Drs. Richard Childs and Matthew Hall — Remdesivir Therapy for COVID-19

>> Remdesivir—the word has been splashed across screens and talks of its promise as a treatment in the battle against the novel coronavirus has cycles through the news for quite some time now.

>> The drug remdesivir has been getting a lot of attention…Remdesivir, a drug that was first made to help fight Ebola…that new possible breakthrough drug is the first treatment to show real promise…

>> But how did remdesivir take center stage? Like most science, it’s had a winding path to the limelight.

>> In the wake of the coronavirus outbreak, well before shelter-in-place orders were enacted and the world was holding its breath to see where we head next, Dr. Richard Childs, a Senior Investigator and Clinical Director of the National Heart, Lung and Blood Institute treated patients in one of the early hot zones of the pandemic. He led a strike team of Public Health Service officers sent to screen and care for Americans on the Diamond Princess cruise ship you might recall was held in quarantine in the port of Yokohama, Japan back in February.

>> Little was known about the virus that had taken a hold of the passengers on board. The only thing that was certain, was that people were getting sick. By the time Dr. Childs and his team arrived, the apprehension had set in.

>> There was tremendous anxiety and fear about using this approach of just having folks quarantined in the room, whether it was going to work or not; could it possibly be extinguished by having people stay in their room. As more and more cases started getting reported, it was becoming clear that this approach was failing, and that something had to be done to get them off the boat.

>> Since no cases had been detected in the US, there was a lot of worry about how to treat or even face patients that were infected with the virus.

>> We didn't fully understand how contagious it was. There was questions about was it airborne or was it a droplet spread? How do you protect yourself? I was excited and thrilled to know that I was going to be part of this important mission, and at the same time, you know, cautious realizing that this was going to be something that potentially had some risks associated with it.

>> When I spoke with Dr. Childs, he described the moment when he realized the situation could get even worse, and fast.

>> It started when we got on the airplane. My thought was that we probably would put masks on once we got into the country. But right when we got on the plane everybody had masks on. It was pretty clear that all the passengers were in the mindset that they were going into an environment where there was a virus that they were going to encounter. So the second we saw that it was just like a wakeup call.

>> Right. I think even just as civilians wearing masks definitely like accentuates like the gravity of the situation. So I can imagine that first shock when you're like, yeah this is—this is serious.

>> Yeah. And, you know, the second thing that's -- that stands out in my mind is going into the room with 25 officers and everybody had a mask on their face. And you could see that everybody knew that this was going to be a mission that was going to have some challenges and was going to have some risks. And, you know, my job was to tell them that the PPE protocols and the PPE matrix that they had all been trained on, were highly effective maneuvers to prevent from getting infected. And that I had extreme confidence in everybody's ability to do their mission. And that they were probably at greater risk when they were out of their PPE away from infected passengers, around other people in Japan, than they were when they were wearing their protective gear.

>> Well, as more and more people started showing symptoms and were evacuated to nearby hospitals, how were medical professionals, including yourself, treating those infected?

>> It was basically what we call supportive care, which is that you provide care measures that support them through the symptoms. So, if they're having diarrhea and they get dehydrated, you give them IV fluids. If they are having shortness of breath, and if their oxygen concentrations are low, you give them supplemental oxygen. If their lungs get so severe that they're not able to get enough oxygen even with the supplemental oxygen, then you put an endotracheal tube down, intubate them and put them on a breathing machine. All these maneuvers are just designed to support the organs that are damaged through the viral infection process and then should just wait until the disease runs its course with the immune system ultimately kicking in and then eradicating the virus. But if the virus out beats the pace of the immune system, then you can have, you know, very serious or even fatal complications. And we know also that when the immune system kicks in, it can wreak, not only havoc on the virus, but it can wreak havoc on the organs that are infected with the virus. And there's, you know, data now that sometimes when that immune response is happening, that there can be problems with inflammation in the lungs, there can be problems with inflammation in other organs, like the heart and the liver and the kidneys. There can be issues with the brain. So, the immune system in some ways ends up, for some people, being a double-edged sword.

>> I see. So, you were treating the symptoms, basically kind of buying time for the immune system to kick in. But the ultimate goal is obviously to eradicate the virus before it spreads, or the inflammation of the immune system causes damage. So, at what point did remdesivir come into the picture? And why was it such a strong candidate for treatment when it was still considered an experimental treatment at the time?

>> So, there were many different antiviral agents that were being empirically used against the virus. A lot of them were drugs that were already approved for treating HIV or treating influenza. And maybe anecdotal information or some laboratory data that would suggest that these drugs might have activity against the virus. With the exception of remdesivir, most of the experts in virology were really not overly optimistic that any of those drugs were going to have activity against this virus. Remdesivir which had been around for a little while and had shown activity against other types of coronaviruses looked like it was the most potent of all these drugs and had already been studied in patients with Ebola. And even though, you know, it appeared to have some activity against Ebola, but didn't improve the odds of survival, the safety profile of the drug was established.

>> Repurposing drugs in the medical community isn’t a rare practice. Oftentimes, researchers will take an existing drug that has been shown to be safe in humans and approved for a particular use and test it to see if can benefit the treatment of another condition or disease. Perhaps one of the more notable examples is the case of sildenafil, commonly known as Viagra, that was originally meant to treat hypertension and heart disease. There is also thalidomide, which was first intended to alleviate morning sickness during pregnancy. But when it was linked to birth defects, the drug was shelved away until it was discovered to be effective to treat leprosy. It’s also now used in many cancer treatment regimens.

Before it becomes a standard of care for COVID, remdesivir, like all other drugs, will have to pass randomized controlled clinical trials. Still, some preliminary data gives scientist hope that it will find a new purpose helping those affected by the virus.

>> The drug development pipeline and timeline takes a significant amount of time and a lot of money, and it could take up to 15 years to develop a drug. And so, one of the things people look to are drug repurposing opportunities.

>> That’s Dr. Matthew Hall, biology group leader and acting chief of the Early Translational Branch at the NIH’s National Center for Advancing Translational Sciences, also known as NCATS. Dr. Hall recently published a review that delved into the development of remdesivr and how it works.

>> We wrote this very quickly because there were research papers out, but there was nothing that really captured, you know, the background for the drug and gave sort of a general overview of it.

>> COVID-19 has really spurred an all-hands-on-deck approach. The outbreak has funneled biomedical research such that scientist who were not experts on coronaviruses have shifted their efforts to studying the SARS-CoV-2 virus. And Dr. Hall is one of them.

>> One of the reasons so many people have turned their attention to it is because we need therapeutics for patients immediately. So in the process of learning ourselves, it seemed appropriate to pull all this information together and put it into a review so that others could learn about remdesivir's path.

>> So can you tell me a little bit about the development or the history of the drug?

>> Yeah, it was actually developed by a drug company called Gilead in a public private partnership, as I suppose Dr. Collins would say, between a number of US government agencies and Gilead as I said. They collaborated together on trying to discover drugs that were active against dangerous viruses. And they actually screened a collection of compounds against a panel of viruses. And Remdesivir was a compound that emerged out of that even before Ebola. And so when Ebola came along they recognized that they had this development candidate. They showed that it had activity against Ebola virus in the models that were appropriate for studying Ebola. And it was deployed for clinical trials at the time in Africa. I believe that it ultimately didn't show a great effect in treating patients with Ebola. And so it wasn't necessarily that successful in that setting. But it's been in humans. We know it's an antiviral. We know how to dose it. And so when the opportunity—not an opportunity anyone wanted—but came along where candidates needed to be identified very, very quickly, it was tested in what we call invitro models. It was tested in dishes where cells were infected with virus and then you can add drugs, candidates and see if they prevent that viral infection or that viral replication.

>> That’s so interesting to think about this like a repository for these like potential drugs that once an outbreak hits, you kind of like throw everything at the wall and see what sticks? Is that kind of the method in a really rough translation of it?

>> Yeah, sure. So, at NCATS we proactively created a library of all drugs that have been approved for use in humans in the United States, Japan and Europe, and we update that annually. NCATS is what we call a disease agnostic center. So we work with people and collaborate with people studying a wide range of diseases. We have an emphasis in the research that we do on rare diseases, underserved populations, and also neglected diseases. And a lot of infectious diseases are neglected. Coronavirus certainly isn't, it's getting a lot of attention.

>> Right.

>> But when a new essay or a new biological way of screening for drug candidates comes along, one of the first things we do is we take this library of all approved drugs and we screen and test them. And we look for those active compounds. So, that would be the throw everything at the wall approach that you're referring to. And you do give yourself the best opportunity to identify something that in the context of drug repurposing, that has already been used in humans that you know is safe, and that you can trial very rapidly. And that's what we're seeing. Whereas a traditional drug development type pipeline takes 15 years and we know from all of the media discussion that a vaccine development pipeline through to having something that's approved could be a year or more in the best-case scenario.

>> Right.

>> So the remdesivir story reinforces the repurposing opportunities exist even within a very focused space like infectious diseases. So it was developed out of the desire to develop antivirals. It was active against Ebola and went into human clinical trials. People doing experiments that showed it was active against other coronaviruses as part of the kind of research that people do in the academic world. And so when the COVID-19 crisis came around, we didn't know a lot about COVID-19. But thanks to research we knew quite a lot about what remdesivir could do. And that's how it came up as a candidate so quickly.

>> Oh, that’s a good way to put it. So, can you describe how remdesivir works at the cellular level and why it's so good at disarming the coronavirus?

>> Yeah, so the way remdesivir works is that it inhibits an enzyme called RNA-dependent RNA polymerase. And I'll try and capture what that does. So for every virus it enters a human cell, and it hijacks the machinery that we have in our cells to replicate itself to make many, many, many viral copies and then they're released from the cell. So it's kind of like coming into your kitchen and using all your stuff to cook dinner. And of course if the patient's gets sick, this kitchen's pretty messy at the end. So it takes advantage of all of the machinery that we have. And then the virus is released. The genome of that virus is captured in RNA in the case of the SARS CoV-2. And RNA-dependent RNA polymerase, its job is to actually take that RNA from the virus and replicate it. And so if you can inhibit the enzyme, RNA-dependent RNA polymerase, you stop the virus from replicating. And so that's an absolutely essential piece of the machinery for replicating the virus. And so it's a real Achilles heel. It would be sort of a terminology that's often used in drug development when you identify, you know, an enzyme or a protein that—stopping that from working will absolutely stop the disease.

Now when remdesivir is given to patients, it's administered intravenously. So you can't take it as a pill. The treatment is by intravenous injection and that's a reflection of just the properties of the drug and how it needs to be administered. So patients who will be getting treated in many cases are, you know, they're already infected and have quite a high what we would call viral load. But by administering this antiviral drug it can improve their symptoms by beginning to inhibit the replication of the virus in allowing the patients to recover more quickly when it works.

>> And work it has. At least in some patients, and often for those who need it the most.

Back in Japan, Dr. Childs used remdesivir to treat the most severe cases for whom supportive care was not enough. He advocated for his patients and was able to secure emergency access to the experimental drug.

>> I ran into an old colleague from BARDA, Dr. Robert Walker. And he had connections already with Gilead and basically establish the pathway for us going forward for how we could acquire the drug from the company, gave us the contacts and then the embassy gave us the contacts with the Japanese Ministry of Health, Labor and Welfare. Once we got those connections together, we were able to start to define the pathway for getting compassionate use drug approved for patients that were the sickest, the ones that were, you know, at risk for dying from the virus. And, you know, the interesting thing is that with a lot of antiviral therapies, the earlier the disease you use them, the better the chance that they're going to help. And we knew that these patients were already very sick. So even if we got the drug, we weren't sure that it was going to make a difference if they were that sick, and if they weren't getting the drug there in the early phases of the disease.

There was a patient that would absolutely have died had it not been for the most aggressive supportive care. And that was a patient that also got remdesivir. And I've never, you know, in my career seen anyone that sick pull through a critical illness. That patient was on ECMO. Their lungs were completely whited out, on ECMO for 22 days and a ventilator for 31 days. And the patient got remdesivir and pulled through and survived. And was discharged from the hospital. So, you know, these are anecdotal observations that made us believe that this drug was doing something.

It's really being part of a team like that that's focused on health and treating the sickest of the sick patients that motivates me to be active and involved in these types of deployments.

>> Remarkably all 13 critically ill patients that Dr. Childs and his team treated, including those that got remdesivir, survived.

>> Fast forward to the end of April and Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Disease and now a household name, announces that data from clinical trials provides evidence that remdesivir does indeed help patients recover more quickly from infection. Here he is during a visit to the White House.

>> The data shows that remdesivir has a clear-cut significant positive effect in dimishing the time to recovery. If you look at the time to recovery being shorter in the remdesivir arm, it was 11 days compared to 15 days. And that’s a p-value, for the scientist who are listening, of 0.001. Although 31 percent improvement doesn’t seem like a knockout one hundred percent, it is a very important proof of concept because what it has proven is that a drug can block this virus.

>> The story of remdesivir exemplifies why in so many ways you can’t template the drug discovery process. It’s had a meandering path to become a drug candidate that could improve human health and potentially saves the lives of thousands of people infected with this runaway virus. Without the research investments from the private and public sectors and the collaborative efforts of scientists around the world, remdesivir would have never made it this far.

And the work continues.

>> I am very active in research now related to COVID-19.

>> That’s Dr. Childs again.

>> We have a focus on pulmonary medicine, cardiovascular medicine, and even now critical care medicine. And these are all areas that the virus impacts. So we have research proposals, collaborations and protocols that we'll be studying patients with COVID-19 probably, you know, for the next six months to a year to try to figure out what parts of the immune system are helpful what parts are harmful, to try to get a diagnostic signature as early as possible in the disease, so that we can predict who's going to have a smooth course and who potentially is going to get into trouble and become severely ill or critically ill.

>> Like Dr. Childs, Dr. Hall will continue to focus his research on the coronavirus.

>> At NCATS we've developed a page we just launched this week called The Open Science Data Portal and we've been like others working on COVID-19 and developing assays biological experiments and screening them against these approved drug libraries. And we're sharing that data with the scientific community and with the general community as quickly as possible through this page at opendata.ncats.nih.gov/covid19. You can literally go there and look at the raw high throughput screening data and learn about the assays that we're using. And so we're doing this in the hope that by comparing the activity of all of these drugs against multiple different biological assays or biological experiments that study the various steps of the virus in its replication process and its effect on cells we'll be able to identify other opportunities for drug repurposing.

>> Both scientists are hopeful that their work will not only advance our understating of COVID, but also help pave the way to deal with future outbreaks.

>> At NIH and as a society we're well equipped with many opportunities at our disposal for the next thing that comes along that none of us want but that occurs.

>> Our hope is that we will not only get insights that will be important for treating and managing complications associated with COVID-19, so that we can get the mortality rate down. But I think that we will learn valuable lessons about the pathophysiology of all kinds of other emerging pathogens that are going to come in the future. The bottom line is we'll be fighting viruses, you know, for a very, very long time. The next virus that comes, we may do much better because of what we've learned from this virus and, you know, this virus impacts so many different organ systems that I would be optimistic that we are going to get insights that are going to have a very important impact for, you know, pandemics to come.

>> To learn more about NIH intramural research please visit irp.nih.gov. And make sure to subscribe to our weekly newsletter for the latest updates. Thanks for tuning in.