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John Whyte, MD, MPH: You're watching Coronavirus in Context. I'm Dr John Whyte, chief medical officer at WebMD. Today I'm joined by Dr Stuart Cohen. He is a professor in the Division of Infectious Diseases at UC Davis. Dr Cohen, thanks for joining me.
Stuart Cohen, MD: You're welcome. Thanks for asking me.
Whyte: There's been a lot of interest in remdesivir. And you're one of the leading authorities, with a trial currently underway. Can you talk to our audience about remdesivir?
Cohen: Remdesivir is an antiviral drug that blocks RNA synthesis. The genetic material of the coronavirus is stopped from being made, and therefore the virus can't be made. In a compassionate use trial of about  patients, it demonstrated some benefit, particularly in people under age 70, but even in the sickest of patients.
In order to determine whether this drug really is effective or not, you have to do what's called a randomized, placebo-controlled trial. You can't tell in a single-treatment trial whether the patients would have gotten better whether they got the drug or not, or whether they would have gotten worse whether they got the drug or not. When you have a randomized trial, you have a group of patients that are getting the medications and then a control group. And since we have no specific drugs for coronavirus, the control group has to be a placebo.
After you've looked at a big enough group of patients, then you are able to determine whether the group that got remdesivir got better than when compared with the group of patients that got a placebo.
Whyte: What about folks who say that that's unethical—that to be put on a placebo is problematic?
Cohen: Well, if there was a real treatment, using a placebo would be problematic. For example, if we were doing a clinical trial of hepatitis C, it would be totally unethical to use a placebo because we have treatments that work great for [this disease]. So you need to have a gold-standard treatment to compare [against] your new treatment.
There is nothing that has been proven to be beneficial for the treatment of COVID-19 beyond just supportive care—great ICU care, great respiratory management, all that other stuff. The patients get better in a percentage. And the question is whether more get better if they get an antiviral drug. So the placebo is just standard care. That's what we would do for anybody without an investigational drug available to use.
Whyte: Right. Because remdesivir is not currently approved for any indication. Is that correct?
Cohen: That is correct. This is the kind of study that will end up getting it licensed, if it deserves to be licensed based on clinical outcomes.
Whyte: Is this what you're currently doing at UC Davis?
Cohen: Yes. This is a large [NIAID]-funded clinical trial. It's multicenter and multinational, and they just finished enrollment on Sunday night. I believe there were over 900 patients enrolled, so there will be plenty of patients and plenty of outcomes.
I suspect that within the next month or so, we should have some preliminary data that will allow us to determine whether this drug is going to be the gold standard for treatment and whether it will move forward toward getting licensed. And then anything else that gets studied will have to be studied against remdesivir as the comparator if this becomes effective.
Whyte: Are they all hospitalized patients? Is that the patient population you're looking at?
Cohen: Yes, these are all hospitalized patients—patients in the ICU or non-ICU patients. But they have to be admitted to the hospital. It's only available as an IV medication, so it's not really an outpatient drug.
Whyte: What are the outcome measures?
Cohen: The outcome measures are a little bit confusing to people, but I'll explain them. There is an eight-numbered scoring system that goes from death at the top to being perfectly fine at the bottom, back to your baseline. What would be defined as a good response is being in one of the three good categories, having started in one of the five bad categories. And so it will end up being significantly improved respiratory function or being off oxygen, or going home and being back to nearly baseline. Those are going to be the clinical outcomes that are going to be evaluated. Obviously, anything less than that would be considered a failure to treatment. And then they will specifically be looking at mortality rates.
Whyte: Do you think you'll have data in 30 days?
Cohen: I'm hoping that they will. Again, this is a [NIAID] trial, so I'm not the principal investigator. I'm one of the investigators, the principal investigator for our site.
Whyte: We talked to Janet Woodcock earlier, the director of the Center for Drug Evaluation and Research at the FDA. She talked about how there are actually many agents that are currently undergoing trial. We've heard mostly about remdesivir, hydroxychloroquine, azithromycin, and convalescent plasma.
But you're an infectious diseases expert. When we think about these treatments, they all have very different mechanisms of action. How does that make sense that we're using drugs for malaria for this type of respiratory problem? We're talking about convalescent plasma and antibodies. What are we learning about the disease through treatments where we're getting some preliminary data?
Cohen: I think it may be easier to explain the convalescent plasma. And then I'll get to hydroxychloroquine.
Cohen: When we vaccinate people against viral illnesses, one of the ways that we measure immunity is by looking for antibodies, looking for an immune response to the vaccine. When we give convalescent plasma, we call that passive immunity. The patients, instead of getting a vaccine, are actually getting the end product of what a vaccine would provide, with the idea that that will help people get better and clear the infection, because now you've provided a good immune response to the virus. It helps the body get over it; it gives it a leg up onto a footstool.
The way hydroxychloroquine works is different. When the virus attaches to a cell, it has to get into the cell. And when it gets into the cell, it gets put in this little bubble. Within that little bubble, hydroxychloroquine changes the acid-base balance so that the virus can't replicate. It stops it from multiplying right after it enters by changing the pH within this little bubble, which is called a phagosome. I think that is the mechanism.
Using HIV as an example, we have things that target the enzymes that replicate HIV. We have drugs that target what's called the protease, which actually splits the HIV proteins up and allows it to be made into a whole virus. We have targets against what's called the integrase, which is what makes the HIV stick into cells and never come out again. And so they're all different targets that people go at when they develop antiviral drugs. One size doesn't always fit all. And for each virus, a different drug and a different target may be preferred.
Whyte: For HIV, it took us many years to get to this point of triple, quadruple therapy from the early days of [antiretroviral therapy]. Let's move over to the vaccine issue, where some folks are suggesting that this is a 12- to 18-month endeavor. We're still searching for a vaccine for HIV. It's taken more than a decade to really fine-tune a vaccine for shingles. What are your thoughts on where we are in vaccine development for coronavirus?
Cohen: That's a very interesting question. I will start out by saying that not every virus is the same. Maybe one way I can describe this is to say that part of the way that viruses survive is to make mistakes when it multiplies so that there are a lot of different viruses that are all very related but just a little bit different. These are called mutations. And the mutation rates for something like HIV are pretty high.
Part of the reason that people haven't been able to develop a vaccine for HIV is because the target keeps moving, and the virus has the capability of moving past that target. So you have a vaccine that targets one thing, and all of a sudden, it slips over to the right by making a few changes and avoids your vaccine.
The coronavirus is new enough that I don't think we totally know what the mutation rate is, how fast it changes. And that may determine how elusive a vaccine is. So if it doesn't mutate rapidly, then I think there's a better chance to develop a vaccine than if it does mutate rapidly.
The other thing is that HIV is a chronic infection and shingles is a chronic infection. Once you get them, you never get rid of them. The vaccine just keeps everything in check. For coronavirus, this is presumably an acute infection and people get over it; eventually they clear the virus. So it's a little more analogous to influenza. I'm not sure that we've been that successful with that.
Whyte: I was going to bring that up.
Cohen: I get that part too. Right.
Whyte: So now I get to ask you, what's your best bet in terms of timing for a coronavirus vaccine?
Cohen: I would say that 12 months is definitely a short line. I would be surprised if it was something that fast. Even though vaccine technology has moved rapidly, you still have to prove that it's safe. You still have to prove that it actually does something. I think 18 months is probably realistic. And then we're going to have to see over the next month or two, as people start doing gene sequences of sequential coronavirus samples, whether it changes a lot. And if it does, then I think it's going to be a lot more difficult, and 18 months may be optimistic.
Whyte: Where do you think we'll be on treatments 6 months from now?
Cohen: I'm hopeful that we will have treatment in 6 months. I'm hopeful that we'll have good news in a month and that we will have something to start working on. And then other drugs will follow it along. There are a lot of drugs being developed.
We've been approached for multiple clinical trials, and there are a bunch of different ways in which people are going at it. I'm much more optimistic about drug treatment than I am about vaccines.
Whyte: That's good. Maybe we can check in with you in another month and see how things are going.
Cohen: That would be great.
Whyte: Thanks for joining us today, Dr Cohen.
Cohen: Thank you.
Whyte: And thanks for watching Coronavirus in Context. I'm Dr John Whyte.
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Cite this: John Whyte, Stuart Cohen. The Promise of Remdesivir for COVID-19 Treatment - Medscape - Apr 30, 2020.