Answering Your Questions On COVID-19 Drug Development

As we continue to navigate these unprecedented times, KCBS Radio is getting the answers to your questions about the coronavirus pandemic. Every morning at 9:20 a.m. Monday-Friday we're doing an "Ask An Expert" segment with a focus on a different aspect of this situation each day, sponsored by the San Francisco Police Department.

Today we’re looking at the potential treatments for COVID-19 and the research being done with Dr. Nevan Krogan, UCSF Professor, director of the Quantitative Biosciences Institute and Senior investigator with the Gladstone Institutes. 

Dr. Krogan, good morning. I know I left seven or eight of your titles off of there.

No, no. That was pretty comprehensive. It's great to be here.

The work you've done - and we've reported on it here at KCBS Radio - before we start getting into specific questions, can you walk us through the basic approach you and the team have been taking around viruses? Because you didn't just start with this novel coronavirus.

Yeah, we have been working on many viruses over the last decade. HIV, ebola, zika, dengue, influenza - so we were well prepared, I would argue, to tackle this novel coronavirus. And the approach that we've taken is a very innovative, highly collaborative international approach where we're trying to generate a map or a blueprint of how the coronavirus comes in and hijacks and rewires our cells during the course of infection.

So the virus has about 30 genes. We have over 20,000 genes and proteins in each one of our cells. So the virus can't live by itself, it needs our genes and our proteins and our cells in order to replicate and infect. So what we did here was essentially study each one of the coronaviral genes and proteins in isolation and identified which human protein that it was sticking to or talking to. And we identified over 300 human proteins that we think the virus potentially needs in order to infect our cells, and then we looked for drugs and compounds - this was led by Kevan Shokat and Brian Shoichet at UCSF - they identified about 69 different drugs and compounds that they thought would target these human proteins that the virus would need. And then in a repurposing effort, we've been trying to determine if some of these drugs and compounds actually had antiviral effects in a laboratory setting.

So a home run would be to say that there's a bottle of medicine already on a shelf somewhere that works against this virus, is that right?

That sounds good to me, yeah, but that's not going to be the case here.

So what is it that you have been able to find, if you could generalize, about this particular virus that may make it different from others?

Well we have, as I said, studied many viruses over the last decade generating these maps. For me, I would say at least at a molecular level, this is probably the most fascinating virus that I've ever studied in that it really gets its fingers into pretty much every major process in our cells. So from that point of view it's completely fascinating. But then you see all these different symptoms and there's not like one set of common symptoms that are seen across all individuals, and maybe that's correlated with how complex it is at a molecular level. 

But that being said, the map that we generated did point us into a couple directions in terms of novel drugs and compounds. And a few days ago we reported on two sets that look incredibly promising and we're continuing to follow up on those.

Let's talk about that a bit because you have gotten some of your work out, and these are fascinating times for scientists, right? Because of the speed at which the world wants answers but the process at which science works.

Yeah, science is very individualistic, it's very siloed and the system is set up and in my opinion really often discourages collaboration and encourages individuals to work by themselves, you know one person wins the Nobel Prize, one person gets the grant, one person gets tenure. And this attitude actually discourages collaboration, especially young investigators, young scientists who bring enthusiasm and new ideas to the table. And what I've seen here, which has been absolutely remarkable, is really this change in thinking in terms of breaking down these silos across different laboratories at the same institutes, which is what we have done. We went across the world collaborating with different institutions. We've been working with a number of groups in New York and Paris and England and Seattle, San Diego, North Carolina. And then also barriers are being broken down really around the world in terms of academia and pharmaceutical companies. 

So everyone has really come together here, I would argue in a very unprecedented way to try to come up with solutions to this terrible pandemic. And my thinking going forward is, why aren't we doing this normally, to study HIV, to study other viruses, other diseases like breast cancer or Parkinson's? So I hope this spirit stays in place once the deaths settle in COVID-19 so we're in a much better position to tackle COVID-22, COVID-24, whatever other disease we want to focus on.

Ok, so let's get to some questions here and again those questions come in to askus@kcbsradio.com. And if it's not something that's in your wheelhouse Dr. Krogan feel free to punt and we'll move it on to the next expert in the line.

How will we understand both the safety and effectiveness of COVID-19 vaccines if the number of subjects tested is smaller than in normal vaccine trials?

Well there's so many great minds and great scientists around the world coming up with different ways to treat or to prevent this virus. So a big push is on therapeutics like we're trying to do, but then there's also a big push on vaccine generation as well. And there's a big debate on if we can even get a vaccine for this particular coronavirus. There's never been a vaccine for a coronavirus in the past; although that being said there's never big this big an effort in trying to find one. So going forward there's a number of great groups, great labs working collaboratively around the world and the hope here is that in maybe 12-18 months we will have a vaccine, one that could be tested properly. That is why this takes a long time, is you need to do these proper tests. And I think there will definitely be enough  subjects for this testing but I think this could realistically take 12-18 months.

This one is kind of related: What are risks for people who take vaccines early as opposed to waiting for a year to see what happens?

Yeah, you want to have more data. The more data you have the more predictive you can be with a particular treatment like a vaccination. So there could be problems that arise when taking a vaccination early, you're not quite sure how it's going to behave. That being said, there's some great minds working on this using cutting edge - bleeding edge - technology to come up with the safest, most efficient vaccine possible. So the hope is we'll have something very soon.

Is there any research going on looking at targeted therapy or immunotherapy drugs for COVID? They unleash your own immune system. Might there be something there along the lines for COVID? For example, Tagrisso used for EGFR mutation.

Yeah absolutely. Our approach is looking at the host proteins and trying to find drugs and compounds and inhibit those proteins that the virus needs. That's the antiviral strategy we're employing. 

But then there's also other approaches like antibody approaches. There's some great work being done here at UCSF from Charlie Craik and Jim Wells, there's trying to find antibodies, biologics that can be used as a potential therapeutic. And then there's strategies like you're alluding to - can you indirectly combat the virus by manipulating your immune system so you're in a much better position to fight it off?

So we're pushing on all fronts and hopefully one or two of these will come to fruition in a short period of time.

I have stage 4 cancer on the drug Tagrisso - a pill, not chemo intravenous. Does this make my immune system kaput and what would be the implications in regards to COVID?

Well the more immunocompromised one is, the more it looks like they're susceptible to COVID-19 and other infections as well. One thing to keep in mind especially in the context of drug repurposing - a lot of the drugs we're looking at are targeting other diseases like neurodegenerative disease or cancer. I think the biggest group that we're looking at are actually anti-cancer drugs. And oftentimes you're going to have to be on these drugs for years to treat a particular cancer, but in this case it's an acute infection and there may only be a stage of say, 7-10 days where you need to take treatments. So if there's toxicity issues, it would be less problematic in this context because it is acute and you don't have to keep taking this for a number of years like you would a lot of anti-cancer drugs. So that's one of the pluses here in trying to come up with a host-directed therapy.

So many drugs pop into the news and sometimes are there for a few days and go away. Here's one: do you know if Leronlimab is an effective drug?

With that one and many other ones, it seems like every day there's a new drug or new treatment coming online and a lot of the data is coming from maybe one laboratory or a couple of experiments. And the message really is that you can't get your hopes up on one particular treatment that gets reported. More data needs to be collected, more information, more clinical trials in order to show if any of these treatments will ultimately be effective. 

So you want to temper the public's enthusiasm here in that it takes a long time. Science takes time. But one of the positive things here is that the science is moving faster than it ever has before. So I think that's a reassurance that can be provided to the public that the best scientists are working together in an unprecedented way and the speed in which all of this is happening has never happened before in fighting any other disease. So I'm very hopeful again that something will come to fruition soon.

I know you looked at so many different compounds: hydrochloroquine is another one that's had its day in the sun for sure. Did it show anything in the testing that your program has done?

Yeah it did, it was actually one of the 69 drugs and compounds that we identified. Keep in mind there's a lot of drug screening that's going on right now where they're screening thousands if not tens of thousands of drugs and compounds trying to find something that would be antiviral.

We took a different approach, alright. We went to this map first - we wanted a foundation in the biology - and then that pointed us in a couple of different directions. So instead of screening tens of thousands, we actually sought to screen less than 100. And we actually got a couple of different categories of drugs and compounds that looked promising, and then we can go back to the biology because that's where we started. And when you have a biological mechanism with respect to a drug or a compound you're 50 steps forward with respect to pharmacology and downstream chemistry.

So back to your question, hydroxychloroquine was one of these. Brian Shoichet had made a prediction that it's actually binding to a couple of receptors that we identified in our map, and we confirmed that it was binding here. It did have antiviral activity in our assays - we've been doing them in both New York and in Paris and we're starting up these assays now here in San Francisco with Melanie Ott. But some work in collaboration with Bryan Roth at the University of North Carolina showed that actually hydroxychloroquine is binding to another receptor connected to the heart. So there's been a number of clinical trials going for hydroxychloroquine - many of them have been stopped. A big one in Brazil was stopped a couple weeks ago because of cardiotoxicity issues, heart issues. So we think we understand at a molecular level why hydroxychloroquine is providing these toxic effects. 

However, we found other drugs and compounds in this similar category which we don't think have the cardiotoxicity effects. They may have other toxicity effects, but we don't think they'll have those heart effects. And this is the power of understanding the biology, because then we can look across a much wider range of compounds and drugs. So we're very confident within this class that something is going to bubble up to the top that's going to be effective. And this is why we're working so hard.

There are three things that must be present to get infected: a vulnerable host (in other words not immune), a place where it can enter the body and enough of the virus. How much virus do you need to become infected?

Well, it's a very good question. I think it's more of a case of how immunocompromised somebody is versus how much of a virus is there in order to infect. You don't need that many viral particles in order for the virus to get inside of you and to propagate. So I look at that as more of the host than the virus. Obviously the more virus you have inside your body that you're getting infected with, the more likely you are to be ultimately infected. But I look at it more as the host and how your immune system is able to fight off not just that virus but other viruses as well.

Anything real about this theory going around that we are reducing our immunity by staying home and avoiding human contact?

Well, this is not my area of expertise. I'm not an epidemiologist but I've heard from some very high-profile people about that particular theory. I don't think the data, in my opinion, supports that particular theory. I think we all need, as a community, to be vigilant and adhere to these shelter in place rules at least for the time being. Flatten the curve, as everybody says. 

And we've seen this with other pandemics. If you look back to 1918, the influenza pandemic, when shelter in place rules were relaxed, that's when you saw the big spike. And actually in San Francisco it started out very good, the 1918 flu pandemic and that was in the summer at a similar time. And then in the fall - November - they said, "alright we've beat this thing" and everybody came back to the community and then in January they had a huge spike in infections. So I think you've gotta learn from the past and you've gotta adhere to these shelter in place rules that are being preached for at least a little bit longer and maybe a lot longer.

A nurse told me that many of the patients she's treated with COVID-19 didn't get a flu shot this year. Is there any broader evidence that flu vaccines might have a mitigating effect on COVID-19?

Yeah I've read that as well. The data out there is not strong enough one way or the other to make a conclusion in that regard.

What is the status of clinical research into oral prophylactics to suppress COVID so we can all get moving in interim until there's an effective vaccine?

There's a number of groups looking at this as a way for treatment. It does make sense, but the question is can you get treatment to a high enough concentration to actually have an effect? And more work is needed to determine that.

Just interested in the link between COVID and strokes. Any basis for that? Would it be inflammation?

That's another good question, it seems like there's a lot of younger people dying from strokes and that's the only symptom that they have. It could be related to where the ACE2 receptor is being expressed in the body. ACE2 is a receptor that the virus needs in order to infect our cells, and a lot of groups are actually looking at that phenomenon, in particular connecting it to areas of the body where ACE2 is most highly expressed.

I just wonder does remdesevir really cure the COVID-19 or just reduce days in the hospital and cut short on mortality rate?

There's been a number of different clinical trials, one big one that was sponsored by NIH and the results were released I think just last week. Their data suggested there was not a reduction in mortality but there was a reduction in terms of how long one stays sick. And there was a reduction from 15 days to 11 days and that seemingly was statistically significant. So by no means is that a silver bullet. I mean, it looks promising. 

My personal feeling is probably remdesevir is going to be more powerful at a particular stage of infection, maybe earlier on infection it would be more potent and I think we need more data to suggest that. But going forward, I think potentially the best treatment will be a cocktail approach, just like we had with HIV, right? There were three drugs that were targeting three different HIV proteins and that was the big breakthrough. So maybe remdesivir is the start and maybe combining that with a drug that hits a host protein or two host proteins plus remdesivir or three host proteins being targeted. There's so much work going on, as you're alluding to, around the world to identify drugs and the hope is some combination of these - and maybe it's including remdesivir - will actually provide a very powerful treatment. Hopefully maybe even by the end of the year.

What prerequisites will people need in order to receive a vaccine against COVID-19? Will they need to be tested beforehand? Or as in the case of the traditional annual flu vaccine, need to be completely symptom-free?

In the past, egg allergies meant an alternative flu vaccine needed to be used. Any word if food or drug allergies might be a problem this time around?

Well I think - that's a very good question. It's outside my area of expertise, I'm not involved in vaccine development. But clearly you'd want somebody who's symptom-free before you give a vaccine. And there's a number of vaccination trials that look like they're going to be starting soon and the big question with these companies making these vaccines is, should they scale up to make a number or millions of these before they actually have definitive data to say that it works? It would be a big financial risk but I think it's one that's worth taking and I think a number of companies are looking to do that in the future.

The last one is kind of personal but I think it speaks to where people are looking for leadership: when will you feel safe getting on an airplane and traveling to NYC?

Yeah I was just thinking about that last night, we have some great collaborations in New York at Mount Sinai Hospital. Yeah that's a very good question, I was thinking about, "when am I going to get on a plane?" and "when am I gonna have a beer in a bar?" I'll probably have a beer in a bar before I get on a plane. I'm hoping that by the end of the year, I'll be on a plane to New York. Maybe November or December, that's my hope.

Ok and I'll buy the first round of that beer.

Sounds good, I won't forget that.