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Interview with John Maraganore

“When you’ve got a public health crisis like this, you’ve got no choice but to deploy all of your resources toward finding a solution.”

Photograph of John Maragnore in plaid jacket, clasping hands together and looking to the side.

Over the next several weeks, Distillations will be talking to people who have special insight into the coronavirus crisis—biomedical researchers, physicians, public health experts, and historians.

In this episode, our senior producer, Mariel Carr, talks with John Maraganore, the CEO of Alnylam Pharmaceuticals, a company developing an antiviral medication for COVID-19. When news broke in January about the new coronavirus, John Maraganore made the decision to pause other drugs in development and pivot to working on an antiviral medication for this new and alarmingly infectious virus.

He says it was a difficult decision, but this virus had all the ingredients to become a pandemic. “And when you have a public health crisis like this, that’s what you do.”

Credits

Host: Elisabeth Berry Drago
Senior Producer: Mariel Carr
Producer: Rigoberto Hernandez
Researcher: Jessica Wade
Audio Engineer: Jonathan Pfeffer
Photo: Keith Bedford/Boston Globe
Original music by Zach Young. Additional songs by Blue Dot Sessions.

Transcript

Lisa: Hello, and welcome to Distillations. I’m one of your hosts, Lisa Berry Drago. In response to the coronavirus pandemic we’ve launched a brand new series focused entirely on COVID-19. Over the next several weeks, we’ll be bringing you interviews with people working at the heart of the crisis, including biomedical researchers, physicians, and public health experts. In this episode our senior producer Mariel Carr talks with John Maraganore, the CEO of Alnylam Pharmaceuticals, a company developing an antiviral medication for COVID-19. When news broke about the new coronavirus in January, John Maraganore made the decision to pause other drugs in development and pivot to working on an antiviral medication for this new and alarmingly infectious virus. He says it was a difficult decision, but this virus had all the ingredients to become a pandemic.

Mariel: Well, thank you so much for joining us. We know you’re busy. Tell us what your company is working on right now with COVID. 

John Maraganore: Yes, a pleasure. So we are currently at Alnylam, we are advancing an RNAi therapeutic for COVID-19 specifically.

So our technology, RNA interference [RNAi], is based on discoveries that were made in the late 1990s that highlighted a way to target RNA for destruction in a very selective manner, obviously. And with RNA interference, obviously we’ve been able to develop medicines for a whole range of different diseases, but one of the areas of interest historically has been viral infections, because many viruses are RNA viruses. And so we can directly target the viral genome, if you will. And so we’re harnessing the RNAi technology that we built at the company for the last 18 years and are advancing an RNAi program that directly targets the SARS-CoV-2 genome, which is an RNA genome, and with the goal of destroying the genome in the cell so that it can no longer replicate.

So basically developing a direct-acting antiviral that blocks the virus from producing new viral particles. And, you know, the approach is about to go into formal development. We’re close to having our development candidate declared, as a company, that would then start a process to bring it to the clinic, which we expect to go in lightning speed into the clinic, you know, certainly by the end of the year. 

So it’s something which we hope will be part of the armamentarium of drugs and approaches that are being developed by our industry to target COVID-19 and find a solution so that we can all get back to our lives at the end of the day. 

Mariel: Great. So tell me when Alnylam started working on this because this is all brand new, right?

John Maraganore: Yeah. It is new. And we started back in January. I mean, we were, you know, hearing the news, listening to what was going on in Wuhan, and obviously began to get concerned about what we were hearing and thought that it could be something which will need a therapeutic intervention.

And our scientists began to look at the gene sequences that were coming out of China related to the coronavirus that was discovered. And we were quite struck with how relatively conserved the virus was that was coming out of China to the original 2003 SARS outbreak that occurred, you know, many years ago.

And that meant to us that the regions of the virus that we can target with our drugs, our RNAi drugs, were very, very conserved. And it allows us to think about targeting the virus in conserved regions of the virus that not only will be applicable for SARS-CoV-2, but could in fact be applicable for future outbreaks of, you know, future coronaviruses that might occur, you know, hopefully won’t, but might occur and probably will occur in the future.

Mariel: Tell me what this means—conserved—that the virus was conserved.  

John Maraganore: Yeah. It means that there are regions of the viral genome that haven’t changed, and the fact that they haven’t changed implies and suggests that they’re essential. So if you’ve got a virus that, you know, replicates and produces new viral particles, and lots of times there are mutations and variations that occur in different regions of the genome for that virus. But then there are regions that are never changed over time, It means that that’s a region that is really important for the virus to be able to survive. 

Mariel:  Got it. So even if it’s changing, there’s this one part of the virus that’s essential for it to keep going and do its damage.  

John Maraganore: Exactly. Exactly. And so it can’t change that region, and because it can’t change that region, we can target that region and therefore, you know, impair the virus from surviving. So that’s the approach that we’re, that—so that happened back in January. So we were beginning to see these sequences coming out of China and like, oh my God, look at that.

This is really quite interesting. And at the same time, we were able to really, and this is somewhat unrelated, but thankfully was happening in the company. We were working on delivery of our molecules to the lung airways, to cells of the lung airways. And these are the cells that are infected by SARS-CoV-2.

So by complete good fortune, I would say, there was a convergence of the work that we were doing on administering our drugs to the lung airways together with the emergence of this virus that, you know, was showing highly conserved regions that could be targeted by RNAi drugs. And those two, you know, important facts came together.

And in January we began this effort to start to develop a drug toward SARS-CoV-2. Now, you know, our hopes at the way beginning of this effort, to be honest, were that this would all go away and that we wouldn’t have to, you know, I mean, we would ultimately want to develop a drug for a virus like this because it might reemerge.

But, you know, the hope was that it wouldn’t be as bad as it has become. But of course, you know, I mean, obviously with the disaster that’s occurred with the pandemic, you know, our efforts have only been heightened in terms of the work that we’re doing. It’s become a top priority for the company now to really advance this product and get it to the clinic as quickly as possible.

We’ve never been able to go from start of a program to start of a clinical study in less than a year. Our previous record was 18 months. So getting this done within a year, if not less than a year, is going to be a complete new paradigm from a timing perspective. And it just speaks to the urgency that our scientists and, you know, our team have to do this as quickly as we can so that we can ultimately find a treatment for this terrible viral infection.

Mariel: And what was the reason that you’d already been working on delivering drugs to the lungs?

John Maraganore: Well, there’s a lot of diseases in the lung airways, right? Whether it’s asthma or COPD or other diseases, cystic fibrosis. So, you know, targeting the lungs was an opportunity of developing medicines for a number of diseases that are known, you know.

And of course it did occur to us by looking at the lungs that we could also target viral infections of the lung, like flu or another virus called RSV [respiratory syncytial virus], for example. But, you know, SARS and coronavirus was not on our radar screen when we did that work. But fortunately the work was being done in a timely manner so that we can now, you know, leverage that work for the benefit of our SARS-CoV-2 effort.

Mariel: Oh, wow, that is a nice coincidence.

John Maraganore: Yes, indeed. 

Mariel: So what was it like as a company to pivot to something like this really quickly, to something that’s happening in real time? 

John Maraganore: Yeah, I mean, again, it’s probably one of the beauties of our technology. The fact that we can use genomic information. We can use the gene sequence as a way to design our drugs.

That is something which we’ve had in our technology from the beginning. And it does allow us, as soon as those gene sequences become known, it does allow us to rapidly deploy our technology to basically develop a new medicine. And so, but, you know, from an internal perspective, what it obviously takes is you rally your group of scientists together, and you look at the need to adjust things within your plans, and you stop some things that you were doing before so that people can shift and focus and work on this new thing coming out. But when you have a public health crisis, that’s what you do.

I mean, you know, you’ve got a situation where, you know, thousands of people, tens of thousands, hundreds of thousands of people will die, and you’ve got no choice but to jump on that as a company and do everything you can to deploy your resources and efforts toward finding a solution. 

Mariel: Wow. Yeah. So does this mean that other things are now just on hold for the time being?  

John Maraganore: Yeah, there were some programs that we had to put on hold. I mean, I think obviously we could return to them later on, but there were some programs that we had to basically slow down or stop for the time being so that we can put our muscle behind this effort. And it’s the right thing to do. I mean, you know, what we do in our industry, what we do with companies like Alnylam, is we make medicines, and, you know, if there’s a public health crisis crying out for a medicine, that’s just a crying call for, you know, efforts like ours to begin to work on it very quickly.

Mariel: Was there a moment when you realized that this is what you had to do? Was it immediate?

John Maraganore: Well, you know, it’s interesting because it, over the course of a couple of weeks, you know, it became a topic of debate within the senior team. You know, some of us had just come back from, you know, the annual health care conference in January, the J.P. Morgan conference, and we were back in the office and, you know, we were all reading and seeing what was going on in China. You know, hard not to see that, given that the news coverage that was going on. And, you know, a number of us felt we should jump on this right away. We should move on it right away. Others were more, you know, more anxious that, boy, that will distract us from other things that we have to do.

And this probably will just go away, and we shouldn’t get, you know, too distracted by this. And so there was actually a live debate at the time within our senior team. You know, thankfully, I was much more in favor of moving, and that helps when you’re the CEO. But there were people on my senior team who appropriately were saying, gosh, can we really do this?

And we’re just distracting us, and it’s unlikely this is going to be a problem in the world. And of course that, they were wrong. I mean, they were voicing an important view, which is great. But at the end of the day, I’m glad that we took the plunge and dove into it, because we, you know, obviously we could have come back to it, you know, weeks later or months later. But we would have lost time. So now, you know, by jumping on it very quickly, we were able to obviously, you know, gain time and move along with this and do everything we can to bring this medicine to the patients as quickly as possible. 

Mariel: You know, we’re used to hearing about outbreaks around the world, and oh, it could come here. But this is really the first time in my life and lots of people’s lives that it has actually gotten to that worst-case scenario.

So I can, you know, I understand, because how could you in your position look at every single possible health crisis and completely pivot, right? I mean, you would be doing that. You’d never get anything done. Right? 

John Maraganore: It would be pretty distracting, you know, to your team. Yeah. If you, if it, because I mean, whether it was Ebola or the swine flu, or, I mean, even the original 2003 SARS. You know, so there are so many examples of health crises that emerge and of course get dealt with through other measures that are effective, which is terrific, thank God. But, you know, as a company, you have to make sure that you think about how you build your team and focus people and not get them distracted by everything that’s going on. But this just had the, in my eyes, this just had the ingredients early on of becoming a pandemic.

And well before it was called a pandemic, it was a pandemic, and you know, there was just no doubt that this was going to have the type of impact that it ultimately did. When you see something that’s so infectious, you know, when you see, you know, R naught [R0] scores that are over, you know, 2 or 3, you know, and you realize, and you just see the situation that was happening in Wuhan with the numbers of people that were infected. 

Given global travel, and given how, you know, the world is configured, I had no doubt at all that this would become a pandemic. And obviously the mortality rate is unacceptably high. And we have to do something to fight it. We can’t just wait for this to pass, you know, because it’ll leave a lot of dead bodies in the path, which is just not acceptable.

Mariel: So tell me about the treatment that you’re working on. How would it be administered? And when? And I guess how often?  

John Maraganore: So this would be a drug that would be given by inhalation, just like, you know, asthma drugs are given by an inhaler. And it would be given to people that are early in their infection.

I mean, what we know about antivirals is that the earlier you give it, the more effective it’s going to be. So ideally, provided it’s safe, and it should be safe. But you’d like to give it as early as possible to people. Now the other approach that we’re going to explore is giving it so-called prophylactically. So not to treat an infection but to prevent the infection. And here we would focus on people that are at risk. So it might be health care workers, might be elderly that are in a nursing home. It might be younger people that have comorbidities that are at risk for bad consequences if they get infected. And it might even be family members of somebody who’s recently been infected. Or people that have through contact tracing been identified as having been exposed to somebody. So it’s still a very large number of people that you can help in prophylactic mode, but you’d basically start administering this drug even before somebody had a bona-fide infection.

And the goal would be to prevent the infection from ever happening to begin with. 

Mariel: Right. And so would that be something that people take continually, or is it more like a one-time thing?

John Maraganore: Yeah, I mean, this is the wonderful thing about RNAi because it’s very, very durable. In other words, it lasts a long time. So even, you know, one administration now, I don’t know if that’s just once for three times over a day or something, but one exposure to the drug would probably last for at least a month.

Mariel: Oh, wow.  

John Maraganore: Yeah. And so effectively, it’s almost like a vaccine, if you will, not long lived like a vaccine and it doesn’t harness the body’s immune system to fight the virus. But it almost has vaccine-like properties in a way that could provide durable protection for people that have been exposed or for health care workers or, you know, the other groups that I talked about. So it could be an approach that would be, in some ways, you know, very much like a vaccine and therefore, you know, would help open up people to, from a societal perspective sooner, at this point. 

Mariel:  So that is, if this is available before a vaccine would be?  

John Maraganore: No, I mean, I think, look, even if the vaccine comes out, we don’t know yet how effective the vaccine is going to be.

You know, hopefully it’s very effective and hopefully our treatment doesn’t ever need to get used, to be honest with you. I really hope that we can all have a really great vaccine that would stop this forever, using our immune system to fight off future infections. But we just don’t know yet.

We just don’t know yet. We also have to consider with our drug that it could also be used for future SARS outbreaks that occur, that are, you know, related but not identical to this one, where a vaccine may not be effective. And so one of the things I think we have to, as a society, recognize is that history will repeat itself here.

You know, we had SARS in 2003. We had MERS in 2009, 2010. You know, both of those were contained because they’re so, they’re relatively more dangerous. But, you know, it’s not, it’s probably going to happen again, the SARS, you know, or coronavirus-type outbreak or pandemic. Now, you know, maybe it’s going to be every hundred years, like the last pandemic that occurred in 1918. I don’t know.

Maybe it’ll be another 10 years, hopefully not. But this drug, the one that we’re developing, as long as we’re targeting these conserved regions of the genome, that should not change in future outbreaks that occur. We should have an approach that would be useful in the future, if or maybe when the next outbreak occurs.

Mariel: Wow. Well, I have to say this is all making me feel more hopeful than I had been feeling. You know, I think a lot of people feel like we now know that this can happen. It’s happened once; it can happen again. It probably will happen again. And we’re pretty much defenseless.

John Maraganore: Yeah. Well, whether it, you know, and hopefully if it happens again, we have drugs like the ones that we’re developing that could be there to treat it.

It could also just be second waves of this that happen. You know, obviously we’re in the first wave now. Hopefully it abates and goes down. But you know, many people believe, and I think we do as well, that there’s likely to be increases in infection in the fall that occur again. So having drugs available for that second wave or even third wave is going to be something which will be important.

Mariel: So why is there not already a drug like this? Is it just because the other outbreaks we’ve seen have gotten contained much more quickly?

John Maraganore: Yeah, yeah, yeah. You know, those other outbreaks got contained or they contained themselves. I mean, there was work being done at the time of the original SARS 2003 outbreak to develop some drugs.

We weren’t doing anything, but other people were. But the outbreak or the virus ultimately got contained, and there was basically no, you know, market, no economic incentive for people to finish their job. You know, one of the things I think is so critical about this pandemic is that the industry needs to finish their job this time, and the public sector needs to support the industry to finish their job and make sure that there’s a right reward, you know, within reason for finishing their jobs so that we can stockpile medicines like this for the future.

So that’s going to be important, I think. That’s sort of something for tomorrow, not for today, because obviously right now we’ve got a, we’re in a hair-on-fire moment, you know, with this pandemic. But, you know, if—and we will get through this, we certainly will get through this—and we’re on the other side of this terrible situation that we’re in right now, you know, if for some reason new medicines haven’t been part of the answer, which I think they will be, we need to make sure that we finish making these new medicines so that the next time this happens, we’re prepared as a society. 

Mariel: Yeah. Do you think science and medicine are going to be different? Do you think that they’ll change because of this pandemic?

John Maraganore: I do. I do. Yeah. I think there’s a lot of learnings from this that frankly are good learnings. You know, one is the fact that during this period there’s been incredible cooperation across science and scientists and clinicians around sharing information in ways that I’ve never seen before—nobody’s ever seen before.

And that ranges from just, you know, papers being published in scientific journals quickly, you know, without paywalls and limitations to people seeing it. You know, it includes just how social media–based approaches to sharing information have been effective. Obviously there’s a lot of junk out there too, so you have to know what’s a good source.

But at the end of the day, the information that’s been shared, and the knowledge that’s been gained, and the pace of that knowledge being gained is just unmatched in terms of anything I’ve ever seen before. I mean, look, it took the industry many, many years to find cures for HIV that ultimately converted, you know, AIDS from a fatal disease to a disease that, you know, people can die with—which is great.

And hopefully we can do something a lot quicker here as an industry. And I think we will. I think this is something which is going to be measured in months, not years from an industry perspective. And, yeah, science and medicine will be different now because I think we’ve learned the power of working together, the power of knowledge transfer in a very different way than before. And I think that’s going to be a powerful force for the future.

Mariel: Any closing words of wisdom for all the people out there that are still worried?  

John Maraganore: I think we’re going to get through this. You know, it’s going to take some resolve by everybody.

It’s going to, without a doubt, be the worst thing that our generation, our groups of people have to go through. I mean, unless you were old enough to make it through World War II, this is that moment for our generation, our society. But just like those people got through the adversity and got through the terrible period that they were living through, we will too.

And science and innovation will prevail. Science and innovation will solve this problem. And it’s going to happen. It’s just going to take a little bit of time, whether it’s, you know, a few more months or a year or 18 months, whatever. That’s a short period of time in the greater scheme of things.

And we will, we will get through this, and we’ll get to the other side of it, and we’ll all be stronger. We will all be stronger when this is done. There’s no doubt about that. 

Lisa: Thanks for listening to this episode of Pandemic Perspectives. We’ll be bringing you more interviews from all sides of this crisis so stay tuned and watch your feeds. As always, you can find all of our episodes plus transcripts and show notes at distillations.org. And you can find tons of educational resources on our website at sciencehistory.org/learn. The Science History Institute remains committed to revealing the role of science in our world. Please support our efforts at sciencehistory.org/givenow. For Distillations, I’m Lisa Berry Drago.

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