A primer on the new coronavirus and COVID-19: BioCentury editors in conversation
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The rapid pace at which COVID-19 has transformed society has rippled through the biopharma industry, affecting not only companies’ business strategies, but their product pipelines and priorities as many of them adapt on the fly to the ever-changing landscape.
In a roundtable session, Editor-in-Chief Simone Fishburn sat down to discuss issues surrounding the COVID-19 outbreak with Executive Editor Selina Koch, Washington Editor Steve Usdin, Senior Editor Lauren Martz and Associate Editor Karen Tkach Tuzman.
The conversation covers strategic and business concerns among biotechs, regulatory developments and the science of making new therapies.
On biotechs’ minds
Simone Fishburn: We’ve been talking to a lot of biotechs and we’ve done a couple of surveys now. What are we hearing are companies’ principal concerns?
Selina Koch: One of their concerns is just how they get business done right now, in particular clinical trials, given that a lot of patients can’t get to hospitals and that in some cases, patients are at more risk if they go in for their treatment than they would be if they stayed home.
SF: What are the therapeutic areas where that’s playing out the most?
SK: Anybody who would be taking a therapy, say something for an autoimmune disease, that suppresses your immune system -- there you’re particularly at risk for getting an infection. But really it’s shaping up to be that anybody who doesn’t have a life-threatening condition, even if you have a pretty severe rare disease, might want to stay home.
SF: But we’re also hearing that oncology trials are still going on. Is that right?
SK: That’s correct. This is rolling out in different regions on different timelines. Italy was hit particularly hard at first, and we looked to them to see what could happen in the U.S or elsewhere. A couple of companies in Milan told us that they’ve been able to keep going with their oncology trials because those patients are given very high priority. They can’t miss their treatment. That may happen here as well.
The main concern here is cash burn.
SF: Lauren, we’ve been speaking to a number of investors. There’s obviously a big economic fallout from this. What’s top of mind for companies, but also for investors? What are you hearing from them?
Lauren Martz: The main concern here is cash burn. These companies can’t conduct their trials, as Selina just said, or they’re having trouble doing their research.
At the same time, it’s difficult to raise money in the current economic environment. On top of that is the fact that people haven’t been able to travel for weeks or months, and not being able to have that face-to-face interaction really affects the ability to get new investors and really to close any deal.
And it’s not just getting in front of investors -- all of your contacts are disrupted. You can’t talk to the lawyers that need to talk to you in order to close these deals. So from the financial perspective, the question is: how do you preserve the money that you have in order to get to the point where you can raise money again in the future?
SF: We’ve seen at least a couple of companies in the last couple of weeks go public. They’ve done all the legwork and have managed to get out. Obviously the beginning of this year there was this feeling that everyone was going to complete their IPOs before the election -- has that ground to a halt?
LM: For IPOs and any financings that were under way, a lot of them seem to have gotten through. But now there seems to be a hard stop and there’s almost nothing going through right now.
A couple of the investors that I’ve spoken with said that for venture rounds, even deals that were under way with investors on board and active deal sheets have had half the people pull out of the deal. For everything that is in process, there’s a better chance of getting through than things that haven’t been started yet.
But even financings that were in process are having trouble. Especially in Europe, at this point, but I assume that’s going to be true in the U.S. too.
Regulators meet the rush
SF: I want to switch gears. Steve, obviously there’s a huge rush to try and get countermeasures out, which includes both therapies and vaccines. First of all, what are regulators doing to clear roadblocks, speed things up and enable products to get out as fast as possible?
Steve Usdin: The immediate need is for diagnostics, both for individuals and surveillance for society, meaning antibody tests that can determine who’s been infected and where the infections have been.
And the FDA has a process called Emergency Use Authorizations which allows them to authorize diagnostics very quickly.
What FDA has also done, which is actually extraordinary, is they’ve said if you’ve got a test and you plan to submit an application for Emergency Use Authorization, you can start marketing it 15 days before you submit the application. And when you submit the application, if it turns out there are big problems with it, FDA theoretically could yank it off the market at that time.
The immediate need is for diagnostics, both for individuals and surveillance for society.
SF: So there are tests going out that have not been validated by regulators. Companies can just say “this is valid” and put it out?
SU: They can do that at their risk.
The other thing that FDA has done is it’s given the states the authority to basically step in and act in FDA’s place to regulate diagnostic tests, and there are some states that are well-positioned to do that. New York State has a very sophisticated regulatory system and they can do that.
SF: What about therapies? The first things that are up are approved therapies that have been repurposed. For any of the regulatory authorities, are there roadblocks that they need to remove, or is that actually fairly straightforward to get those out as fast as possible?
SU: That’s really quite straightforward. There are designs for randomized, controlled master protocols. A lot of compounds might be tested under what they call large-scale expanded access protocols, which are similar to individual compassionate use approvals. Basically FDA sets really wide parameters and anybody who falls within these parameters can get access to it. The companies have to collect basic information. It’s essentially a large pragmatic trial.
Science, sequences and spikes
SF: I want to pick up on what Steve said about diagnostics and go to Karen -- can you give us a broad overview of the different kinds of diagnostics? On a high level, how are they segregating and how are they going to be used?
Karen Tkach Tuzman: At a high level, one of the key tests is PCR - polymerase chain reaction. That is really detecting the virus by taking the viral RNA segments of it that you expect are specific to this virus and amplifying them. It’s detecting viral load that way. Some of those tests can take a couple of hours, the turnaround on some are still on the order of days.
A different bucket is antibody-based tests, where what you’re looking for is the presence of antibodies against the virus in somebody. That won’t tell you if they have the virus right now, but it’ll tell you if they have seen it at some point and it’ll tell you if they generated an immune response.
Other diagnostic modalities are emerging on the back of new technologies. There’s a flavor of CRISPR that involves a Cas13 enzyme and this cleaves RNA. This is an RNA virus, so what you can do is deploy that CRISPR enzyme to cut where it sees the RNA sequence of this virus and create a signal that you can detect perhaps more rapidly than some of the other diagnostic modalities available.
The spike protein is maybe the top antigen that’s come out as a target for monoclonal antibody therapies.
And then finally, you might have whole viral genome sequencing. Whereas the PCR tests will detect just a snippet of the viral genome to confirm if it’s there and how much, the whole genome sequencing will allow you to see if the virus has been mutating, and that allows you to track the epidemiology and look for the emergence of new mutants that could maybe even wreak more havoc.
SF: We hear a lot about the spike protein. How is the biology evolving of what we know about this virus and how is that being used to create therapies against it?
KTT: The spike protein is maybe the top antigen that’s come out as a target for monoclonal antibody therapies. This would be used in a therapy where you’re generating antibodies to block up the viral protein and lead it to be gobbled up by the immune system and preventing the entry of the virus into cells.
The spike protein is on the outer shell of the virus, sort of ringing all around it, and what we know is that it’s similar to the spike protein of other related coronaviruses that we’ve targeted before but it’s different in some key ways and there’s been structural data that’s been coming out that’s been helping tease out those differences.
It looks like the spike protein, for example, might bind to the receptor that internalizes the virus a bit tighter than some of the other spike proteins we’ve seen in coronaviruses in the past. That’s one key place at which people are intervening.
In some cases that’s involving repurposing of antibodies against spike proteins that we’ve seen before in other coronaviruses and in other cases that’s generating new antibodies. Chloroquine, for example, and the Gilead Sciences compounds [remdesivir], are targeting different places in the pathway.
Chloroquine is believed to affect viral internalization through the cellular endocytosis pathway by trying to prevent that from happening.
Remdesivir is thought to act by blocking viral RNA synthesis. Once the virus is inside the cell already, remdesivir prevents it from synthesizing new copies of its genome.
There are other steps along the way in the virus life cycle that people are targeting with repurposed and new agents.
But a separate place people have been targeting is the downstream immune response. This is thought to be more important for late-stage disease, once you have acute respiratory distress syndrome.
Here, we’re looking at agents to block the cytokine storms that seem to be emerging in people with really severe disease. In particular, monoclonal antibodies blocking IL-6 have emerged as a key therapy that people are trying. This is something that people have been using to block cytokine storms in CAR T cell therapies and so there’s hope that will help here as well.
SK: Early on in the disease a lot of groups, whether they’re academics or companies, are trying to boost the immune response. But then later on, once you have this runaway immune response, you want to go in the other direction. So there’s two different strategies there, depending on where you’re at in the disease.
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