The Search for a Treatment

our emotions, even how we cook. One topic, though, that we haven't yet covered is the question of treatment that takes on the virus directly. That may be one way for us to solve the corona problem, although it also may not be depending on the science. We may simply have to depend ultimately on social isolation to make the virus go down. So how far are we along the way to determining what drugs work? Here? Are the treatments that have gotten a lot of publicity actually working? Are

they plausible? Have the studies that have been released actually demonstrated efficacy? Or are we much too early in the process to know how things are going to work out? If we find a treatment, will it be scalable? Here to discuss all of this with me is doctor Angela russ Mussel. She's a research scientist and a virologist at the Columbia University Mailman School of Public Health, and she's

worked extensively on viruses and evola. Angela, first of all, thank you for taking the time to be here with us. What treatments are out there now that are being studied that you think potentially holds some promise And we're not talking about vaccines at all today, but we're going to start by talking just about treatments, right So, there are

several treatments in clinical trial right now. It's important to note that there are no treatments at this time that have been demonstrated to be effective and safe for treating COVID nineteen. The main drugs that I've been hearing about

are three different drug regiments. So there is a drug called rumdz a viere that was tested for ebola, and it wasn't effective for ebola, but it's a fairly broad spectrum anti viral drug and it has shown promise against MERS coronavirus in animals and against this coronavirus SARS coronavirus two in cell culture experiments. So that drug is being tested.

It's not currently approved for use in humans, but there is quite a bit of safety data that was gathered during the trials for ebola, So if that drug does prove to be effective in a controlled trial, it should be relatively quick process to get it out to the public. Another drug that's being looked at is hydroxy chloroquin, which is an anti malarial drug that's also used to treat rheumatoid arthritis and lupus. Sometimes that has been tested with

the antibiotic zithromycin. There was a lot of press about this also because President Trump has asserted that this is a game changing, miracle drug. It's really important to note that the controlled studies in a sufficient number of patients to determine whether or not it's effective are still ongoing.

So the only papers that have been out about chloroquin or hydroxy chloroquin have used very very small numbers of patients and there were some issues with the trial design in terms of the controls that were used to evaluate

its efficacy. So despite what we've heard some politicians talking about, those drugs are not proven at this time to be effective at treating COVID and then Finally, they're also looking at a combination of HIV protease inhibitors, and these drugs were chosen because they showed some efficacy anecdotally against SARS classic and so people thought that they might be useful here. Additionally, they were used with an anti influenza drug to treat

a patient in Thailand. That patient recovered, so they concluded that it might have had an effect. But as with the other drugs that I just mentioned, it's critical to test those in a large group of patients with proper controls to determine if they actually are effective or not.

A smaller clinical trial done in China that was controlled and randomized looked at those two HIV drugs and saw no effect in overall outcome, meaning that whether a patient received those drugs or just supportive care, there was no difference in the number of patients that eventually died from severe COVID disease. So the WHO is evaluating that drug combination as well in a larger group of patients to see if at a population level that would have a

more a greater impact in terms of treating COVID. So those are the three drug regimens that have advanced the furthest in clinical trials, and we should start seeing some trial data from those, I would think in the next couple months, so that we can have a better idea of whether or not some of these existing drugs can be repurposed for treating COVID. Why is the timescale months for clinical trials here? I mean, the course of the

disease is not that long. And of course, ordinarily one would want to have very careful experimental design and when we would want to have peer review of the studies and so forth and so on. But under crisis conditions, the ordinary person, and I'm treating myself as that here, think, you know, why can't the duration of the study just be as long as the course of the disease runs. And even if you run it a couple of times, that doesn't mean that it has to take months. So

why are we talking about months? There are several factors. In order to demonstrate efficacy, you really need to have larger patient groups. So people in different places are doing different things, they are in different environments, and they have different levels of hospital care. And also genetically we're very different from one another. There's a lot of individuals, individual

variation in the population. So when you are trying to enroll patients in a clinical trial, you're going to be seeing people coming from all different sorts of circumstances with all different kinds of potentially confounding variables, so pre existing medical conditions. People are going to be different ages, They're going to be both male and female. Each case will

be different. So in order to understand how these drugs work in general for a person off the street, you really need to look at a lot of people, and that just takes a lot of time. Another issue is the ethics of it. So when clinical trials are done, you need to have informed consent from all of those patients, and patients are allowed to drop out of the trial

at any time. In addition, many clinical trials will have criteria for patients to be removed from the trial if it appears that they are being harmed by the trial itself. Let's say somebody has an allergic reaction to an experimental drug. You would not want to continue treating that patient with

that drug because that could potentially harm them. So in order to get these types of numbers that we really need to apply the knowledge of whether a drug is effective or not and safe to a large population of people. You just really need to enroll a lot of patients, and they have to be able to remain in the trial, and you have to do quite a lot of statistical analysis to make sure that you're accounting for all of these potential variables that a large diverse population of people bring.

Everything you just said seems completely logical and appropriate for a well designed clinical trial of a drug. It makes me very happy and relieved to think that under ordinary circumstances, when scientists start checking on the efficacy of a new potential treatment, they do everything you've said, large sample size, sophisticated statistical analysis, ethical constraints, and allowing people to withdraw. All that makes perfect sense. None of that makes sense

to me under crisis conditions. And help me out here, because my instincts are clearly at odds with that of at least some of the scientific community here. But it just seems very difficult for me to get my head around the idea that we should proceed as normal when we're in the middle of a global pandemic. Certainly this has been accelerated. The process of approving the trial, of

coordinating a trial has been accelerated. Another thing that is being done sort of to balance potential benefit of these drugs for patients who need it most, who don't have time to wait for a clinical trial, because as you pointed out, it is a public health crisis. The FDA has approved the use of hydroxychloroquin prescriptions off label for compassionate use in patients that really have nothing left to lose, that patients who will die without some kind of intervention.

So there is a balance between doing these types of randomized, properly controlled, properly statistically powered clinical trials as well as access to the drugs for patients who really have nothing left to lose, and well, even if they don't benefit, it's worth a try. The danger in that is that when people are deciding to self medicate or demanding these prescriptions off label for disease that's potentially not very severe,

that's the type of thing that should be avoided. But you are correct that it is a crisis and that patients who are in the most dire condition, with the most severe need should have access to some of these experimental medications. Whether we have proof that they work or not.

We'll be back in just a moment. I now want to ask you about the French study which I myself read, where on a very very small sample size there were fewer than forty five people in the entire trial, and of those only a very very small number I think, only six if I remember correctly, got the particular combination

of hydroxy chloroquine and zethromycin together. But that study was exciting, and you could sort of understand why there was such a reaction to it, even from the President, by virtue of the fact that among that tiny number of people, those six people, the study reported that all had been completely cleared of signs of the virus when they study them quite a short time later, something like six days later. I mean, reading that study shows you what got everybody excited,

also shows you the limitations of the study. What do you think of as the real problem with that study? If there is one? Oh boy, there are several problems with that study. One of the issues were the controls that were selected for that study. They were patients from a different institution, and usually when you're doing a study like that, you want to use patients from the same cohort of patients, so the same patient pool that you're

treating people in. They effectively from what I can tell, selected patients, just other patients to compare it to, and that's not really a great comparison. Also, you pointed out it was very small, So when you're talking about six patients out of a group of I think there were twenty in the total treatment group, that is not sufficiently

powered to make any conclusions at all. Those patients could have cleared the virus on their own, they could have gotten better, we just can't say because not enough patients were investigated. There are some other issues as well. One issue is that the journal that that paper was originally published in after a very short time of being a preprint, is controlled. The editor in chief of that journal is the senior author of the paper. Did he a Raoul?

And furthermore, Elizabeth Bake from microbiome Digest has pointed out that there are some issues with his publication record. There are some papers that he has published with questionable data, and not necessarily that that indicates that he's falsifying data

or or engaging in any intentionally nefarious work. But some questions have been raised about the research integrity in general of papers that he has authored, and just the conflict of interest with you know, him being the editor in chief of the journal that this was rushed to publication in does not do a lot to support the notion that the trial was rigorously evaluated by a panel of

non conflicted peers. So there are a lot of questions about that particular investigator and the studies coming out of his group, as well as some of the claims that he has made on social media and in the media, which is you know, has sort of fueled this their miracle drugs and they're going to solve everything. There are both scientific as well as really ethical reason That's why

that work may be somewhat problematic. So we've now evaluated that study and you've called it significantly into question and very helpful ways. There's a lot there that I had not known before and that I think is not generally

available outside of the expert sphere. However, and here to the big However, if I were someone who were very sick with coronavirus right now, we're pretty sick, significant shortness of breath enough to have to be admitted to a hospital, and I had to choose among available options, I'm pretty sure that I would ask for this treatment combination. Not because I would be convinced of the rigor of the study just because there isn't any really other option out there.

And indeed, you know, just anecdotally, someone who might know who was in the hospital, was really sick, was on eventilator in New York, was actually given this treatment. And I thought to myself, good, So, I guess what I'm wondering is about a kind of paradox, right. I mean, here you are saying the science is bad and inadequate, and yet it still might be better evidence than anything else we have, and therefore a reason to give it a try in an individual case. Now, I don't think

I'm crazy. I mean, is that what you would do if you were suddenly hospitalized or someone close to you were suddenly hospitalized with a serious case. I mean, I think that for that reason this has been used in those circumstances that would be an appropriate circumstance in which to use this. But with the caveat that that is definitely a decision for the physician treating a particular patient to make. There may be counter indications for taking either

of those medications. I have read that there are potentially drug interactions that can occur between zithromycin and hydroxy chloroquin specifically. I'm not sure personally why for the rationale of including a zithromycin other than it's an antibiotic that could potentially treat secondary bacterial infections, which are probably playing a big

role in the most severe patients. So it's possible bole that a different drug besides zithromycin for somebody, for example, who might be allergic to a zithromycin, or have a bad reaction to a zithromycin, or have a drug interaction problem, they could be given potentially a different antibiotic, and those would all be decisions that would be made by the

physician treating the patient in each individual circumstance. I agree with you that for patients who are on a ventilator where there is no other option, a physician should be able to make a decision about whether to treat that patient with an unproven medication that is available and FDA approved for other uses. That is a really individual decision that needs to be made in terms of patient physician care. That's separate from doing a large scale clinical trial to

determine definitively whether those drugs actually work. You mentioned that Zythromycin is a broad spectrum antibiotic. It's not an anti viral agent, and so you were speculating that, you know, if it's having an effect, maybe the effect that it's just having is helping to deal with whatever other bacterial infections maybe going on simultaneous to the viral infection. What's

the mechanism for hydroxy chloroquin that is an antiviral agent? Right, So what is the mechanism if you can explain it in lay person's terms for us, by which that's supposed to have an effect If it is indeed having an effect, So that's not known. Hydroxy Chloroquine is actually an anti malarial and malaria parasites are not viruses. Actually they're single

celled parasitic organisms. A group in China looked at the effect of chloroquine, which is a related drug in vitro on SARS coronavirus and SARS coronavirus to replication and they

speculate that the block occurs during the entry process. So when a virus infects a cell, the virus attaches to a host receptor and is taken up inside the cell in a compartment called an endosome in order for the virus to begin replicating its genome, which is a critical step in viral replication, the virus has to escape, essentially

from that endosomal compartment. That escape process is triggered by the acidification of the endosome, so the endosome pH drops and that provides a chemical environment in which the virus confuse with the endosomal membrane and get inside the cell.

What hydroxychloroquine and chloroquin do is they prevent endosomal acidification, and that has been proposed as a mechanism for how it would act as an antiviral drug, So it prevents the virus from actually getting into the part of the cell that it's going to replicate in by blocking that

acidification process and keeping it trapped in those endosomes. Another one of the potential treatments that's being tested that you mentioned is remdesvere, an antiviral drug that I think said did not work against ebola, but did have some effects against mers. Tell us a little bit about this drug and why it's thought that it might actually be effective

against this coronavirus. So, remdesiviere is a broad spectrum anti viral drug that's in a class of drugs called nucleoside analogs, and they are a chemical mimic of the ATCG molecules that make up DNA or RNA. Technically an RNA it's

you instead of T, but they're called nucleoside bases. And most people are familiar with, you know, the genetic code which is made up of at season gs and the enzymine, cytosine, and guanidine, and these When the virus genome is replicating, these are put by an enzyme called, in the case of viruses, an RNA polymerase. They are put into a

chain and that makes the new genetic material. What these nucleoside analogs do is they get inserted into this chain instead of the atcorg that is actually supposed to be there, and that can cause the genome to be catastrophically mutated

effectively with these non functional base analogs. It's also been proposed that these nucleoside analog drugs can also activate certain innate antiviral signaling pathways, and they can also interfere with the activity of the polymerase enzyme that is making the new copies of RNA. In the case of a coronavirus. So these drugs did show promise in preclinical studies against ebola, but then it turned out not to work in actually

Bola patients. There might be some reasons for that that don't actually have to do necessarily with the mechanism of the drug. One thing about ebola patients is that they aren't necessarily coming into an ebola treatment unit or ETU when they are early on an infection. Oftentimes, when an ebola patient is symptomatic, they will show up at the ETU after they're already very sick. And I study ebola, I study the host response to ebola in my animal

models that I study. Once those animals have sort of reached a point of no return in terms of their host response just being completely screwed up by systemic ebola infection, then targeting the virus's ability to replicate may not be

very helpful. And I wonder if that is why in patient trials, why remdzevir was not as effective as it appeared to be in preclinical trials, Because often in preclinical trials, when you're working with an animal model, you know exactly how much that animal was infected with and at what time that animal was infected. People don't necessarily know when they got infected, so remdesivir's ability to treat ebola patients will have a lot to do with at what point

in the infection you can treat them. For COVID, we know that remdesivir has some efficacy against SARS coronavirus two in vitro in cultured cells, and we know that it seems effective in non human primates that were infected with Mer's coronavirus, which is another related coronavirus that causes a similar type of disease. Whither it will work in patients, I think will be dependent on when those patients are diagnosed.

So remdesivir treatment as a last resort for patients who are already severely ill may or may not have an effect. If remdesivir does work by triggering some of these anti viral immune responses, it's possible that some of those responses may be protective. We just don't know until we are

able to test this. But that is why it's so important to test these treatments on people at different stages of the disease and with different clinical manifestations of the disease, because we really need to know if, for example, remdesivir does appear to work, if treatment begins very early, then we need to know that so that patients can begin treatment initially when they are diagnosed, rather than waiting for

them to progress to severe disease, for example. So those have a lot of implications for the types of decisions that physicians and clinicians will make if that drug does prove to be effective. Just a quick mention of the HIV protease inhibitors which in one patient seem to maybe anecdotally have an effect, what would the theory of the mechanism be there, and what's your virological instinct about the

probabilities of that approach panning out. So I've seen a couple preprints that have suggested using in silico, meaning in computers analysis alone, showing that there may be some interaction with the M one protease of coronaviruses. I'm not clear if that is the mechanism. I haven't personally seen data to suggest that those protease inhibitors that normally target the HIV proteases also would have an impact on the coronavirus protease.

It's certainly possible many proteases have conserved structural features in terms of how they work. I haven't seen any data though, that conclusively demonstrates the mechanism by which those HIV protease inhibitors would be functional. And I'm really grateful to you for your time. Before I let you go, I just want to ask, is there something I'm not asking you that I should be asking you with respect to the

treatments that are out there. Is there some important point that you think we need to hear that I haven't directed you towards. I think the only important point that I like to get across is that the trials that are proceeding now are going as fast as they can. But it really is critical to show efficacy. And another

great example of this is Ebola. So during the West African Ebola outbreak, a number of patients that were evacuated from West Africa were then treated with an experimental drug called ZMP that everybody heard about, and many of those patients recovered and people attributed to that to look at wonderful z MAP. It works so well. Z MAP failed

the same clinical trial that m Dozevier did. It now appears quite clear that getting just supportive care, so fluids, potentially breathing support, other types of treatments for the symptoms of Ebola disease. That type of supportive hospital care has been itself effective at really improving the case fatality rates

for ebola. So it's possible that all those patients that go z MAP, who were all you know, in the United States for the most part, or Europe in state of the art, I see us getting world class supportive care that may have had more of an impact than z MAP, But because it was a handful of patients with no control group, we couldn't evaluate z MAP, so people, I think sort of jumped to the conclusion that it was z MAP that was doing this and not the

other different types of care that those patients were receiving. So we just need to be really careful about attributing positive outcomes to the wrong thing. Lest you know, people start prescribing these drugs widely. They don't do anything. It gives people a false sense of security, and it could

ultimately be more harmful to public health and helpful. Angela, thank you so much for your time and your expertise and your extremely clear headed analysis and your excellent way of making it all understandable even to a layman like me. Thank you so much for your time. Well, it's my pleasure. Thank you for having me on and giving me the opportunity to talk to your listeners about this. I learned

a lot from talking to doctor Angela russ Mussen. In particular, she was extremely clear about the necessity of patience and good scientific technique in trying to figure out what treatment actually will respond to the novel coronavirus in a way that works. Like a lot of people, I'm eager for

there to be a treatment that works right away. And you might have heard in my voice some wish, some fantasy that we could sidestep some of the most slow moving and precise scientific features of experimentation in order to get to a treatment, but Angela made it extremely clear that the danger in doing so is that we might end up mistakenly treating people with drugs that aren't actually solving the problem, a phenomenon that she noted did happen

in some instances in ebola. Response, that means that we need to do the slow, careful science in order to make sure that people are cured, and in the mean time, physicians will keep on using experimental treatments, even if they don't know that they work for certain, in the hopes that they will have some effect. That combination makes me a little more hardened. But at the same time, my ultimate takeaway from listening to Angela is that randomness is

a real risk. It is simply possible that we don't have immediately to hand any treatment that will effectively address the health challenges that we're facing. And if that's so, it's social distancing for all of us and for a lot longer. If there's progress with respect to any of these treatments, you can be sure we'll discuss that issue and get behind the story of the science until I speak to you next time. Be careful, be safe, be well.

Deep background is brought to you by Pushkin Industries. Our producer is Lydia Jane Cott, with research help from zooe Wynn. Mastering is by Jason Gambrell and Martin Gonzalez. Our showrunner is soph Given. Our theme music is composed by Luis Gera special thanks to the Pushkin Brass Malcolm Gladwell, Jacob Weisberg, and Mia Loebell. I'm Noah Feldman. I also write a regular column for Bloomberg Opinion, which you can find at bloomberg dot com slash Feldman. To discover Bloomberg's original slate

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