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.