Name: Close to the Edge Episode 4: John Evans, CEO of Beam Therapeutics

Description: Close to the Edge Episode 4: John Evans, CEO of Beam Therapeutics

Thumbnail URL: https://cadmoremediastorage.blob.core.windows.net/b53fd908-a994-46e9-a82d-30d414a89231/videoscrubberimages/Scrubber_19.jpg?sv=2019-02-02&sr=c&sig=qXw9Upuwu9yW8vp8AmndvA9J3aOz72068SYB6Qrl3DM%3D&st=2025-01-11T06%3A41%3A18Z&se=2025-01-11T10%3A46%3A18Z&sp=r

Duration: T00H56M25S

Embed URL: https://stream.cadmore.media/player/b53fd908-a994-46e9-a82d-30d414a89231

Content URL: https://cadmoreoriginalmedia.blob.core.windows.net/b53fd908-a994-46e9-a82d-30d414a89231/CTTE EP5.mp4?sv=2019-02-02&sr=c&sig=UK82uKQ0%2Fp5%2FmtHSZSGsOCy9JY3rwLq2VJ%2FEDF0k%2Fms%3D&st=2025-01-11T06%3A41%3A21Z&se=2025-01-11T08%3A46%3A21Z&sp=r

Upload Date: 2023-10-19T00:00:00.0000000

Transcript: Language: EN.
Segment:0 .
[MUSIC PLAYING]
KEVIN DAVIES: Hello, and welcome to Close to the Edge, the new series from GENEDGE, where we invite chief executives and leaders from groundbreaking biotech and pharma companies to sit down with us to discuss their science, their technology, and their business strategy. I'm Kevin Davies, Editor at Large with GEN and the author of the new book Editing Humanity.
ALEX PHILIPPIDIS: And I'm Alex Phillipidis, Senior Business Editor with GEN, Genetic Engineering and Biotechnology News, the publication covering the biotech industry for 40 years. Close to the Edge is an offshoot of GENEDGE, our new premium subscription channel from GEN, providing in-depth exclusive news, interviews, and analysis of key trends in the biotech industry, coupled with a range of multimedia offerings such as this one. More details of our free trial offer at www.genengnews.com/genedge. That's G-E-N-E-N-G-N-E-W-S dot com slash GENEDGE.
KEVIN DAVIES: On today's episode we welcome John Evans, the founding CEO of Beam Therapeutics, a pioneering precision genome editing company in Cambridge, Massachusetts. It's commercially developing a new technology for genome editing called base editing. John, a warm welcome to Close to the Edge.
JOHN EVANS: Thank you, Kevin. Thank you, Alex. It's great to be here.
KEVIN DAVIES: Thanks so much for joining us. Before we dive into Beam Therapeutics, your company, let's start with the big picture. How would you assess the current state of the genome editing field, which is obviously dominated by CRISPR, and its rapid evolution from basic research technology to a clinical genetic therapy?
JOHN EVANS: Yeah, it's a great question. Actually, I would zoom out one click further. I actually think that we are really part of a general trend in medicine towards one-time therapies. Right? Of course, we have small molecules for 100 years. We've had protein therapeutics and biologics for 40 years. But increasingly there's this vision for a third class, which are these one-time curative therapies.
JOHN EVANS: That begins with gene therapy. Right? Where we're just going to add some extra gene into the cell that may be missing. Maybe we do that with ADAV, maybe we do it with lentivirus. And that's going to be potentially helpful in a lot of different conditions. But then always there's been this idea that, wow, if we could actually edit the genome, if we could get down to the fundamental basis of the genome that spell out the genes that are functional in life and manipulate them at that level, it might even be a more powerful and more durable effect.
JOHN EVANS: And so that's where gene editing comes from. That has been coming actually for a couple of decades now. but really it is true, we're kind of more of at an exponential phase now. So you begin with meganucleases, zinc fingers, TALENs, and then, as you note, CRISPR. And with CRISPR it sort of explodes. The reality is, with the improvements have been just making it easier and easier to use, and to sort of rapidly retarget genome editing systems to different spots in the genome.
JOHN EVANS: And that just increases the pace of change dramatically. And so it is true that CRISPR has taken this to a whole other level. And now, of course, within CRISPR, as you know, and we'll talk about, you have layers of innovation that are now happening there. So it really is a, I like to call it a sort of a Cambrian explosion of different innovative tools for manipulating the genome.
JOHN EVANS: And hopefully the question we can ask in 10 or 15 years is what percentage of the therapeutics pie is dedicated to these kinds of one-time curative therapies. And I think it's going to be a lot more than it is today.
KEVIN DAVIES: Well, you'll answer that question at the end of the show, hopefully. Tell us a bit about your own background and what you were doing that led to the launch of Beam.
JOHN EVANS: Yeah. I do not come from this field. I come up in these small molecule cancer field actually. Originally I was at Infinity Pharmaceuticals here in Cambridge, and then Agios. At Agios I was there for about eight years running business development, helped start the rare disease group there, and then was working on a couple of drugs targeting IDH gain-of-function mutations. IDH is a metabolic enzyme and in AML about 20% of patients have one or the other of these two mutations, and we had drugs that could turn it off.
JOHN EVANS: And so it was an incredible story. And we basically got two drugs approved for acute leukemia about four years after filing the IND. It was really light speed in the clinic. And the power of that is that we knew exactly who to treat based on their mutation. So that's precision medicine. And so you're taking all the guesswork out of clinical development.
JOHN EVANS: We know where to go. We know what the drug needs to do. And if it does it early in phase one, you ought to see a signal that tells you you might have a drug here, and then the FDA and patients can work with you to speed it up. In 2017 I was ready for the next challenge. And I ended up as part of ARCH as a venture partner. It's a venture group that does some really big picture companies and really disruptive technologies.
JOHN EVANS: And learned about Beam. And as you'll hear, I think what really attracted me to Beam was the fact that it was sort of the ultimate precision medicine. It picked up on that same theme in terms of how we develop drugs that I had been learning at Agios. But maybe unlike the small molecule world, these are now finally platforms, where if you can do it once you can do it 20 times.
JOHN EVANS: That's because they're really easily reprogrammable, which is that same point about CRISPR, applied now to therapeutic development as well.
KEVIN DAVIES: It's one thing to hear about an exciting technology and a fledgling new company. It's another to then step in to become the CEO. Help us connect those dots.
JOHN EVANS: Yeah. At Arch I was doing a few different things. But one of them, it was clear from the beginning, could be Beam. And I met David Liu at his office in Harvard, and he walked me through the technology, which we'll talk about, and it really did capture my imagination right away. And so this technology is capable of doing single base editing.
JOHN EVANS: So now, in contrast to some of the earlier genetic tools, I know we'll go into the details of this, we're basically capable of changing single letters in the genome with high precision and efficiency. And at this point, you now can treat the genome as a code that you can rewrite. And so for me that was just incredibly exciting. It was still conceptual so there was, I think, a term sheet between two venture groups, ARCH and F-Prime, which is the Fidelity venture arm.
JOHN EVANS: And then David, and he was bringing a founding team together, which later included Feng Zhang and Keith Joung, as you know. These are three leaders in the CRISPR fields, early inventors of genome editing techniques and Cas9 and things like that. And so I was just thrilled to meet all of them, and they needed help getting it going. And so that was the role I stepped into, to do some of the initial build.
JOHN EVANS: I was also doing some other things for ARCH at the time, but it was clear right away that Beam was a potential rocket ship. Over the course of 2017 it just grew and grew. We started hiring people and I was full time in the company in about eight months.
KEVIN DAVIES: Before we dive a little bit more into the technology, you have to tell us what Beam stands for.
JOHN EVANS: Yes. The idea was sort of precision, right? A laser beam, and also the optimism, like a sunbeam as well. And then the secret story as well is that it can be an acronym, which stands for base editing and more. And so the joke is that we're always looking for "and more" and what that can be.
JOHN EVANS: So if anybody has good ideas let us know. We're always doing tryouts.
KEVIN DAVIES: Alex, over to you.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. Now, a lot of our viewers will probably appreciate the history of base editing. But for those who are newer to this space, what is space editing and how does it differ from CRISPR Cas9?
JOHN EVANS: Yeah. Great question. Gene editing, traditionally, is solving one problem, which is a pretty profound problem, which is how do we target a single location in the genome? If you think about it, there are four different letters A, G, C, and T, and every one of your cells has three billion of them in a row. OK? And so in some combination of those letters we need to figure out, how do I go to this gene and not all those other genes.
JOHN EVANS: Right? And so what the gene editing tools, zinc fingers, TALENs, and CRISPR have solved is how do I target one address out of the genome? And it is a profound breakthrough. With CRISPR, you can do it simply by adding in a short programmable RNA element onto the CRISPR protein. And the CRISPR protein is always the same.
JOHN EVANS: And then if you swap out that little RNA cassette, you basically get a new medicine because then you're going to target a new spot so the address changes. And so the reason why CRISPR suddenly exploded is the ease of use of that system. You can really rapidly retarget it to different places in the genome. So that's incredible. The drawback, I think, to this first generation of tools, which includes some of the CRISPR tools as well, is once you get to that address the only thing that was possible was a cut.
JOHN EVANS: OK? The analogy often you may have seen is that of scissors for the genome. And so you get to a target site. Once that target is recognized it cleaves the DNA into two fragments. And then you're sort of up to the cell as to what happens next. The cell will mostly not want that to happen.
JOHN EVANS: A double-stranded break is alarming to the cell. It's a genotoxic event. So it'll basically rush to put the pieces back together again. In doing so, it'll generally make mistakes. And so you'll get damage at the target site that is random, random insertions or deletions. Those are called indels. And so that will scramble a gene sequence and you'll basically disrupt that gene.
JOHN EVANS: And so these tools are very good at knocking out gene function because you'll scramble that gene sequence. But using them to sort of reprogram genes, or repair genes, or make other sort of deliberate changes to gene sequences has been much more difficult and generally pretty inefficient. And if you look at the field, generally the programs that are moved forward have been more like knockouts or deletions.
JOHN EVANS: And so that was the backdrop for base editing. And so basically David Liu felt originally that we needed to keep taking a harder look at this and find new ways to do this. And he had some very clever and pioneering scientists in his labs take up this project and make some really incredible innovations. As I know you know, Alexis Comar in his group did the original C base editor.
JOHN EVANS: And later Nicole Gaudelli, who's actually now at Beam running our Genetic Technologies Group, took on the invention of the A base editor. So we can make two different kinds of single-base changes now. And the basic trick is we use CRISPR to bind. It's the same address recognition and opening up of the DNA. But we've stopped its ability to cut.
JOHN EVANS: So we're no longer cleaving. We're not scissors anymore. And then we take advantage of the fact that basically a short strand of DNA, when that binding event happens, is exposed as a single-stranded loop. And then the insight that Alexis and Nicole had was, let's use a deaminase, a chemical enzyme that only recognizes single-stranded DNA, so it will leave alone all of your double-stranded DNA, and is capable of recognizing one kind of base, and just literally chemically modifying it from one to the other.
JOHN EVANS: So we do a C-to-T change with the C base editor, we do an A-to-G change with the A base editor. We don't need to have a double-stranded break. So once we let go, that change will be incorporated as a permanent edit to the cell. We don't need to change other bases around it. And so that coding sequence is preserved. And now you can basically have this highly-efficient, chemistry-driven edit where we know the editing outcome.
JOHN EVANS: It's not random anymore. We know exactly the edit that will result. That allows us to think really therapeutically about what we're doing. And the last point I'll make is we're also not dependent on complicated repair pathways to process this edit. It's chemistry. Once you're in the cell, you'll go to the nucleus, search the genome, open the DNA, edit the base, and let go, and that edit will be permanent.
ALEX PHILIPPIDIS: Now, it's interesting, the technology you mentioned, David Liu's lab at the Broad Institute and Nicole Gaudelli, who's with your company. How did Nicole come to join Beam and become part of the team?
JOHN EVANS: Yeah, we were very fortunate, actually, to be able to hire several folks out of our founders labs. We have a number of people out of David Liu's lab, Feng's lab, Keith Joung's lab, joined us. And these are exceptional scientists. I like to joke that we're competing as much with academic posts to hire some of these folks as we are with other biotech companies. But they chose to follow the technology and they chose to join Beam.
JOHN EVANS: And I think it's really a testament to probably those two pieces. I mean, one is, I think, the technology is just so exciting. And they of course have been there at the birth of it. And so I think they appreciate the real potential and have the passion to see it translated, now, to hopefully impact patients in many ways. And also I think we have a really special company and really special culture that's grown here.
JOHN EVANS: It's a really pioneering group of very bold scientists doing something really incredible. And I think that team spirit has been in place from day one. And frankly, I give a lot of those folks credit for initiating Beam and then it has simply grown from there.
ALEX PHILIPPIDIS: How much of a role do Feng Zhang and Keith Joung play in guiding Beam on your journey?
JOHN EVANS: Oh, absolutely. I mean, they're central. I mean, so all three of our founders have been incredible supports for us. Obviously, early days in the company formation, we met with them every week. Actually we still do meet with them every week. The early days, the topics were, how does one start an editing company? And what can we learn from the attempts to start other editing companies?
JOHN EVANS: These were all co-founders of Editas, of course. So they go way back to the beginnings of the field. And so we got a lot of really good advice from them in that era. More recently, obviously, the science has evolved so much. And so their labs are doing really interesting things. And we continue to talk to them and keep up to speed on what's happening at Beam, what's happening in the field.
JOHN EVANS: So they've been incredible helps to us. Obviously, with David, you have ongoing development of new base editing innovations in addition to what's happening at Beam. With Feng, we actually in-licensed a whole series of technology from his lab, including both RNA systems and a CRISPR system called Cas12b which we have. And then with Keith Joung, of course, you know, Keith is one of the real leaders in the entire field of gene editing, including in thinking about off-target assays and how do we make these safe enough to be medicines, which of course is central to being a biotech in this field.
JOHN EVANS: And so he's been incredibly productive in that area. So really it's a team effort. It's a team among the founders, and then, of course, within the company as well. And all of those different contributions have been critical to get us to where we're at now.
ALEX PHILIPPIDIS: Now it's been close to 18 months since you took Beam public. You raised about $180 million. How satisfied are you with the progress you and the company have made since then, and noting that the market cap, last check, is a little over $5 billion.
JOHN EVANS: Yes. It's been really exciting. I would say that progress, even since then, has exceeded my expectations. And it's just exciting to work on technology that works, I think, at the end of the day. One of the things that happened that you all will appreciate is just the technology development. So when you start a new company, there's an amazing Nature paper and some of that original work.
JOHN EVANS: And you license it in. The first step is, does it repeat? We have this whole reproduction crisis in sciences. It doesn't always work exactly as advertised. Or maybe it works, but it works narrowly, under a certain set of conditions. Well, it turns out base editing worked very broadly and very fast. And so that was a huge advantage which just allowed us to push the pedal to the metal.
JOHN EVANS: An important person I would highlight here is our president and CSO, Pino Ciaramella. So he joined us-- he was employee number seven, I think, so really early days, really the founding CSO of the company. And he came from Moderna, where he had spent four years, and helped basically build their entire vaccines platform, which is of course become quite famous more recently.
JOHN EVANS: And so he really helped us figure out, OK, this is looking like it's going to work. How do we really blow this off and accelerate development in lots of different directions at once? And that sort of same kind of platform thinking that Moderna has pioneered, we've really tried to build into Beam. So I give him and his team a ton of credit for this. But basically the progress has then been really steady ever since then.
JOHN EVANS: So when we went public, we had a really good, promising editing data already well and above what you could do with, let's say, a nuclease doing something like homology-driven repair to try to correct genes. But since then, we've actually invented even new versions of our base editors. And we've published some of those. So new versions of the A base editor that are even more potent than what came out of those original publications.
JOHN EVANS: New versions of the C base editor. So really an incredible amount of innovation has happened. So that's sort of step one. Step two, in the last 18 months, has been real in vivo proof of concept of disease correction. So we've now shown in vivo animal models of correcting disease, of sickle cell anemia, with two different approaches, which we can talk about later. With a CAR-T product targeting T cell leukemias.
JOHN EVANS: We've shown really dramatic results there. And then in vivo correction in the liver, in mouse models, of glycogen storage disorder and alpha-1 antitrypsin deficiency, where we're literally taking the one letter that is misspelled out of 3 billion in that cell, and returning it back to normal. So it's a really profound set of progress. And then, finally, what people are looking for is advancing to the clinic.
JOHN EVANS: And that has really come along as well. We've put a tremendous amount of effort into our delivery platforms. Those are looking really good. Ex vivo programs are now reaching towards the clinic. We'll be filing our first IND later this year for a sickle program, and another couple shortly after that, a second one in sickle and one in the CAR-T products.
JOHN EVANS: And then, in vivo, we've been working on lipid nanoparticle delivery to the liver. We've shown some great primate editing data there. So that will come shortly after that. So really that imminence, now, of clinical development of actually thinking about treating patients with some of these technologies is now on us. And I think, again, we're so happy to be at this point, where, I mean, literally, the company was founded no more than four years ago and we're going to be treating patients soon.
JOHN EVANS: In fact, I mean, these constructs for base editing were only reported, whatever, five years ago or so. So it's a pretty profound progress. And it shows you, again, we're kind of on that exponential curve of technology development.
ALEX PHILIPPIDIS: What, if any, surprises or roadblocks or even obstacles have you seen since going public?
JOHN EVANS: Yeah, you know, it has been fairly steady, I think, since going public. I think it's all been OK. I mean, early days, I'd say we had more uncertainty. For this audience, you may appreciate one of the core challenges is, with CRISPR, you can land many places, but you can't land everywhere. So things like the recognition domain that's required to begin a binding event, we had to work through, if that's there, great, if it's not, what do we do?
JOHN EVANS: And so we basically now have a whole series of editors that are tuned to recognize different kinds of recognition sites. And that's expanded our toolkit. You know, off-target profiling has been something that we've had to focus on because it's just new. Nobody's ever done this kind of editing before. But again, really profound progress in sort of understanding that, actually, when we deliver this in the right way with our most professional editors, we really have minimal to sometimes undetectable off-target profiles.
JOHN EVANS: And looks quite ready. So I'd say, in the last 18 months, it's been less roadblocks and more just heads-down execution. We're growing fast. I think, as things have worked across the pipeline in these very different application spaces for us, it requires us to grow in many directions at once. And so I think that's probably been the major challenge. We're now 250 people for just a four-year-old company.
JOHN EVANS: And so that's a lot of people to bring in and to integrate. But you know, people have done an amazing job. It's just an incredible team, and I think really aligned around the vision of creating lifelong cures for patients with this technology.
ALEX PHILIPPIDIS: That growth and headcount growth would seem to be a challenge of operating as a public company. What are some other challenges and advantages of being public?
JOHN EVANS: Yes, I mean, certainly the other challenge being public is that you are constantly thinking about investors and communicating with them. So it just takes a lot of time. There's, of course, the entire SEC process. It's much more highly regulated. But you know, that's also the opportunity of it. We knew from day one-- and this is a conversation that Pino and I had with the founders right away-- the basic belief at Beam was this looks like a potentially best-in-class editing technology.
JOHN EVANS: And we need to bring it to patients wherever they may be so that it can help them. And we're not going to just choose one therapeutic area, and then, five years later, maybe we'll get to a second, and then sort of go in serial order. We need to make base editing an option wherever genetic medicine is possible. And so from day one we said, OK, what does that mean?
JOHN EVANS: We're going to do all the delivery modalities in parallel. That's a fairly ambitious idea. So we're doing ex vivo programs, blood cells, T cells, what we're doing with the nanoparticles, we're doing AAV viral vectors, all in parallel. And then we're going to have a big, broad pipeline with many diseases. And those are all really still active.
JOHN EVANS: And we're going to start to forward-integrate. I mean, almost on every front, we've sort of seen capabilities that we'd like to get outside, but actually, you know what, it would make more sense to build it internally, and integrate it, and make it part of this innovative engine we're building. And so that's driven a lot of the growth. So from day one, if you put all that together, it was clear to us we needed access to capital.
JOHN EVANS: And so we did a few private rounds in the company, originally venture-backed, and then more crossover types of capital. But going public was always going to be something we needed to do. And now we have an incredible base of investors who are following the story and who share that long-term vision that we have to create a significant, independent, leading company that can create what we think of as the leading platform for precision genetic medicine over the long term.
JOHN EVANS: And so they've been incredible partners to us. And the ability to get that capital and invest it in what we see as a really attractive set of opportunities has been a huge upside to going public for sure.
ALEX PHILIPPIDIS: Great. Kevin, over to you.
KEVIN DAVIES: Well, John, you raised the subject of Beam's broad and growing pipeline. Let's talk a little bit about that. Besides the ones that you just mentioned, what are some of the other major projects and disorders that you're going after?
JOHN EVANS: Yeah, so I'll just highlight a couple of them, some of them which I did mention, some of which I didn't. I mean, I think that lead is sickle. This is, of course, a very crowded space. But we looked at the editing. And especially as those editor improvements kept stacking on themselves-- and we actually concluded that we think we have, potentially, the best-in-class editors, and actually we have two of them.
JOHN EVANS: So as you know, many people are editing to raise fetal hemoglobin. With our Beam 101, we actually can edit at a higher level and raise the fetal hemoglobin to a significantly higher level than is possible currently with nucleus technology. So that looks like a potential best-in-class program for an already clinically validated strategy, which of course CRISPR and Vertex and others are pursuing, which is incredibly exciting.
JOHN EVANS: We pair that with Beam 102, which of course, right in our sweet spot, sickle is the most famous point mutation in all of genetics. And so we have an editor that can literally take that one misspelled letter and turn it back to something that's normal. And now potentially create cells that don't have the sickle mutation anymore. And so that's a really first-in-class, pioneering approach.
JOHN EVANS: We're thrilled with that program. That's beam 102. So those two programs are moving forward really quickly. And I'm just so excited for the impact we're going to make in sickle cell disease as an industry, I mean, all of the companies working together. It's just an incredible time. The second program I'd highlight would be in the oncology space. So CAR-T, of course, you know everybody is editing T cells to train those immune cells to attack the tumor.
JOHN EVANS: In our case, we are targeting T cell leukemias. And basically you need extra edits to make that work. And we take advantage of the fact that, with base editing, not only are we very precise, but that lack of cutting allows us to add edits on top of each other without damaging the cell. Because if you create too many double-stranded breaks at once in the cell, actually it becomes toxic. And so we actually have a cell that has four different edits in it.
JOHN EVANS: So it's a quad-edited cell, each edited at 96% efficiency, to knock out four different genes. This is, again, a first in the industry. And many more applications like this are possible. And we're very excited about that program. So that's moving quickly. And then the liver portfolio, the two that I highlighted, in each case really correcting disease-causing point mutations.
JOHN EVANS: So you have glycogen storage disorder, which is a rare, very severe condition where you can't reprocess glycogen into glucose, which means you can't fast. And so you literally can't sleep overnight without potentially having a hypoglycemic shock and dying of low blood sugar. And so these patients have to wake up every two to three hours and feed themselves, with potentially perilous results if they were to miss it.
JOHN EVANS: So it's a horrible disease. Two point mutations cause about 60% of the disease. And we have editors that correct both of those back to normal, which is very exciting. And then alpha-1 antitrypsin deficiency is a huge illness. Everyone has the same point mutation, this E342K mutation. And it needs an A-to-G change, again, to correct back to normal. There's about 60,000 patients in the US who have that mutation.
JOHN EVANS: And again, we have an editor that would correct it. And now, if we can successfully correct that, we're doing two things to these patients. One is that gene will stop producing the toxic form of the mutant protein, which causes liver damage in these patients. And now it will successfully create the normal protein, which can secrete out of the cells into your bloodstream, where it's supposed to be protecting your lungs from breakdown.
JOHN EVANS: And these patients get incredible lung breakdown and emphysema, and ultimately can even get double lung transplants. So one edit now is going to, again, create cells that no longer have the mutation in them. And we'll have both a correction for the liver and the lung phenotype. So there's a lot more cooking at Beam, I will say. Each of those areas-- hematology, immunology, in vivo genetic diseases, we have lots of on-deck targets and research programs ongoing.
JOHN EVANS: And one of the beauties, again, of that platform approach, once we've done it once in any of these tissues, we can do it many times, with relatively simple reengineering. And so each of those programs are incredibly exciting on their own. But they also open the door to so many more things that can come behind. And we're hard at work thinking about what that would be and prioritizing among those ideas.
KEVIN DAVIES: We can't have you on the show without noting and crediting the fact that your colleagues published a proof-of-principle article in GEN's sister journal, The CRISPR Journal. It was the cover story, in fact, I think back in April of this-- oh, you have it there. That's fantastic. Yes, brilliant. We didn't plan that, I confess. And one of the interesting facets of that study is that your team kind of went back to the drawing board and re-architected, if that's the word, the base editing complex.
KEVIN DAVIES: Why was it necessary to do that? And what are the potential advantages now that you've succeeded in rearranging the components to give you added flexibility?
JOHN EVANS: Yeah, it's such a great story. So as I described before, we have the CRISPR protein that can sort of target the gene. And then the basic idea of the base editor is you tether a deaminase to it. And it just drags it along. And then when that binding event happens, the deaminase will just locally find its substrate and then edit. And it generally works really well.
JOHN EVANS: But some members of our team-- and particularly Ian Slaymaker, and then working with Nicole, but Ian really pioneered this-- had the idea of like, well, that's fine, but can't we also think about doing this in other ways? And so what they actually ended up doing was finding different ways to insert the deaminase into the CRISPR enzyme in different locations and almost embedding it within the CRISPR protein.
JOHN EVANS: And what you end up with is just a much more sort of finely-tuned mouse trap. And the nice outcome of that is actually it changes some of the behaviors of the editor, specifically changing the targeting window of where it will edit within a certain landing region. And that turns out to be quite interesting. And for the sickle program, specifically the Beam 102, where we're again editing that point mutation that causes sickle, as I said before, there actually wasn't a great landing site initially for that editor.
JOHN EVANS: And so that was one that took us a little while to get worked out. But this technique worked. And so basically what it does is it just lands at a little bit different, shifts the window, and suddenly that target base is right where you want it. And so one of our first pioneering values is fearless innovation. And so we have just an incredible group of people at Beam who are willing to try things that are quite counterintuitive.
JOHN EVANS: I think it was Feodor Urnov, in one of the articles, who described this approach as "potentially crazy."
KEVIN DAVIES: [CHUCKLES]
JOHN EVANS: But it worked, and it worked really well. And I think kudos to the team for trying it and making it happen. There's lots of other stuff like that that we continue to push the boundaries of. And I think it's a really important part of our platform culture.
KEVIN DAVIES: And one of the other conceptually interesting aspects of that work is that when you're going after trying to correct the actual sickle-cell point mutation, you're not correcting it back to the wild type variant that's presence in 98%, 99% of the world's but because the chemistry won't allow you to do that. But you are able to convert it to this rare benign variant that does occur naturally in a very small subset of people, but appears to be absolutely neutral when it comes to the function of the proteins so you get the effect that you wanted.
JOHN EVANS: Yes, exactly. So when you think about-- David Liu has a famous pie chart that he shares a lot when he thinks about what are all the mutations that cause disease. So why do we care about single-base changes? Well, we care because point mutations are more than half of those. And so that's obviously a huge class of types of mutations we want to go after.
JOHN EVANS: The dominant within that are called transition. So basically this A-to-G change and back again, and then the C to T and back again. And so about 30% of all mutations are those, or a little more. And so a lot of our correction programs are within that group. Sickle is not in that group. So sickle, in theory, you would want an A-to-T change. And so that's what's called a transversion change.
JOHN EVANS: But a fortunate accident is it turns out that, if you make the A-to-G change at that site, you get another normal human variant. And so that was just a good fortune of clinical genetics that helped us out there. And so there are people who have that exact allele variant and they are normal. They don't have any disease. It carries oxygen normally.
JOHN EVANS: It does not sickle, anything like that. The key is to get rid of that A. It's the A that causes a valine at that site in the sickle protein. And that causes this LEGO-block-like stacking, under low oxygen conditions, where you get this polymerization. And that's what causes the sickle cells to bend and become rigid.
JOHN EVANS: And then, when they're going through your capillaries, they block and you get these incredible crises. So it's just an amazing sort of biochemistry-to-disease story. But yes, as long as we can edit that A out, we get a normal phenotype.
KEVIN DAVIES: I really liked your comment earlier-- the most famous mutation in human history. I think one could certainly make a very strong case for that. You touched on the move, hopefully later this year, John, into the clinic. That's obviously a huge step for any company. And based on all of your own internal results and the other preclinical mouse work in particular that David Liu's academic lab have been publishing, certainly the signs look very promising, I would say, for base editing.
KEVIN DAVIES: What is the plan? If you could say a little bit more about the plan to go in the clinic. And do you have any trepidation about starting to work with base editing in human patients?
JOHN EVANS: I mean, you know, no trepidation other than we take this very seriously. I mean, this is an incredible responsibility to bring new medicines of any kind, I think, forward. You know, I've lived this before. But certainly gene editing is something that you have to really be careful about. And it's a huge responsibility. In terms of the process, so basically you've put together what's called an IND, an Investigational New Drug application.
JOHN EVANS: So we will file our first IND in the second half of this year. We won't treat a patient immediately. There's basically a series of steps where the FDA needs to review that, then you work with your clinical sites to open that up, and then you start screening patients and identify who will come in for first treatment. So that will happen sometime next year. But it begins the process.
JOHN EVANS: And it is an incredible process. But I am cautiously optimistic. I think, if you look at the editing field, it has really progressed. I think obviously CRISPR-Vertex, that data set is incredibly exciting and provides proof of concept to the field. But also it shows, I think, actually, that the translation from the mouse models that are commonly used in this field, where you're literally editing human cells and that and grafting them into this special mouse model, and then waiting 16 weeks to see if that engraftment holds, that has been fairly predictive of what they've seen in the clinic.
JOHN EVANS: And so I think we have some confidence that it'll be predictive in our case as well. And we've had very good-looking-- again, potentially best-in-class-- preclinical data in that exact model. FDA input-- we've been to the FDA now with these packages and sort of gotten their feedback. And again, you know, the field is maturing slowly. It's still new.
JOHN EVANS: But we know a lot about what these other programs look like. We were able to say, here is our proposal, to the FDA. And we got pretty predictable responses back. And so, again, I think the FDA is getting more used to editing as a paradigm. So this is one of the benefits, frankly, of working in a field like sickle, where there's a lot of other competitors and activity. But you benefit, frankly, from others have gone there, there's a little more of a clear path.
JOHN EVANS: And the same is true on the CAR-T side. And then in vivo, obviously Intellia is in vivo, right now, in the liver. And others are coming as well. So you know, I think the field is generally advancing. And I think we look at our own data within each of these areas. And we feel very confident and excited, frankly, that this could be profoundly transformative for patients who are really seriously in need of new options.
KEVIN DAVIES: Yeah, that's great. We'll be following your steps into the clinic with great interest. Alex, back to you.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. And thanks to you for watching Close to the Edge. That's the new show from GEN Edge, the premium subscription channel of genetic engineering and biotechnology news. I'm Alex Philippidis, joined by Kevin Davies. And we're talking to John Evans, the CEO of Beam Therapeutics. John, with genome editing, safety is never far from the conversation. How confident are you that beam-- or maybe the base editing community as a whole-- has addressed the concerns around off-target effects that we've seen with other technologies?
JOHN EVANS: Yeah, I mean, you know, off-target assays have been foremost in all of our minds from day one. And frankly, foremost on everybody's minds in the editing field. I mean, so the power of any gene editing technology is it is permanent. It is durable, even compared, in some cases, to gene therapy. So in gene therapy, in theory, it is going to be durable. But we've seen in the liver, we've seen in other tissues where maybe it will wear off over time.
JOHN EVANS: Because the gene you're adding is not integrated into the gene. So here we are. And so when we make an edit, it will last as long as that cell lasts. And frankly, if that cell divides, it'll carry the edit into both copies and so that the edit will be durable. And that's for sure.
JOHN EVANS: So we have to be very careful about what we do. And particularly we don't want to edit anything off target and have a dangerous outcome. So that said, I mean, again, Keith Joung has been pioneering this for a long time out of his lab. The assays have also gotten incredibly sophisticated. I mean, our ability to measure exactly what happens within the genome when we put in any editing system into any cell through whole genome sequencing, through an incredible series of off-target assays, has become quite sophisticated.
JOHN EVANS: And 3 billion bases sounds like a lot, but it's actually not that big. It's a few gigabytes of information. And so you can get down to single-base resolution of did I or did I not have an impact on any of these cells in the genome through some of these techniques. And so I actually think that our ability to see what's happening is pretty good.
JOHN EVANS: And I think the field has made an incredible amount of progress in terms of off target. So I'm just generally confident about off-target and the state of the field. With base editing in particular, we had a few different things we looked at. I mean, one is sort of traditional to the rest of CRISPR, which is can you bind in the wrong place, does your guide have a binding mistake.
JOHN EVANS: Again, we have really good assays to measure that. And if it were to happen, you can sort of figure out would that be a problem or not. Of course, in the case of base editing, the consequences of such an off-target event would be, at most, a deamination event, a single base change, instead of a double-stranded break. So that has some advantage. We then measure, can the deaminase accidentally hit other parts of the genome, either DNA or RNA, by accident?
JOHN EVANS: And basically the answer is mostly no. Some of the early C base editors can do that, but at a fairly low level. The A base editors do not. And at real-world doses, what [INAUDIBLE] has looked like an RNA editing signature goes away. Because we're really in and out in editing pretty quickly at reasonable concentrations. So I think the off-target profile, at this point, we're very confident in it.
JOHN EVANS: And then I would just say, also, on target, at least with nucleases, you also have this occasional concern about these larger unpredictable deletions that can happen that are hard to measure. But people have been reporting them more and more. Of course, we don't have that with base editing. So we avoid any kind of double-stranded break consequences, damage pathway upregulation, things like that.
JOHN EVANS: It's actually a very mild edit on the system. I like to joke that it's almost like the cells didn't notice they'd been edited. And we think that, in many applications, that's going to be helpful to get those cells as robust as possible for things like engraftment or transfusion.
ALEX PHILIPPIDIS: Targeting is one challenge. Another is delivery. What has Beam been thinking about in terms of the delivery of base editing? Are you thinking of viral vectors, non-viral, or more of a pick-and-choose menu?
JOHN EVANS: Yeah, D, all of the above.
ALEX PHILIPPIDIS: [CHUCKLES]
JOHN EVANS: There's no question that delivery remains the big challenge in the field. Anybody will say that. We've gotten very good at a few things, which is great-- So. Blood cells, T cells, liver, eye, this is good. But we're not done yet. We need to do much better if we're going to address all the patient need that is out there. Our general strategy, as I said in the beginning, was let's go after all the different delivery modalities that are possible in parallel.
JOHN EVANS: But let's be relatively modest in our ambition. Let's let the novelty be the payload, which was base editing. And let's stick to tried and true, electroporation of blood cells, electroporation of T cells, lipid nanoparticle only to the liver, AV only to the retina. And these are places where there's approved products and a lot of fundamental tracks have been laid. More recently, actually, we have started to raise our ambitions.
JOHN EVANS: And I think, now that base editing is really rolling and we feel like we've shown that it can work in a broad variety of circumstances and we have increasing confidence that's a potential best-in-class technology, we've started to push the envelope on innovation there as well. And so we are actively working on other kinds of delivery. So for instance, we acquired a company called Guide Therapeutics earlier this year.
JOHN EVANS: Really exciting company out of Georgia Tech. They have a platform to do in vivo, high-throughput screening of many different lipid nanoparticle formulations, and testing to target beyond the liver with those. So now you can think about, can I target blood cells, can I target T cells, can I target muscle, brain, lung, directly, in vivo, with just an infusion instead of needing some more complicated delivery. So that's really exciting.
JOHN EVANS: We love LNPs because of course they're scalable to manufacture, they're relatively lower cost, they're of course now precedented quite significantly with the vaccines that have happened. You can re-dose them. There's no packaging capacity limits. So we're very excited about that platform. In addition to AAV, actually we're also doing some work on novel viral vectors.
JOHN EVANS: We think that there's some real space there for innovation. So that's work we've been doing. So I think we are just at the beginning phases, I think, of thinking through what delivery can do. And it is absolutely the other piece of the puzzle here, along with editing. Actually the third that I would mention-- editing, delivery, and then, ultimately, it's manufacturing as well.
JOHN EVANS: I think, when we think about what I said at the beginning, an integrated platform for precision genetic medicine, it's really that payload, the delivery, and then being able to make it. So we are building a manufacturing facility in North Carolina. It'll be 100,000 square feet. That's the biggest in the editing field as I know.
JOHN EVANS: And just design so that, under one roof, when we have a new biology insight or someone else comes to us with a biology insight, we can pull the right editor, the right delivery modality, and then make it, and do that as part of one program or one collaboration, and not have to put three or four deals together to move things forward for patients.
ALEX PHILIPPIDIS: How soon before that comes online?
JOHN EVANS: A couple years. So it's a new build, from scratch. So I think we're just breaking ground as we speak. And there's an amazing team down in North Carolina driving that forward. So we're excited to see it happen.
ALEX PHILIPPIDIS: Now, the genome editing field is getting rather crowded these days with new startups. One of them is Prime Medicine, also founded by David Liu, to commercialize prime editing. There's Verve Therapeutics, which just had a successful IPO. How are you collaborating with both of those companies?
JOHN EVANS: Yeah, great question. So I mean, it is continuing, in terms of the innovation, on multiple fronts. And we're excited about that. So we want to make that happen faster. So one of the things, on the business development side, we haven't done big deals to partner off all of our stuff. Some of the other companies did some large, field-based deals. We actually prefer to keep things wholly owned if we're going to drive them within our core pipeline.
JOHN EVANS: But that said, there's so much more to do for patients than we can do ourselves. And so we are always looking on what I call kind of the white space of what else we do. And so often, actually, what I call these innovator-innovator partnerships are going to be really exciting ways to unlock some of that. And so we've done two of those, as you noted, but it won't be the last.
JOHN EVANS: We'll do more. One was Verve, as you said. So Verve was started by some cardiology experts out of the Broad and Penn, led by Sek Kathiresan, who's now CEO. And really incredible vision to basically create one-time cures for heart attack, which, of course, is still the leading cause of death in the world, and do it with editing.
JOHN EVANS: And so we basically put all of our technology into them and said, this is great, you're much better for those targets than we would be. And so we are exclusively supporting them. They've done an incredible job. They have beautiful results with these base editors, which are now moving forward as well, towards the clinic. This would be a liver-to-liver program, basically knocking down PCSK9 to lower cholesterol.
JOHN EVANS: And as you said, really exciting IPO. We have some program rights in the US within their programs, which will help us work with them later, which is really exciting. Second was Prime, as you said. So in this case, rather than a therapeutic application, we have another editing platform. So this came out of David Liu's lab, some really pioneering work.
JOHN EVANS: Similar, in a way, to base editing, where now, again, we're separating out targeting from editing, but instead of having a CRISP plus a deaminase to do single-base changes, we're going to do a CRISPR plus a reverse transcriptase to do sort of short-range rewriting of genes. And this is very exciting, because you can think about the flexibility of that.
JOHN EVANS: And that includes to really put in arbitrary amount of information over short distances using Prime. And so very exciting. And so basically we worked with David, and actually our same founding venture capital groups, Arch, F-Prime, and then GV, Google Ventures, to come up with a pretty innovative structure. So basically it's a new company, Prime Medicine, which is still in stealth but it does exist.
JOHN EVANS: And they are going to go after prime editing as a technology. They took the license to that technology from the Broad. We then created to deal with Beam where basically we're sharing. And so we get primed editing technology exclusively, basically in fields that we're already working in. So if you're making those same kinds of changes that we can make with base editors, the same kinds of diseases we're targeting, sickle, alpha-1, things like that, then we're using prime editing for that.
JOHN EVANS: And then Prime Medicine, the company, is designed to go after other kinds of changes and other kinds of diseases. And so it's sort of a divide-and-conquer approach. And in return, we're giving them all of our delivery and kind of CRISPR technology so that hopefully they don't have to recreate the wheel on a whole bunch of stuff that we've already invested in. And so I think it's a really creative, win-win solution.
JOHN EVANS: And so we helped get them started. But they're now really launched and making great progress. So again, I think this is the kind of thing that I think our industry needs to do more of. And so we're thrilled with those two relationships. And frankly, we want to do more things like this. And particularly as we create this sort of engine with all these different pieces under one roof, I think the opportunity to do that increasingly is going to be there.
ALEX PHILIPPIDIS: John, you also have a collaboration with Magenta Therapeutics. How is that going.
JOHN EVANS: It's going great. So Magenta is also nearing the clinic with that program. So this is something that I didn't mention with sickle but it's worth a conversation. So in sickle, I mostly talked about our editing programs and how they have an advantage over what has come traditionally. But really, with sickle, we're not done with editing. So it's not enough to just be a better editor. Because currently, to get these edited cells back into the patient, we have to make them go through what's called conditioning.
JOHN EVANS: And so you basically have to give them chemotherapy to wipe out the rest of the old cells so that your new, edited cells can come in and replace their blood system. And it works. And for a lot of patients for whom sickle is a death sentence, and it's an incredibly severe, painful disease, that's a great solution.
JOHN EVANS: And so there will be lots of patients treated with this first gen of conditioning. That said, we need to do better. So we need to get rid of that chemo transplant step is basically the idea. And so Magenta has been a pioneer in this area. So they've been thinking about more-targeted, non-chemo types of approaches to more selectively get rid of the old stem cells, but maybe leave more of your blood compartment untouched so that your new, edited stem cells can go in.
JOHN EVANS: And so we're partnered with them to get access to what we think is a really exciting conditioning program there. I think, in addition to that, I would flag that we're also interested in other kinds of approaches to change that conditioning regimen, and/or thinking about in vivo delivery long term. Again, as I said, with guide therapeutics and lipid nanoparticles, we think that's another exciting possibility.
JOHN EVANS: So we're thrilled. We think Magenta's vision is right. One way or the other, we're going to treat and fix transplant. And then, in doing so, we're going to be able to now get these medicines to increasing numbers of patients, earlier in life, and ultimately-- and maybe particularly as it moves to an in vivo setting-- you can think about treating patients around the world.
JOHN EVANS: So you think about the burden of disease in Africa and other places, where coming into a hospital for a month for a transplant is not going to be possible, but a one-time infusion would be. And so I think we see this as a steady path where the technology is going to go through these waves of innovation. And we want to be basically driving all the segments of that growth, through our technology, to make sure we're bringing the right regimens to really create great solutions for these patients.
ALEX PHILIPPIDIS: And just looking a little bit beyond Beam, genomics stocks have taken a bit of a beating since the beginning of the year, after a very strong run-up last year. To what do you attribute that dip, and how quickly do you anticipate a turnaround?
JOHN EVANS: I don't watch the stock price. And I tell everybody at Beam not to watch the stock price. I've lived in public companies for a long time now. And I think attributing any move in the stock price over the course of three months or so is probably a loser's game. I'm not sure I would be any better than anyone on the street to figure that out. What I would say that I think you can read into the valuations is I think, if you look over the last couple of years, I think a couple of things have happened.
JOHN EVANS: I think there has been a little bit of a switch turned in terms of gene editing in general. I think the valuations have certainly gone up as people have realized that this is actually reaching the clinic and that clinical data is imminent. And then obviously the positive data out of CRISPR and Vertex and others coming, I think, is a huge driver as well. And I think the excitement about some of the next-gen technologies that Beam and others represent to even further the innovation in this space.
JOHN EVANS: So I think you can see that kind of big macro move, where gene editing has gone from being something that's maybe on the horizon and theoretical to something that is really present and people are really excited about and they do see as the future. Beyond that, I think I don't spend a lot of time thinking about why it's gone up or down recently.
ALEX PHILIPPIDIS: All right, Kevin, over to you.
KEVIN DAVIES: And of course the Nobel Prize didn't hurt, right?
ALEX PHILIPPIDIS: [CHUCKLES]
JOHN EVANS: Yes, well, exactly. And we're thrilled for Emmanuelle and Jennifer for sure. I think that was a really great recognition of some incredible science that has happened here. And more to come, I expect.
KEVIN DAVIES: John, just a couple of questions before we close. At Beam, you've mentioned you're looking at a handful of disorders, and we've talked about a few of them. But there are thousands-- 6,000, 7,000-- known genetic disorders. And as you said, there's so much more you'd like to do for patients than you could possibly do yourselves, even with 250 colleagues.
KEVIN DAVIES: So I'm curious, if would-be partners approach you with a really strong, cohesive plan to address a rare disease that's simply not on your radar, is there a way that you can support that effort?
JOHN EVANS: Yeah, absolutely. And again, we've done it with Verve. I mean, I think we've done that once already. And actually, it's funny, I agree about the 6,000, 7,000 rare diseases. And in some ways, you kind of have that conversation as you're thinking about, mutation by mutation, what are we going to fix. The reality is we're going to use base editors in a lot of other ways.
JOHN EVANS: So in addition to point mutation repair, I mean, effectively, if you think about it, every base pair in the genome has either an A or a C. So they're all editable. And so any base pair that has some function, we can alter that function and modify it. And so I think, increasingly, about base editing as a general-purpose, high-efficiency, and precise genome modification tool which is going to be used to intervene in a lot of different disorders.
JOHN EVANS: And some of those are going to be not just monogenic Mendelian disorders, but actually more common conditions, polygenic disorders. You know, we're really at the very beginning. Preventive medicine, I think, is a future. So yes, we have a lot to do. And so we are absolutely always open to those conversations. We're sometimes creative in setting that stuff up ourselves.
JOHN EVANS: But we love finding teams. And as I said, Verve is a great canonical example of where a team found us and we just thought it was a match [INAUDIBLE].
KEVIN DAVIES: Well, at the beginning of the show, you brought up the pie chart, and you posed the sort of rhetorical question, how far do you think genome editing could go to address that. I mean, let me throw that question back to you.
JOHN EVANS: Yeah, I mean, I won't take my own bait and give you a percentage, other than to say, what is it today? Less than 1%. And it'll be a lot more than that in the future. There's no question in my mind about that. What I would say is I really do believe there will be a series of almost tailwinds that are going to push us in that direction. So if you think about patient-friendly a one-time cure is and how family-friendly that is right, just go through this one procedure, and then ideally, knock on wood, you really are done with the disease-- or much of it-- for the rest of your life.
JOHN EVANS: Think about the reduced burden on the health care system that represents. So now you're not coming here for sickle, you're not coming back into the hospital for pain crises every month, you're not needing constant diagnostic checkups, you're not having things go wrong as this disorder progresses. In some cases, you're not using expensive other therapies. So we will displace some amount of chronic, expensive specialty medicines for some of these disorders.
JOHN EVANS: And again, that ideally is going to actually save the system money. Of course, we all know that these sort of one-time cures will be very expensive to start. But remember, that's it. Once you've paid it. And so I think, if you think about a lifetime payment for medical care and potentially therapeutic care, I really believe these sorts of medicines can ultimately be value-providing and cost-saving to the industry if we can figure out how to pay for that obviously lumpy amount.
JOHN EVANS: And it's not a trivial challenge, which I don't want to minimize. And the final thing I'd say is you are potentially treating people still in the prime of their lives, sometimes even children. And if you do the pharma-economic analysis, and you say, what is the economic benefit of that-- which of course is missing the moral point, I think, of treating these diseases-- but nonetheless, it is very positive.
JOHN EVANS: You're restoring people to hopefully long, happy, productive lives. So I think society is going to really try to rearrange itself to support this kind of an approach. And I think it will be a groundswell in medicine. Our job is to do it safely, do it right, start with the most severe patients who are in the most need, show that it can be transformative, and then steadily and gradually expand that out to more places where we can have more of an impact, and bring it around the world, and make sure it's affordable enough to get to patients everywhere who could benefit.
KEVIN DAVIES: Well, you're on a very important journey. And we look forward to covering you as you proceed. John Evans, thanks so much. That concludes this episode of Close to the Edge. And our special thanks to our guest, John Evans, the CEO of Beam Therapeutics. And we wish that team the best of luck going forward. If you want more information on base editing, do check out Guideposts, the podcast series from The CRISPR Journal, including recent episodes with David Liu, the co-founder of Beam Therapeutics, recorded earlier this year, as well as the classic one with Alexis Komor and Nicole Gaudelli from Beam, who were both so instrumental in the development of the original base editing technology.
KEVIN DAVIES: Coming up on Close to the Edge, we'll be interviewing more outstanding chief executives, including Lawrence Reed from Decibel Therapeutics and Ted Love of Global Blood Therapeutics.
ALEX PHILIPPIDIS: GEN Edge is your source for the latest in-depth information on biotech entrepreneurship from the GEN team. We hope you'll take a closer look and consider a free trial subscription. Close to the Edge is produced by Jamie Cohen and [? Leana ?] [? Jabbs. ?] For Kevin Davies, I'm Alex Philippidis. Thanks for watching. Goodbye for now.
ALEX PHILIPPIDIS: [MUSIC PLAYING]

Cadmore media player playing video Close to the Edge Episode 4: John Evans, CEO of Beam Therapeutics

Video Player

Transcript

Segments

End of Video Player Control