WEBVTT - The Search for a Treatment 0:00:15.356 --> 0:00:22.876 Pushkin from Pushkin Industries. This is Deep Background, the podcast 0:00:22.876 --> 0:00:26.036 where we explore the stories behind the stories in the news. 0:00:26.556 --> 0:00:30.076 I'm Noah Feldman. If you've been listening to our show 0:00:30.276 --> 0:00:34.156 this past month, you'll know that coronavirus is basically the 0:00:34.276 --> 0:00:38.156 only thing we've been thinking about. We've tried to explore 0:00:38.316 --> 0:00:42.156 how this global pandemic is influencing every aspect of our lives. 0:00:42.676 --> 0:00:46.676 Our body is, of course, our economy, our civil liberties, 0:00:47.276 --> 0:00:51.676 our emotions, even how we cook. One topic, though, that 0:00:51.716 --> 0:00:54.636 we haven't yet covered is the question of treatment that 0:00:54.676 --> 0:00:58.036 takes on the virus directly. That may be one way 0:00:58.076 --> 0:01:01.076 for us to solve the corona problem, although it also 0:01:01.196 --> 0:01:03.516 may not be depending on the science. We may simply 0:01:03.556 --> 0:01:06.676 have to depend ultimately on social isolation to make the 0:01:06.756 --> 0:01:10.076 virus go down. So how far are we along the 0:01:10.116 --> 0:01:13.756 way to determining what drugs work? Here? Are the treatments 0:01:13.756 --> 0:01:16.676 that have gotten a lot of publicity actually working? Are 0:01:16.716 --> 0:01:20.436 they plausible? Have the studies that have been released actually 0:01:20.476 --> 0:01:23.396 demonstrated efficacy? Or are we much too early in the 0:01:23.476 --> 0:01:25.516 process to know how things are going to work out? 0:01:26.236 --> 0:01:29.196 If we find a treatment, will it be scalable? Here 0:01:29.196 --> 0:01:31.796 to discuss all of this with me is doctor Angela 0:01:31.876 --> 0:01:35.596 russ Mussel. She's a research scientist and a virologist at 0:01:35.636 --> 0:01:39.556 the Columbia University Mailman School of Public Health, and she's 0:01:39.556 --> 0:01:47.556 worked extensively on viruses and evola. Angela, first of all, 0:01:47.596 --> 0:01:50.556 thank you for taking the time to be here with us. 0:01:51.516 --> 0:01:55.916 What treatments are out there now that are being studied 0:01:56.516 --> 0:01:59.796 that you think potentially holds some promise And we're not 0:01:59.836 --> 0:02:02.236 talking about vaccines at all today, but we're going to 0:02:02.316 --> 0:02:06.476 start by talking just about treatments, right So, there are 0:02:06.556 --> 0:02:10.756 several treatments in clinical trial right now. It's important to 0:02:10.836 --> 0:02:13.516 note that there are no treatments at this time that 0:02:13.556 --> 0:02:18.196 have been demonstrated to be effective and safe for treating 0:02:18.236 --> 0:02:22.876 COVID nineteen. The main drugs that I've been hearing about 0:02:22.916 --> 0:02:27.036 are three different drug regiments. So there is a drug 0:02:27.036 --> 0:02:31.396 called rumdz a viere that was tested for ebola, and 0:02:31.476 --> 0:02:35.116 it wasn't effective for ebola, but it's a fairly broad 0:02:35.196 --> 0:02:38.676 spectrum anti viral drug and it has shown promise against 0:02:39.036 --> 0:02:44.876 MERS coronavirus in animals and against this coronavirus SARS coronavirus 0:02:44.916 --> 0:02:49.996 two in cell culture experiments. So that drug is being tested. 0:02:50.516 --> 0:02:55.356 It's not currently approved for use in humans, but there 0:02:55.516 --> 0:02:59.116 is quite a bit of safety data that was gathered 0:02:59.196 --> 0:03:03.156 during the trials for ebola, So if that drug does 0:03:03.276 --> 0:03:06.316 prove to be effective in a controlled trial, it should 0:03:06.316 --> 0:03:11.636 be relatively quick process to get it out to the public. 0:03:12.116 --> 0:03:15.596 Another drug that's being looked at is hydroxy chloroquin, which 0:03:15.636 --> 0:03:18.836 is an anti malarial drug that's also used to treat 0:03:18.916 --> 0:03:24.276 rheumatoid arthritis and lupus. Sometimes that has been tested with 0:03:24.556 --> 0:03:28.916 the antibiotic zithromycin. There was a lot of press about 0:03:28.956 --> 0:03:33.276 this also because President Trump has asserted that this is 0:03:33.276 --> 0:03:37.036 a game changing, miracle drug. It's really important to note 0:03:37.116 --> 0:03:40.596 that the controlled studies in a sufficient number of patients 0:03:40.636 --> 0:03:43.876 to determine whether or not it's effective are still ongoing. 0:03:44.396 --> 0:03:47.316 So the only papers that have been out about chloroquin 0:03:47.636 --> 0:03:51.316 or hydroxy chloroquin have used very very small numbers of 0:03:51.356 --> 0:03:54.916 patients and there were some issues with the trial design 0:03:55.036 --> 0:03:58.996 in terms of the controls that were used to evaluate 0:03:59.036 --> 0:04:03.956 its efficacy. So despite what we've heard some politicians talking about, 0:04:04.436 --> 0:04:08.316 those drugs are not proven at this time to be 0:04:08.396 --> 0:04:12.916 effective at treating COVID and then Finally, they're also looking 0:04:12.996 --> 0:04:17.356 at a combination of HIV protease inhibitors, and these drugs 0:04:17.396 --> 0:04:23.716 were chosen because they showed some efficacy anecdotally against SARS 0:04:23.796 --> 0:04:28.356 classic and so people thought that they might be useful here. Additionally, 0:04:28.396 --> 0:04:32.396 they were used with an anti influenza drug to treat 0:04:32.436 --> 0:04:37.156 a patient in Thailand. That patient recovered, so they concluded 0:04:37.196 --> 0:04:40.236 that it might have had an effect. But as with 0:04:40.436 --> 0:04:43.796 the other drugs that I just mentioned, it's critical to 0:04:43.836 --> 0:04:47.076 test those in a large group of patients with proper 0:04:47.116 --> 0:04:50.796 controls to determine if they actually are effective or not. 0:04:51.436 --> 0:04:55.356 A smaller clinical trial done in China that was controlled 0:04:55.396 --> 0:04:59.596 and randomized looked at those two HIV drugs and saw 0:04:59.716 --> 0:05:03.836 no effect in overall outcome, meaning that whether a patient 0:05:03.916 --> 0:05:07.916 received those drugs or just supportive care, there was no 0:05:07.996 --> 0:05:11.796 difference in the number of patients that eventually died from 0:05:11.876 --> 0:05:16.956 severe COVID disease. So the WHO is evaluating that drug 0:05:16.996 --> 0:05:19.556 combination as well in a larger group of patients to 0:05:19.636 --> 0:05:23.196 see if at a population level that would have a 0:05:23.276 --> 0:05:27.636 more a greater impact in terms of treating COVID. So 0:05:27.676 --> 0:05:30.516 those are the three drug regimens that have advanced the 0:05:30.556 --> 0:05:34.516 furthest in clinical trials, and we should start seeing some 0:05:34.596 --> 0:05:37.236 trial data from those, I would think in the next 0:05:37.276 --> 0:05:40.396 couple months, so that we can have a better idea 0:05:40.556 --> 0:05:43.316 of whether or not some of these existing drugs can 0:05:43.356 --> 0:05:48.636 be repurposed for treating COVID. Why is the timescale months 0:05:49.276 --> 0:05:52.556 for clinical trials here? I mean, the course of the 0:05:52.596 --> 0:05:57.556 disease is not that long. And of course, ordinarily one 0:05:57.596 --> 0:06:00.636 would want to have very careful experimental design and when 0:06:00.636 --> 0:06:03.196 we would want to have peer review of the studies 0:06:03.236 --> 0:06:05.916 and so forth and so on. But under crisis conditions, 0:06:05.916 --> 0:06:08.916 the ordinary person, and I'm treating myself as that here, think, 0:06:09.676 --> 0:06:12.396 you know, why can't the duration of the study just 0:06:12.556 --> 0:06:15.116 be as long as the course of the disease runs. 0:06:15.116 --> 0:06:17.076 And even if you run it a couple of times, 0:06:17.116 --> 0:06:19.276 that doesn't mean that it has to take months. So 0:06:19.396 --> 0:06:22.596 why are we talking about months? There are several factors. 0:06:22.956 --> 0:06:26.316 In order to demonstrate efficacy, you really need to have 0:06:26.516 --> 0:06:31.156 larger patient groups. So people in different places are doing 0:06:31.196 --> 0:06:34.956 different things, they are in different environments, and they have 0:06:35.036 --> 0:06:39.276 different levels of hospital care. And also genetically we're very 0:06:39.316 --> 0:06:42.396 different from one another. There's a lot of individuals, individual 0:06:42.476 --> 0:06:46.156 variation in the population. So when you are trying to 0:06:46.276 --> 0:06:49.556 enroll patients in a clinical trial, you're going to be 0:06:49.596 --> 0:06:53.036 seeing people coming from all different sorts of circumstances with 0:06:53.116 --> 0:06:58.516 all different kinds of potentially confounding variables, so pre existing 0:06:58.556 --> 0:07:01.716 medical conditions. People are going to be different ages, They're 0:07:01.756 --> 0:07:04.796 going to be both male and female. Each case will 0:07:04.836 --> 0:07:08.756 be different. So in order to understand how these drugs 0:07:08.796 --> 0:07:11.996 work in general for a person off the street, you 0:07:12.036 --> 0:07:15.236 really need to look at a lot of people, and 0:07:15.316 --> 0:07:18.436 that just takes a lot of time. Another issue is 0:07:18.516 --> 0:07:22.276 the ethics of it. So when clinical trials are done, 0:07:22.676 --> 0:07:25.876 you need to have informed consent from all of those patients, 0:07:26.396 --> 0:07:28.676 and patients are allowed to drop out of the trial 0:07:28.796 --> 0:07:32.916 at any time. In addition, many clinical trials will have 0:07:33.636 --> 0:07:36.916 criteria for patients to be removed from the trial if 0:07:36.956 --> 0:07:40.556 it appears that they are being harmed by the trial itself. 0:07:41.076 --> 0:07:44.876 Let's say somebody has an allergic reaction to an experimental drug. 0:07:45.476 --> 0:07:48.316 You would not want to continue treating that patient with 0:07:48.356 --> 0:07:52.316 that drug because that could potentially harm them. So in 0:07:52.436 --> 0:07:55.156 order to get these types of numbers that we really 0:07:55.196 --> 0:07:58.836 need to apply the knowledge of whether a drug is 0:07:58.876 --> 0:08:03.716 effective or not and safe to a large population of people. 0:08:03.876 --> 0:08:06.036 You just really need to enroll a lot of patients, 0:08:06.076 --> 0:08:08.236 and they have to be able to remain in the trial, 0:08:09.116 --> 0:08:11.156 and you have to do quite a lot of statistical 0:08:11.196 --> 0:08:14.316 analysis to make sure that you're accounting for all of 0:08:14.356 --> 0:08:18.876 these potential variables that a large diverse population of people bring. 0:08:19.876 --> 0:08:24.756 Everything you just said seems completely logical and appropriate for 0:08:24.996 --> 0:08:28.476 a well designed clinical trial of a drug. It makes 0:08:28.476 --> 0:08:32.076 me very happy and relieved to think that under ordinary circumstances, 0:08:32.476 --> 0:08:35.396 when scientists start checking on the efficacy of a new 0:08:35.476 --> 0:08:38.996 potential treatment, they do everything you've said, large sample size, 0:08:39.236 --> 0:08:43.236 sophisticated statistical analysis, ethical constraints, and allowing people to withdraw. 0:08:43.556 --> 0:08:46.636 All that makes perfect sense. None of that makes sense 0:08:46.636 --> 0:08:49.276 to me under crisis conditions. And help me out here, 0:08:49.276 --> 0:08:52.876 because my instincts are clearly at odds with that of 0:08:53.356 --> 0:08:56.196 at least some of the scientific community here. But it 0:08:56.276 --> 0:08:59.036 just seems very difficult for me to get my head 0:08:59.036 --> 0:09:02.636 around the idea that we should proceed as normal when 0:09:03.036 --> 0:09:07.436 we're in the middle of a global pandemic. Certainly this 0:09:07.516 --> 0:09:11.676 has been accelerated. The process of approving the trial, of 0:09:11.756 --> 0:09:15.556 coordinating a trial has been accelerated. Another thing that is 0:09:15.636 --> 0:09:19.076 being done sort of to balance potential benefit of these 0:09:19.196 --> 0:09:21.516 drugs for patients who need it most, who don't have 0:09:21.596 --> 0:09:24.236 time to wait for a clinical trial, because as you 0:09:24.316 --> 0:09:27.716 pointed out, it is a public health crisis. The FDA 0:09:27.836 --> 0:09:33.316 has approved the use of hydroxychloroquin prescriptions off label for 0:09:33.436 --> 0:09:38.356 compassionate use in patients that really have nothing left to lose, 0:09:38.436 --> 0:09:41.476 that patients who will die without some kind of intervention. 0:09:42.116 --> 0:09:47.516 So there is a balance between doing these types of randomized, 0:09:47.796 --> 0:09:52.876 properly controlled, properly statistically powered clinical trials as well as 0:09:52.956 --> 0:09:56.196 access to the drugs for patients who really have nothing 0:09:56.276 --> 0:09:59.916 left to lose, and well, even if they don't benefit, 0:10:00.316 --> 0:10:04.636 it's worth a try. The danger in that is that 0:10:04.716 --> 0:10:09.996 when people are deciding to self medicate or demanding these 0:10:10.036 --> 0:10:14.716 prescriptions off label for disease that's potentially not very severe, 0:10:15.196 --> 0:10:18.276 that's the type of thing that should be avoided. But 0:10:18.796 --> 0:10:21.436 you are correct that it is a crisis and that 0:10:21.556 --> 0:10:25.596 patients who are in the most dire condition, with the 0:10:25.596 --> 0:10:28.476 most severe need should have access to some of these 0:10:28.516 --> 0:10:32.076 experimental medications. Whether we have proof that they work or not. 0:10:33.036 --> 0:10:44.956 We'll be back in just a moment. I now want 0:10:44.996 --> 0:10:49.716 to ask you about the French study which I myself read, 0:10:50.116 --> 0:10:52.716 where on a very very small sample size there were 0:10:52.716 --> 0:10:54.876 fewer than forty five people in the entire trial, and 0:10:54.916 --> 0:10:56.836 of those only a very very small number I think, 0:10:56.836 --> 0:11:00.716 only six if I remember correctly, got the particular combination 0:11:01.156 --> 0:11:07.516 of hydroxy chloroquine and zethromycin together. But that study was exciting, 0:11:07.556 --> 0:11:09.716 and you could sort of understand why there was such 0:11:09.756 --> 0:11:13.516 a reaction to it, even from the President, by virtue 0:11:13.556 --> 0:11:15.596 of the fact that among that tiny number of people, 0:11:15.636 --> 0:11:20.036 those six people, the study reported that all had been 0:11:20.036 --> 0:11:24.236 completely cleared of signs of the virus when they study 0:11:24.276 --> 0:11:26.916 them quite a short time later, something like six days later. 0:11:26.956 --> 0:11:29.236 I mean, reading that study shows you what got everybody excited, 0:11:29.276 --> 0:11:31.956 also shows you the limitations of the study. What do 0:11:31.996 --> 0:11:34.636 you think of as the real problem with that study? 0:11:34.636 --> 0:11:38.156 If there is one? Oh boy, there are several problems 0:11:38.156 --> 0:11:41.276 with that study. One of the issues were the controls 0:11:41.316 --> 0:11:44.876 that were selected for that study. They were patients from 0:11:44.916 --> 0:11:49.156 a different institution, and usually when you're doing a study 0:11:49.236 --> 0:11:52.516 like that, you want to use patients from the same 0:11:52.636 --> 0:11:55.796 cohort of patients, so the same patient pool that you're 0:11:55.796 --> 0:11:59.676 treating people in. They effectively from what I can tell, 0:12:00.796 --> 0:12:04.956 selected patients, just other patients to compare it to, and 0:12:05.076 --> 0:12:09.996 that's not really a great comparison. Also, you pointed out 0:12:10.036 --> 0:12:13.196 it was very small, So when you're talking about six 0:12:13.276 --> 0:12:16.156 patients out of a group of I think there were 0:12:16.196 --> 0:12:21.076 twenty in the total treatment group, that is not sufficiently 0:12:21.236 --> 0:12:24.956 powered to make any conclusions at all. Those patients could 0:12:24.996 --> 0:12:27.876 have cleared the virus on their own, they could have 0:12:27.956 --> 0:12:31.636 gotten better, we just can't say because not enough patients 0:12:31.756 --> 0:12:36.676 were investigated. There are some other issues as well. One 0:12:36.756 --> 0:12:40.796 issue is that the journal that that paper was originally 0:12:40.836 --> 0:12:44.436 published in after a very short time of being a preprint, 0:12:45.396 --> 0:12:48.876 is controlled. The editor in chief of that journal is 0:12:48.996 --> 0:12:52.316 the senior author of the paper. Did he a Raoul? 0:12:52.916 --> 0:12:59.316 And furthermore, Elizabeth Bake from microbiome Digest has pointed out 0:12:59.556 --> 0:13:03.956 that there are some issues with his publication record. There 0:13:03.996 --> 0:13:09.076 are some papers that he has published with questionable data, 0:13:08.796 --> 0:13:13.196 and not necessarily that that indicates that he's falsifying data 0:13:13.436 --> 0:13:17.716 or or engaging in any intentionally nefarious work. But some 0:13:17.836 --> 0:13:21.756 questions have been raised about the research integrity in general 0:13:21.796 --> 0:13:26.276 of papers that he has authored, and just the conflict 0:13:26.316 --> 0:13:29.236 of interest with you know, him being the editor in 0:13:29.316 --> 0:13:31.756 chief of the journal that this was rushed to publication 0:13:31.836 --> 0:13:35.636 in does not do a lot to support the notion 0:13:35.756 --> 0:13:40.876 that the trial was rigorously evaluated by a panel of 0:13:42.316 --> 0:13:46.396 non conflicted peers. So there are a lot of questions 0:13:46.436 --> 0:13:51.036 about that particular investigator and the studies coming out of 0:13:51.076 --> 0:13:54.156 his group, as well as some of the claims that 0:13:54.316 --> 0:13:57.636 he has made on social media and in the media, 0:13:57.916 --> 0:14:01.236 which is you know, has sort of fueled this their 0:14:01.396 --> 0:14:05.196 miracle drugs and they're going to solve everything. There are 0:14:05.236 --> 0:14:09.556 both scientific as well as really ethical reason That's why 0:14:10.276 --> 0:14:13.876 that work may be somewhat problematic. So we've now evaluated 0:14:13.956 --> 0:14:16.436 that study and you've called it significantly into question and 0:14:16.596 --> 0:14:18.196 very helpful ways. There's a lot there that I had 0:14:18.196 --> 0:14:19.876 not known before and that I think is not generally 0:14:19.876 --> 0:14:24.116 available outside of the expert sphere. However, and here to 0:14:24.196 --> 0:14:27.756 the big However, if I were someone who were very 0:14:27.796 --> 0:14:31.916 sick with coronavirus right now, we're pretty sick, significant shortness 0:14:31.916 --> 0:14:33.956 of breath enough to have to be admitted to a hospital, 0:14:34.436 --> 0:14:37.996 and I had to choose among available options, I'm pretty 0:14:38.036 --> 0:14:40.956 sure that I would ask for this treatment combination. Not 0:14:41.076 --> 0:14:42.876 because I would be convinced of the rigor of the 0:14:42.876 --> 0:14:47.916 study just because there isn't any really other option out there. 0:14:48.396 --> 0:14:51.516 And indeed, you know, just anecdotally, someone who might know 0:14:51.596 --> 0:14:53.156 who was in the hospital, was really sick, was on 0:14:53.236 --> 0:14:56.716 eventilator in New York, was actually given this treatment. And 0:14:56.756 --> 0:14:59.996 I thought to myself, good, So, I guess what I'm 0:14:59.996 --> 0:15:01.956 wondering is about a kind of paradox, right. I mean, 0:15:02.036 --> 0:15:05.796 here you are saying the science is bad and inadequate, 0:15:06.236 --> 0:15:10.196 and yet it still might be better evidence than anything 0:15:10.196 --> 0:15:12.076 else we have, and therefore a reason to give it 0:15:12.076 --> 0:15:13.876 a try in an individual case. Now, I don't think 0:15:13.916 --> 0:15:16.076 I'm crazy. I mean, is that what you would do 0:15:16.156 --> 0:15:18.676 if you were suddenly hospitalized or someone close to you 0:15:18.716 --> 0:15:22.036 were suddenly hospitalized with a serious case. I mean, I 0:15:22.076 --> 0:15:24.716 think that for that reason this has been used in 0:15:24.756 --> 0:15:28.796 those circumstances that would be an appropriate circumstance in which 0:15:28.836 --> 0:15:32.036 to use this. But with the caveat that that is 0:15:32.116 --> 0:15:36.916 definitely a decision for the physician treating a particular patient 0:15:37.036 --> 0:15:41.476 to make. There may be counter indications for taking either 0:15:41.516 --> 0:15:45.316 of those medications. I have read that there are potentially 0:15:45.436 --> 0:15:51.636 drug interactions that can occur between zithromycin and hydroxy chloroquin specifically. 0:15:52.316 --> 0:15:56.636 I'm not sure personally why for the rationale of including 0:15:56.676 --> 0:16:00.716 a zithromycin other than it's an antibiotic that could potentially 0:16:00.716 --> 0:16:05.156 treat secondary bacterial infections, which are probably playing a big 0:16:05.276 --> 0:16:09.436 role in the most severe patients. So it's possible bole 0:16:09.516 --> 0:16:13.636 that a different drug besides zithromycin for somebody, for example, 0:16:13.676 --> 0:16:16.836 who might be allergic to a zithromycin, or have a 0:16:16.876 --> 0:16:20.716 bad reaction to a zithromycin, or have a drug interaction problem, 0:16:21.076 --> 0:16:23.996 they could be given potentially a different antibiotic, and those 0:16:24.276 --> 0:16:26.836 would all be decisions that would be made by the 0:16:26.876 --> 0:16:31.316 physician treating the patient in each individual circumstance. I agree 0:16:31.356 --> 0:16:33.956 with you that for patients who are on a ventilator 0:16:33.996 --> 0:16:37.036 where there is no other option, a physician should be 0:16:37.156 --> 0:16:40.436 able to make a decision about whether to treat that 0:16:40.556 --> 0:16:46.156 patient with an unproven medication that is available and FDA 0:16:46.196 --> 0:16:51.076 approved for other uses. That is a really individual decision 0:16:51.156 --> 0:16:54.756 that needs to be made in terms of patient physician care. 0:16:55.316 --> 0:16:58.916 That's separate from doing a large scale clinical trial to 0:16:59.116 --> 0:17:03.516 determine definitively whether those drugs actually work. You mentioned that 0:17:03.636 --> 0:17:07.076 Zythromycin is a broad spectrum antibiotic. It's not an anti 0:17:07.196 --> 0:17:10.396 viral agent, and so you were speculating that, you know, 0:17:10.436 --> 0:17:12.796 if it's having an effect, maybe the effect that it's 0:17:12.796 --> 0:17:16.236 just having is helping to deal with whatever other bacterial 0:17:16.276 --> 0:17:20.756 infections maybe going on simultaneous to the viral infection. What's 0:17:20.756 --> 0:17:25.116 the mechanism for hydroxy chloroquin that is an antiviral agent? Right, 0:17:25.156 --> 0:17:27.636 So what is the mechanism if you can explain it 0:17:27.676 --> 0:17:31.196 in lay person's terms for us, by which that's supposed 0:17:31.236 --> 0:17:33.316 to have an effect If it is indeed having an effect, 0:17:33.876 --> 0:17:38.116 So that's not known. Hydroxy Chloroquine is actually an anti 0:17:38.116 --> 0:17:44.996 malarial and malaria parasites are not viruses. Actually they're single 0:17:45.076 --> 0:17:49.756 celled parasitic organisms. A group in China looked at the 0:17:49.876 --> 0:17:54.356 effect of chloroquine, which is a related drug in vitro 0:17:54.756 --> 0:17:58.956 on SARS coronavirus and SARS coronavirus to replication and they 0:17:59.036 --> 0:18:03.356 speculate that the block occurs during the entry process. So 0:18:03.396 --> 0:18:06.436 when a virus infects a cell, the virus attaches to 0:18:06.676 --> 0:18:09.676 a host receptor and is taken up inside the cell 0:18:10.116 --> 0:18:13.076 in a compartment called an endosome in order for the 0:18:13.156 --> 0:18:16.556 virus to begin replicating its genome, which is a critical 0:18:16.596 --> 0:18:20.876 step in viral replication, the virus has to escape, essentially 0:18:20.956 --> 0:18:26.636 from that endosomal compartment. That escape process is triggered by 0:18:26.996 --> 0:18:31.316 the acidification of the endosome, so the endosome pH drops 0:18:31.716 --> 0:18:35.436 and that provides a chemical environment in which the virus 0:18:35.516 --> 0:18:38.796 confuse with the endosomal membrane and get inside the cell. 0:18:39.436 --> 0:18:44.596 What hydroxychloroquine and chloroquin do is they prevent endosomal acidification, 0:18:44.716 --> 0:18:47.916 and that has been proposed as a mechanism for how 0:18:47.916 --> 0:18:51.236 it would act as an antiviral drug, So it prevents 0:18:51.276 --> 0:18:54.116 the virus from actually getting into the part of the 0:18:54.156 --> 0:18:57.156 cell that it's going to replicate in by blocking that 0:18:57.236 --> 0:19:02.276 acidification process and keeping it trapped in those endosomes. Another 0:19:02.316 --> 0:19:04.796 one of the potential treatments that's being tested that you 0:19:04.836 --> 0:19:09.396 mentioned is remdesvere, an antiviral drug that I think said 0:19:09.636 --> 0:19:13.596 did not work against ebola, but did have some effects 0:19:13.676 --> 0:19:17.756 against mers. Tell us a little bit about this drug 0:19:17.876 --> 0:19:20.356 and why it's thought that it might actually be effective 0:19:20.756 --> 0:19:26.476 against this coronavirus. So, remdesiviere is a broad spectrum anti 0:19:26.596 --> 0:19:30.676 viral drug that's in a class of drugs called nucleoside analogs, 0:19:30.716 --> 0:19:37.756 and they are a chemical mimic of the ATCG molecules 0:19:37.836 --> 0:19:42.276 that make up DNA or RNA. Technically an RNA it's 0:19:42.356 --> 0:19:45.956 you instead of T, but they're called nucleoside bases. And 0:19:46.076 --> 0:19:48.796 most people are familiar with, you know, the genetic code 0:19:49.556 --> 0:19:55.436 which is made up of at season gs and the enzymine, cytosine, 0:19:55.476 --> 0:19:59.916 and guanidine, and these When the virus genome is replicating, 0:20:00.476 --> 0:20:04.516 these are put by an enzyme called, in the case 0:20:04.516 --> 0:20:08.756 of viruses, an RNA polymerase. They are put into a 0:20:08.836 --> 0:20:12.796 chain and that makes the new genetic material. What these 0:20:12.876 --> 0:20:17.796 nucleoside analogs do is they get inserted into this chain 0:20:18.036 --> 0:20:22.316 instead of the atcorg that is actually supposed to be there, 0:20:22.836 --> 0:20:27.676 and that can cause the genome to be catastrophically mutated 0:20:27.916 --> 0:20:33.756 effectively with these non functional base analogs. It's also been 0:20:33.796 --> 0:20:39.116 proposed that these nucleoside analog drugs can also activate certain 0:20:39.516 --> 0:20:44.476 innate antiviral signaling pathways, and they can also interfere with 0:20:44.516 --> 0:20:48.356 the activity of the polymerase enzyme that is making the 0:20:48.476 --> 0:20:51.956 new copies of RNA. In the case of a coronavirus. 0:20:52.676 --> 0:21:00.036 So these drugs did show promise in preclinical studies against ebola, 0:21:00.596 --> 0:21:02.996 but then it turned out not to work in actually 0:21:03.076 --> 0:21:06.916 Bola patients. There might be some reasons for that that 0:21:07.036 --> 0:21:10.036 don't actually have to do necessarily with the mechanism of 0:21:10.036 --> 0:21:13.956 the drug. One thing about ebola patients is that they 0:21:14.076 --> 0:21:18.356 aren't necessarily coming into an ebola treatment unit or ETU 0:21:19.116 --> 0:21:23.356 when they are early on an infection. Oftentimes, when an 0:21:23.356 --> 0:21:26.436 ebola patient is symptomatic, they will show up at the 0:21:26.476 --> 0:21:31.796 ETU after they're already very sick. And I study ebola, 0:21:31.836 --> 0:21:34.916 I study the host response to ebola in my animal 0:21:34.996 --> 0:21:38.436 models that I study. Once those animals have sort of 0:21:38.436 --> 0:21:41.436 reached a point of no return in terms of their 0:21:41.436 --> 0:21:46.236 host response just being completely screwed up by systemic ebola infection, 0:21:46.836 --> 0:21:50.476 then targeting the virus's ability to replicate may not be 0:21:50.636 --> 0:21:54.596 very helpful. And I wonder if that is why in 0:21:54.836 --> 0:21:58.636 patient trials, why remdzevir was not as effective as it 0:21:58.716 --> 0:22:03.076 appeared to be in preclinical trials, Because often in preclinical trials, 0:22:03.116 --> 0:22:06.436 when you're working with an animal model, you know exactly 0:22:06.436 --> 0:22:09.556 how much that animal was infected with and at what 0:22:09.676 --> 0:22:13.996 time that animal was infected. People don't necessarily know when 0:22:14.036 --> 0:22:19.596 they got infected, so remdesivir's ability to treat ebola patients 0:22:19.636 --> 0:22:22.876 will have a lot to do with at what point 0:22:22.956 --> 0:22:27.116 in the infection you can treat them. For COVID, we 0:22:27.236 --> 0:22:31.596 know that remdesivir has some efficacy against SARS coronavirus two 0:22:31.876 --> 0:22:35.076 in vitro in cultured cells, and we know that it 0:22:35.076 --> 0:22:38.036 seems effective in non human primates that were infected with 0:22:38.156 --> 0:22:42.396 Mer's coronavirus, which is another related coronavirus that causes a 0:22:42.476 --> 0:22:46.876 similar type of disease. Whither it will work in patients, 0:22:46.956 --> 0:22:50.876 I think will be dependent on when those patients are diagnosed. 0:22:51.436 --> 0:22:55.756 So remdesivir treatment as a last resort for patients who 0:22:55.796 --> 0:22:59.236 are already severely ill may or may not have an effect. 0:22:59.716 --> 0:23:03.756 If remdesivir does work by triggering some of these anti 0:23:03.836 --> 0:23:06.876 viral immune responses, it's possible that some of those responses 0:23:06.876 --> 0:23:09.916 may be protective. We just don't know until we are 0:23:09.956 --> 0:23:12.116 able to test this. But that is why it's so 0:23:12.196 --> 0:23:16.916 important to test these treatments on people at different stages 0:23:16.956 --> 0:23:20.356 of the disease and with different clinical manifestations of the disease, 0:23:20.436 --> 0:23:24.316 because we really need to know if, for example, remdesivir 0:23:24.356 --> 0:23:28.316 does appear to work, if treatment begins very early, then 0:23:28.356 --> 0:23:30.716 we need to know that so that patients can begin 0:23:30.836 --> 0:23:34.396 treatment initially when they are diagnosed, rather than waiting for 0:23:34.436 --> 0:23:37.636 them to progress to severe disease, for example. So those 0:23:37.636 --> 0:23:41.036 have a lot of implications for the types of decisions 0:23:41.116 --> 0:23:45.196 that physicians and clinicians will make if that drug does 0:23:45.236 --> 0:23:48.596 prove to be effective. Just a quick mention of the 0:23:48.956 --> 0:23:52.476 HIV protease inhibitors which in one patient seem to maybe 0:23:52.516 --> 0:23:55.836 anecdotally have an effect, what would the theory of the 0:23:55.876 --> 0:23:59.476 mechanism be there, and what's your virological instinct about the 0:23:59.556 --> 0:24:03.596 probabilities of that approach panning out. So I've seen a 0:24:03.636 --> 0:24:08.916 couple preprints that have suggested using in silico, meaning in 0:24:09.356 --> 0:24:15.156 computers analysis alone, showing that there may be some interaction 0:24:15.316 --> 0:24:20.156 with the M one protease of coronaviruses. I'm not clear 0:24:20.276 --> 0:24:23.916 if that is the mechanism. I haven't personally seen data 0:24:23.996 --> 0:24:28.556 to suggest that those protease inhibitors that normally target the 0:24:28.676 --> 0:24:34.636 HIV proteases also would have an impact on the coronavirus protease. 0:24:35.316 --> 0:24:40.836 It's certainly possible many proteases have conserved structural features in 0:24:40.956 --> 0:24:44.796 terms of how they work. I haven't seen any data though, 0:24:44.836 --> 0:24:48.996 that conclusively demonstrates the mechanism by which those HIV protease 0:24:49.036 --> 0:24:52.476 inhibitors would be functional. And I'm really grateful to you 0:24:52.676 --> 0:24:54.556 for your time. Before I let you go, I just 0:24:54.596 --> 0:24:56.876 want to ask, is there something I'm not asking you 0:24:56.916 --> 0:24:59.436 that I should be asking you with respect to the 0:24:59.436 --> 0:25:01.636 treatments that are out there. Is there some important point 0:25:01.676 --> 0:25:03.876 that you think we need to hear that I haven't 0:25:03.996 --> 0:25:07.596 directed you towards. I think the only important point that 0:25:07.676 --> 0:25:11.636 I like to get across is that the trials that 0:25:11.676 --> 0:25:14.916 are proceeding now are going as fast as they can. 0:25:15.596 --> 0:25:19.836 But it really is critical to show efficacy. And another 0:25:19.916 --> 0:25:23.956 great example of this is Ebola. So during the West 0:25:23.996 --> 0:25:27.996 African Ebola outbreak, a number of patients that were evacuated 0:25:28.116 --> 0:25:31.316 from West Africa were then treated with an experimental drug 0:25:31.556 --> 0:25:35.676 called ZMP that everybody heard about, and many of those 0:25:35.756 --> 0:25:40.756 patients recovered and people attributed to that to look at 0:25:40.836 --> 0:25:43.916 wonderful z MAP. It works so well. Z MAP failed 0:25:43.956 --> 0:25:47.156 the same clinical trial that m Dozevier did. It now 0:25:47.156 --> 0:25:51.196 appears quite clear that getting just supportive care, so fluids, 0:25:52.036 --> 0:25:57.356 potentially breathing support, other types of treatments for the symptoms 0:25:57.396 --> 0:26:01.196 of Ebola disease. That type of supportive hospital care has 0:26:01.276 --> 0:26:05.316 been itself effective at really improving the case fatality rates 0:26:05.356 --> 0:26:08.916 for ebola. So it's possible that all those patients that 0:26:08.956 --> 0:26:10.996 go z MAP, who were all you know, in the 0:26:11.116 --> 0:26:14.596 United States for the most part, or Europe in state 0:26:14.596 --> 0:26:18.516 of the art, I see us getting world class supportive 0:26:18.596 --> 0:26:21.276