phase II, then perhaps skip an actual Phase III and let clinical evidence accumulate in real-world use. We’ll see.

The isolate-from-plasma route has the advantage of being polyclonal (a mixture of antibodies to several different features of the viral proteome), but that has a potential disadvantage as well, as pointed out here. “Antibody-dependent enhancement” is a concern for this sort of therapy and for vaccines as well – in general, the antibodies developed against one virus can actually make later infections with later viruses even worse. If the antibodies bind to the new viral proteins but do not actually neutralize them, they can enhance cellular uptake of them, which is exactly what you don’t want.

There are also a number of organizations working on monoclonal antibodies to particular coronavirus proteins (here’s another recent summary of this area, PDF here). As you’ll see in that paper’s Table 1 and Table 2, there are a number of epitopes that were targeted for the SARS and MERS coronaviruses (an epitope, for those just jumping into this subject, is an exposed region on a protein that you can potentially raise an immune response to). This new coronavirus, like the others, bristles with “spike” proteins that interact with human cell receptor proteins, so those are high on the list. We’re seeing similar work being done right now on 2019-nCoV; see the bottom of the page on that BioCentury list linked in the first paragraph).

When would these come on line? Monoclonal antibody production is a big industrial field, and there’s a lot of expertise out there. Regeneron’s CEO (Lenny Schleifer) said last week that the company could get 200,000 doses/month coming from their own production in August, but we have to remember that he was saying that in front of President Trump at a White House meeting. To my eyes, that’s about as optimistic an estimate as one could possibly commit to; I would expect things to take longer (and note that Schleifer appears to be just talking about the production aspect, not the demonstration of efficacy and safety in the clinic).

Now to vaccines. That list I’ve been referring to has a long string of people working in this area, and that’s a good thing, because a vaccine is probably the best long-term solution. A safe and effective vaccine, let me amend that, while noting that proving both of those is what makes vaccine development the field it is. You have the antibody-enhancement problem mentioned above, you have the potential for a pathogen to mutate its way out of efficacy, and you always have the risk of immunological side effects. Readers my age and older will recall the 1976 “swine flu” debacle, in which a huge campaign was launched to vaccinate the public against an epidemic that never actually materialized, while also setting off hundreds of well-publicized cases of Guillain-Barré syndrome. That is a well-known immune disorder that usually occurs after a mild viral infection, where the nervous system’s myelin sheaths come under attack. It generally resolves, but not always, and can land patients in intensive care. The swine flu vaccine (a live-attenuate-virus preparation) is the largest vaccine-driven GBS incident that I’m aware of, and we do not want to repeat that. Vaccines by definition are being given to large numbers of healthy people – it’s vital that you do not cause more trouble than you’re trying to prevent.

That said, I have little doubt that a good 2019-nCoV vaccine can be realized. But that too is going to take time, and it’s definitely not going to be coming on in time to help us right now. No one knows if we’re going to be seeing this pathogen as a regular feature in human disease or if it will disappear like some others have. It’s reasonably likely that the virus will decrease in the currently affected areas during the warmer months (perhaps becoming more of a problem in parts of the Southern hemisphere?), but we don’t know that for sure, either. If it’s going to be with us, though, we will be vary glad of a vaccination program.

What that vaccine will look like is anyone’s guess. There are a lot of “traditional” development programs underway, along with some that we haven’t had available in the past. Moderna and others are working on RNA- and DNA-derived vaccines, which have the advantage of being potentially faster to develop, but the disadvantage of never having been all the way through human trials yet for anything.  It’s a field with a lot of promise, but it needs a lot of proof, too. This Stat article has some interesting info on synthetic biology approaches to a vaccine (nanoparticles, etc.), but those also remain unproven. It may well be that more tried-and-true vaccine development (immune response via proteins, rather than via DNA/RnA) blows all of these things from the landscape eventually, but for now I’m glad to have a lot of approaches going on.

Past antibodies and vaccines we get to more exotic stuff like direct siRNA treatments, which Alnylam and others have announced work on. No disrespect to some good researchers and companies there, but I have these on a lower rung than the other possibilities. I don’t see these things as having any shorter path to development than the more well-worked-out antibody and vaccine routes, and they have more uncertainties around them. Not least in dosing – getting good systemic levels of something like an siRNA therapeutic is very much nontrivial. The oligonucleotide vaccine idea at least has the potential for a smaller dose needed, since it’s just trying to prime the immune system in general.

I’ve no doubt missed some other approaches, and I’ll update this post with more information as I have been doing for the small-molecule one. Final thoughts? I think that the biologic agents are likely to be the main line of defense against this coronavirus; there is every reason to believe that we can get an effective therapy out of one or more of these approaches. But none of them are going to be coming on in time to help the crisis we’re looking at right now. As I said before, look around you: we are fighting this epidemic with the tools we have on hand at the moment, and the chances of anything new and dramatic arriving shortly are very, very low. Months, many months, maybe a year or two, and that’s if everything goes really, really well. That’s when the good stuff will be arriving.

40 comments on “Covid-19 Biologic Therapies Reviewed”

  1. milkshake says:

    actually camostat is available in Japan by prescription, and is is quite safe, and cheap (it is generic). We just do not know how well it works.

    1. APAJ says:

      Other research has also found Nafamostat, structurally closely related, to prevent MERS infection through TMPRSS2 inhibition (link in handle). “but risks of complications (incl anaphylaxis) must be weighed in non-emergency care”, so I’d hardly suggest it as a preventive medication…

    2. Student says:

      How long will it be available after proving efficacy? I doubt they have 20 millions treatment courses in storage to treat an epidemic.

      Thats the problem with all repurposed drugs. There are no (large) stockpiles to treat a significant amount of patients.

      1. milkshake says:

        It is a fairly simple API, and it is already off patent. There are several manufacturers in Japan. If it shows efficacy, it could be rushed into production on the timescale of 1 month. It is the type of drug that seems safe enough to be taken as a prophylactics, so it could help the healthy population too. We just do not know how effective this is

  2. As2O3 says:

    Both my partner and I, living in a Chinese city quite close to Wuhan, likely had the disease at the very beginning of January – both rather mild; mainly fever, muscle aches, stuffy nose and diarrhea. The thing is, while most symptoms disappeared within 6-7 days the bad stomach has persisted, and we’ve twice since had mild fever – with my partner having tonsillitis right now. There does seem to be some rumors on the Chinese internet of this disease possibly becoming chronic in some patiens, but have any paper been published yet?

    1. Aleksei Besogonov says:

      This sounds like a complication from a bacterial infection. This is fairly common in pneumonias.

      You can try a course of antibiotics and see if it helps.

      1. As2O3 says:

        The thing it, it’s been almost 2 months since we more or less recovered… I treated us both with azithromycin originally, thinking it was a bad case of food poisoning. My partner’s breathing issues developed, and he was diagnosed with phneumonia on Jan 10 and sent home from the hospital with tobramycin. By then my symtoms had mostly cleared up, and his breathing issues resolved a day or two later, with what seemed like sinusitis persisting for another week.

        Just a couple of days ago, on March 8th, he once again got a fever, now with tonsillitis… (He’s on amoxicillin right now, the only antibiotic we had left lying around.) I realize this might be completely unrelated; both our original symptoms to Sars-CoV-2 (this was before the panic spread outside Wuhan), and the tonsillitis to whatever we had the first week of January – but that’s an awful lot of coincidences tied together with 2 months of diarrhea… (Between the ensuing panic among neighbors, the draconian measures and risking our pets’ lives we’d sadly have to be near death before returning to a hospital to get it checked out – probably why the statistics from China are looking so rosy.)

        1. Rick Deveraux says:

          Stomach problems are well known side-effects of taking Azitromycin – and many other antibacterials as well. This is the result of them not just affecting the bacteria causing the disease, but also the bacteria that are necessary for the correct functioning of the gut.

          From what you’re saying, it seems that your husband has been on some kind of antibacterial compound for a good chunk of the past two months. It is possible that taking all these compounds has prevented his gut from returning to the usual composition of the intestinal flora.

          This is merely an hypothesis – to really know the cause of this you would have to visit a doctor.

        2. Chris says:

          Are u sure u have COVId? They make test?

    2. MadBioSTEM says:

      What are the GI symptoms? There has not been enough reported on the GI symptoms and their persistence. When does diarrhea set in and how long does it last?

      1. milkshake says:

        about 25% of patients get few days of watery diarrhea, some dull stomach pains and a lack of appetite.

    3. Jaime says:

      As203 – new to the thread but haven’t seen any updates from you in the last couple days – wanted to check-in and see how you and your partner are doing?

      1. As2O3 says:

        He recovered from the tonsillitis, but was complaining about testicular pain a day ago. I’ve been feeling a bit “off” lately too, with a stuffy nose and headache – but it could just as well be hypochondria, allergies (spring is arriving), or just cabin fever and lack of exercise from being in a semi-quarantine for two months… With the amount of people getting infected we’ll know sooner rather than later anyway.

        1. Chris says:

          I have massive Lung inflammation but no viral Azithromycin help . Did u have sure Covid ? Someone makes test?

          1. As2O3 says:

            There were no tests available for SARS-CoV-2 in early January, we’re both fairly young (30ies), so I’m guessing we got off easy. I cannot be sure, and honestly, having 4 pets and living where we do I do not want to get tested. It doesn’t really matter anymore anyway, not with the current spread of the disease. Either we’re hypochondriacs and going crazy from the semi-isolation here, or someone in Europe will soon realize that (some?) people remain infected (infectious?) long after the acute symptoms are gone.

  3. Emjeff says:

    “One thing that I want to emphasize up front, as I did in the earlier post, is that none of these things are available right now, and that it’s very likely that none of them will be available for many months even if things run as quickly and perfectly as possible.”

    Umm…ok, then.

  4. Barry says:

    I will speculate that I’m not the only one wondering why the “Antibody-dependent enhancement” argument is made against Immunoglobulin therapy, but not against vaccines.
    Vaccines also evoke a polyclonal response. Some of those antibodies will bind to the target without clearing it, just as w/ immunoglobulin therapy.
    The weakness of immunoglobulin therapy in my mind is that it is humoral only, lacking any T-cell arm. Even a recombinant antigen vaccine or a killed vaccine will provoke some T-cell response because viral fragments will be presented on “professional antigen-presenting cells”. Immunoglobulin therapy circumvents B-cell activation but ignores T-cell activation.

    1. MrXYZ says:

      The issue of vaccine-induced antibody-dependent enhancement (ADE) has been a major concern in the Dengue field, where strong immunity against one serotype can lead to weak cross-reactivity and ADE against other serotypes.

      This appears to be what happened in the Phillipines.

      1. Cuibono says:

        Precisely!
        Dengue and DHF might be signalling here.
        Perhaps indeed that will explain the age mortality pattern we are seeing. Maybe older adults have been exposed to previously unrecognized corona virus epidemics

    2. VAX and FACS says:

      A vaccine might be more likely to induce ADE of infection compared to a cocktail of monoclonal, neutralizing antibodies (especially because it’s easier to control the dose of mAbs vs Abs induced by vaccines).

      You’re right that there’s no T cell component to an antibody therapy, but even if CD8 responses are important, I’d still bet on the major correlate of protection being related to neutralizing antibody titer.

  5. Jeff says:

    Just a bit of idle curiosity: I wonder how many of the people who are screaming for Covid-19 vaccines NOW! are past anti-vaxxers…?

    1. loupgarous says:

      …and how long will it take before we see the inevitable TV ads recruiting plaintiffs for lawsuits against damage which could be traceable to COVID-19 vaccines and other biologicals. You know that Big Law’s already salivating over the billables from THAT.

    2. Moon Unit says:

      I was wondering the same thing — someone I was talking to suggested that the true anti-vaxx believers think it’s a false flag operation.

      Personally I think it’s irrelevant. Covid-19 is an Earth-based contagion, which spreads fast due to the planar nature of that planet. Meanwhile, all US citizens were beamed to the moon in our sleep during Y2K, so we will be Perfectly Safe.

    3. Anti-Vaxer says:

      It’s incredible to me the lengths that science folks go to to mock people that argue against vaccines or for advocating that vaccines are actually safe. There’s a number of vaccines that EVERYONE knows have been dangerous-the one Derek mentioned above, the gardasil vaccine, etc. and yet people are still like “lols anti-vaxxers so dumb”

      1. Drew Wakefield says:

        i know right?! i would so rather have the fake corona flu than autism personally~~

        1. Reign Forrest says:

          Hehe!

        2. ScienceNatureJAMA Publishing Group says:

          Dear Honorable Doctor Walkefield:
          We at ScienceNatureJAMA Publishing Group are good fans of yours and want to help you fight the autism.
          Rate card available on request.
          Dr. Hoss Cartwright, Senior Editor and CEO.

  6. loupgarous says:

    Eventually, the one thing China will have more of than any other nation is recovered COVID-19 patients. Whether
    (a) it sets up a program for harvesting plasma from recovered patients and
    (b) shares the plasma outside its borders,
    (c) that approach to immunizing COVID-19-naïve patients actually works and
    (d) doesn’t cause worse issues than it prevents (e.g., antibody-dependent enhancement)
    we don’t know.

    1. Klaus Witte says:

      Small peptides have been shown to inhibit entry of coronaviruses into host cells via binding to ACE2. This was originally studied because of the SARS outbreak, but should be valid for all viruses using ACE2 as target for cell attachment and entry.
      (see Struck et al. 2012, https://doi.org/10.1016/j.antiviral.2011.12.012)

  7. Giannis Zaxarioudakis says:

    Other antibody or antibody-like approaches not mentioned in the article.

    1) Soluble hACE2. There are onngoing clinical trials for COVID and it has already passed safety phase I trials [https://pipelinereview.com/index.php/2020022673884/Proteins-and-Peptides/APEIRONs-respiratory-drug-product-to-start-pilot-clinical-trial-to-treat-coronavirus-disease-COVID-19-in-China.html]

    2) Enzymatic dead hACE2-Fc. This seems to be the best approach. Almost guaranteed to work. Likelihood of resistance close to zero. Has already been proven effective for SARS1.0

    3) Human Monoclonal antibodies that bind the Spike binding domain of ACE2. These haven’t been developed. Their big benefits are that they are almost guaranteed to work with few side effects as they are unlikely to block ACE2 enzymatic activity.

    If (3) are developed with low picomolar kD and Fc mutations that increase binding to FcRn then even 10mg should be enough to protect a person from the disease for months. The cost of 10mg of antibody is usually less than $1. The tragic thing is that this type of antibodies could have been stockpiled in case of SARS reemergence. Hindsight is 20/20 of course.

  8. Charles H. says:

    A different idea. What about a “probiotic” spray of bacteria that like to eat corona viruses? Sort of the opposite of sterilizing the surfaces, but safe enough to spray it on, say, oranges.

    This wouldn’t treat the active disease, but would reduce it’s ability to spread. And it could be a skin cream that you rub on your hands as well. Clearly there’s a problem that there aren’t enough corona virus particles around for it to live on, so the spray would need to contain food for the microbes.

    A couple of problems are that I don’t know if such microbes exist, and the possibility of mutation. But if it were available, it could really cut down the transmission rate.

    1. c says:

      Not sure if this is a joke, but this sounds like a terrible idea.

      Just wash your hands if you want to avoid transmission by touch.

      1. Charles H. says:

        It’s not a joke, though it may not be feasible. Wash your hands doesn’t deal with the surfaces, and sometimes they can’t be “sterilized”.

        OTOH, I’m definitely not a biologist, much less a microbiologist. It may be a silly idea, though it sounds reasonable to me. I suspect that it’s real problem is that no such microbes exist, but if they did I wouldn’t know.

  9. Eleven fingerrrrrrsssss says:

    Even if we get a vaccine we’ll still need a healthcare system. For health, not profits or optimising the quantity of Martin Shkrelis.

    Look how Korea is doing and more evidence that the 3 to 4 percent mortality is very highside.
    https://asiatimes.com/2020/03/why-are-koreas-covid-19-death-rates-so-low/

  10. Eleven fingerrrrrrsssss says:

    Some demographics.

    Don’t forget1/2 of Chinese smoke and most of them are in very bad air pollution both exacerbaters of respiratory ilness.

    https://www.statnews.com/2020/03/03/who-is-getting-sick-and-how-sick-a-breakdown-of-coronavirus-risk-by-demographic-factors/?utm_source=fark&utm_medium=website&utm_content=link&ICID=ref_fark

  11. Ped64 says:

    How could you not talk about remdesivir
    The antiviral in phase iii
    ?
    It has trials in China / japan / Italy and USA
    Seems it’s get some attention
    To Block the enzyme as well and stop the virus from reproducing

    1. loupgarous says:

      Derek covered remdesivir with other small molecule drugs being considered for treating COVID-19 in the March 6th post.

  12. Anonviral says:

    The ebola crisis appears to show that on the fly antiviral repurposing doesn’t do much. They tried them but it didn’t stop the second epidemic post-2014. Clinical practices and vaccines seem to be what made the current epidemic stop. Anti-viral small molecules seem to be more applicable to chronic infections such as HIV. It’s easy to miss that point based on conventional strategy….” if this hit the virus polymerase it must work, what are we doing wrong?”. It must be something fundamental…..viruses of certain types beat the diffusion limit and dont allow small molecules to be relevant to stop the viral machinery.

  13. A vaccine wouldn’t need to be given to the whole population at once. It could be given to volunteers taken from the populations most at risk, on an experimental basis, where they were monitored for side effects and to see whether it worked. If it did, the effort could be scaled up to a larger stage, then to an even larger one, until it got to general approval.

    Yes, that’s not the current regulatory regime, so you’d need politicians willing to take the blame for accidental injuries done in the process, but if there were such politicians it’d work.

    The statistical procedures for handling such a process would be more complicated and the results would be less accurate than they are under today’s rules, but they could be sorted out. It helps that the desired effect would be a very large one, and an immediate one: none of this looking for a 20% improvement in an outcome that often takes years to happen.

  14. Dr. Benjamin P. Repsold says:

    Flu vaccine vs. Immunoglobulin ?
    Do you rather use immunoglobulin IM/IV (which increase/boost the immune system) instead of a flu vaccine (which suppresses the immune system) ?

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