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Close to the Edge Episode 7: Nessan Birmingham, CEO of Triplet Therapeutics
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Close to the Edge Episode 7: Nessan Birmingham, CEO of Triplet Therapeutics
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Language: EN.
Segment:0 .
KEVIN DAVIES: Hello, everyone. Welcome to Close to the Edge, the new show from GEN Edge, the premium subscription service from GEN: Genetic Engineering News magazine in which we interview chief executives and, in some cases, executive chairpersons of pioneering biotech and pharma companies. We're really looking forward to this episode. I'm Kevin Davies, editor at large with GEN and the author of Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing.
ALEX PHILIPPIDIS: And I'm Alex Philippidis, senior business editor with GEN. We're up to episode seven of this series. Do you believe that? Our special guest today is Nessan Bermingham, a serial entrepreneur and veteran of venture capital who is executive chairman and former CEO of Triplet Therapeutics, executive chairman of Korro Bio, co-founder of both and chairman of F-star. Howdy, Nessan, and thank for coming on at Close to the Edge.
NESSAN BERMINGHAM: Hi. Thank you for the invitation.
KEVIN DAVIES: Nessan, serial entrepreneur seems to be a pretty handy description for your career. We're going to talk in depth about your past and present activities in the rest of the program. Your career began in a way with a PhD at St. Mary's Hospital in Paddington, which by sheer coincidence is where I did my PhD, perhaps a couple of years ahead of you before moving to the US. What prompted you to shift from biomedical research to the business side of the industry?
NESSAN BERMINGHAM: Well, within academia, a lot of discoveries were being made as we think about biology and our understanding, mechanistically, of some of the key drivers of disease. I think the actual conversion from basic science to actually human therapeutic applications really captured my attention very early on. And this real concept of being able to take very granular observations and think about how do them apply from a therapeutic application, therapeutic modalities as we think about what's the most appropriate therapeutic modality and what's the most appropriate patient population to go into.
NESSAN BERMINGHAM: So really, very quickly it moved from, after my post-doc at Baylor College of Medicine in Houston, Texas, moved into industry and starting to actually understand how do you convert these observations, actually, into human therapeutics.
KEVIN DAVIES: Right. The biotech companies you founded or co-founded, over the years, run the gamut from small molecule drugs and biologics to medical devices, diagnostics, gene editing. What, if anything, did these entities have in common or do you just simply seize exciting opportunities as they arise?
NESSAN BERMINGHAM: Really, many of them, I think-- a consistent theme across many of them are really around cutting edge technologies or cutting edge observations. And when we think about it, I think Intellia is, for example, a great example of that. Since around 2000, I've been looking at editing approaches such as zinc fingers, TALENS, meganucleases that have been out there. And in parallel to that, watching technology such as lipid nanoparticle delivery systems as we utilized for siRNA and ASOs in addition to overall chemical modifications for nucleic acid deliveries into human cells.
NESSAN BERMINGHAM: The challenge from an editing standpoint was probably twofold. So one, was very much, as we think about the right editing tool, what is the one that's most appropriate as we think about overall size, deliverability, overall effectiveness, when we think about the edit we're actually looking to do. And then secondly, as we think about the actual application of it.
NESSAN BERMINGHAM: So it's great to have a tool. But if you don't really have the application for it, there is nothing really that you can do. And I think the CRISPR-Cas9 system was discovered at a point in time where, really, there was this interface of a lot of different data systems out there, so a tremendous amount of work done by companies like Alnylam, like Ionis, at the time, now Isis Pharmaceuticals-- or sorry, I meant Ionis Pharmaceuticals.
NESSAN BERMINGHAM: And I really started to understand this concept of how does the cell respond to nucleic acid that's been delivered to it, how do we think about packaging it. And then we had this very effective cutter with the CRISPR-Cas9 based system that allowed us, really, to be very specific in targeting. So then from a therapeutic application standpoint, and this is one of the differentiators, I think for Intellia, was very much this idea about if we're going to make a permanent modification, we need to be sure that the target we're actually going after, once we modify it, that is going to be safe and very well tolerated.
NESSAN BERMINGHAM: And that really allowed us down to targeting initially TTR because there have been a tremendous amount of data from Ionis, from Alnylam around actual knocking that down above 85% to 95% over an extended period of time. That really addressed the disease and was not associated with deleterious impacts on patients, not from a target standpoint. It was absolutely critical as we thought about that systemic first in human clinical trial.
NESSAN BERMINGHAM: And we've seen this consistently across the company's-- Triplet, it's the same example. An observation made by multiple academics-- which we'll talk a little bit more about that. Korro, the same thing. Tal Medical, from the device standpoint, really cutting edge observations made by academic or researchers that were published and really then building on that for human therapeutics.
KEVIN DAVIES: Yeah. So you've been the CEO of several companies. You're not currently holding that role. But would you take it on again if the right opportunity arose?
NESSAN BERMINGHAM: I think for the right opportunity, absolutely. I think the area that excites me the most is really thinking about the strategic-- the concept for the company, the overall building the strategy, recruiting in the people into it. And I've been very fortunate with the people I've been able to work with over the past 20 plus years, and then really the initial execution of that strategy.
NESSAN BERMINGHAM: But there is a point, and again, Intellia is a great example of it, were really the strategy is built in and now it's really the execution of it. And when you think about-- a lot of people talk about entrepreneurial spirit versus sort of a maintenance and execution CEO. They're very distinct roles. And it's very rare that you can get a CEO, I believe, that really can actually cross that gamut.
NESSAN BERMINGHAM: I certainly cannot. I'm on the entrepreneurial side-- start the company up, get it up and going, strategy, first couple of business development deals, financing. But there's a point, really, where I am not the right person to be running that company anymore.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: And really that's where we see, in our industry, where you start to then see the CEO cycling through as the company itself actually evolves and needs different capabilities to enable them to execute.
KEVIN DAVIES: Yeah. He might have some advice for other executives about knowing when to hand over the reins. But we'll come back to that a bit later. Alex, over to you.
ALEX PHILIPPIDIS: Thanks, Kevin. Nessan, you mentioned the spectrum of specialties you've worked in. Is it more rewarding to work in therapeutics as opposed to diagnostics? Which area do you find more challenging and why?
NESSAN BERMINGHAM: So the reason why I rotate into therapeutics more than diagnostics is we've seen great and tremendous developments in the area of diagnostic. And I think we're on the cusp of seeing a lot more. So as we think about genomes being sequenced, the cost of the genome sequencing coming way down, as we think about snippets association or variant association with disease on very specific genetic backgrounds, we're learning a tremendous amount around that.
NESSAN BERMINGHAM: And I think we're really at the tipping point as we actually think about being able to actually pre-diagnose the potential for certain diseases-- cardiovascular, neurodegenerative and others. And so we're going to see a significant shift in that over time, I believe. The challenge, from my standpoint, is diagnosing something, for example, like Huntington's disease and not having a therapeutic there for that patient.
NESSAN BERMINGHAM: It clearly is important money, for instance, for the patient or the individual to know what may lie ahead of them. But once it's diagnosed, there's absolutely nothing you can do. And you, effectively, are sitting there watching that patient or that individual deteriorate over time and the actual common impact it has on their families, their friends, society overall. So really, as we think about the diagnostic aspect, it really is ensuring that we have therapeutics that we can very quickly bring to bear that are either, in some respects, chronic, palliative therapies or curative, which is where I believe we're moving to now as we think about these diseases.
NESSAN BERMINGHAM: And ideally, getting into these diseases, that what you're diagnosed, you're actually treating immediately or hopefully, curing it immediately. So that the actual long-term impact is not really being realized. And the actual continued deterioration, which leads to additional effective indications in those individuals that are not actually realized also.
ALEX PHILIPPIDIS: Wow. You've had two stints with Atlas Venture. You returned, the second time, in 2018 as a partner and you were a managing partner at Omega Funds. What are some of the challenges and rewards of working in venture capital? What brought you to the field and what made you step back from that kind of work more recently?
NESSAN BERMINGHAM: So I've been tremendously fortunate to work with Atlas for many years, off and on. And they really have backed all the companies or nearly all of the companies that I've been involved with. When we think about venture capital as a whole, it's a tremendously challenging and highly stimulating job. So when you think about the exposure that you have for novel discoveries, for the people that you get to meet, the companies you get to build and actually as you think about the growth and frankly, the death of some of those companies, we talk a lot about the successes, but the failures are actually equally as important as you think about what you learned from them and how that actually educates you as you think about additional indications or additional avenues to explore.
NESSAN BERMINGHAM: Atlas, from day zero, really, have been very much focused on starting companies and building those companies up to certain points. And they're not afraid of blue sky science and novel areas of exploration. A great example, companies like Alnylam, companies like deCODE and Exelixis. Just this concept of being able to-- and these, obviously, are older companies, that really at the time, absolutely, cutting edge and that really hasn't changed over the history of Atlas, over time.
NESSAN BERMINGHAM: I think that really speaks to a willingness in the venture, especially the seed venture community, to really go after these discoveries and actually figure out how best to actually utilize them. So you have a piece of a puzzle, but it's one piece of a multi-piece puzzle that you need to build. So really, it's how do you build that and that's the capability and the expertise and the challenge and the fun.
NESSAN BERMINGHAM: And rather than the difference from a venture standpoint to an operating standpoint is, at the venture, you have a portfolio of companies or ideas that you're actually working with. So your day can be extremely varied, and you can be moving from oncology into inflammation into neurodegeneration in the space of a 12 hour period or a 24 hour period. In operations, you're dealing with a very, in some respects, a very linear, strategic initiative or imperative within that organization.
NESSAN BERMINGHAM: And unlike venture, while it's linear from an application or a focal component within the organization, you then are dealing with the actual stratification or multilayered elements within that linear structure. So you obviously have your pipeline. So you've got basic research. You've got translational research. You've got clinical research, potentially, in there.
NESSAN BERMINGHAM: You've got, then, IP. You've got corporate, legal. You've got finance. If you're at fundraising, if you're a public company, obviously, you've got governance-- a very different governance structure publicly versus privately. You're dealing with independent or public market investors. So really, there's a tremendous breadth you have to deal with, but there's a central focal point that research and key tenant of that company in its own right.
NESSAN BERMINGHAM: So both are extremely challenging, but in very, very different ways.
ALEX PHILIPPIDIS: Mm-hmm. OK, Kevin, over to you.
KEVIN DAVIES: Thanks. We wanted to spend a bit of time talking about Intellia because, of course, hugely in the news in the last few weeks for all the right reasons. So you, obviously, saw the promise of genome editing, as you touched on a few minutes ago, pretty early on. What stands out when you think back about how you pulled the company together? There was a lot of jockeying, it seems, as some of the other big names in the field were getting ready to launch companies like Editas and CRISPR Therapeutics.
KEVIN DAVIES: So how did Intellia emerge from this morass?
NESSAN BERMINGHAM: Well, it was interesting. We spent a lot of time, prior to Atlas and also while I was in Atlas, looking at the editing technologies that were out there. So you had people like Keith Young, with the [INAUDIBLE],, really interesting discovery. The modularity of it was actually very intriguing as we looked at actually thinking about that application for human therapeutics. You had the meganucleases and clearly, had its own IP considerations and fraught with its own complexity as you thought about who owned the IP for that.
NESSAN BERMINGHAM: And you had [INAUDIBLE],, really the leader for editing overall with the zinc fingers. So we've been watching it for a very long time. But I think our challenge, very much, was they were not as-- either efficiency were a challenge, manufacturability, specificity. So really we were constantly looking to see what is the next sort of evolution of it. And obviously, Emanuelle and Jennifer's publication came out, which was just phenomenal to see that come through, and not a surprise.
NESSAN BERMINGHAM: It was a surprise at the time. In hindsight's, it's a wonderful thing. Bacteria, [INAUDIBLE],, very complex as you think about just the breadth that's actually in these systems. And to actually see an immune system come out from that was just wonderful to see. But really, then, it was like, well, how do you think about turning that into a drug?
NESSAN BERMINGHAM: And I was fortunate enough to know Shaun Foy and get [INAUDIBLE] Rodger Novak, which ultimately became CRISPR Therapeutics, and start looking at and evaluating opportunities with them and thinking about the development technology. But ultimately, myself and Atlas made the determination to start our own company which ended up becoming Intellia. My kids named it. So it became Intellia.
NESSAN BERMINGHAM: And really the difference between Intellia, CRISPR Therapeutics and Editas, it's like different flavors of ice cream. There are multiple different ways you can think about building a drug and how you actually want to go after things. And I think our concept, myself and Atlas, was very much-- we want to build a modular system that once you validate it in one indication, you can then very quickly just change your glide sequence.
NESSAN BERMINGHAM: And within that organ or in that system, that really allows you, then, to very quickly build a very broad pipeline across it. So unlike the sort of approach-- and we wanted to do that, I'm sorry, systemically. So really, it wasn't worth pulling cells out of the body, modifying and putting them back in, but actually, we were just injecting the drug into your body.
NESSAN BERMINGHAM: And this may give you a little bit of insight into how I think all of this is ultimately going to go, which I'll be happy to share with you in time. So that was the concept. So we looked at it and said, for us to be able to do that, there are elements we need to bring into the organization. So obviously, the people we hired were very fortunate, John Leonard, Dave Morrissey, Tom Barnes, Jennifer King-- as we think BD, just really as we think about overall execution, just was great from an execution standpoint.
NESSAN BERMINGHAM: But as we thought about delivery vehicles, bringing in lipid nanoparticles from a delivery standpoint, which Novartis have been working on and was part of our partnership with them, that really was a game changer for us. Because it gave us this packaging system, or think about it like your car. It gave us a car that we could fill with stuff, deliver it to the body and that would hone in to the right cell type for us.
NESSAN BERMINGHAM: So that was really important. The other aspect was really around the manufacture identity modifications and the concept of using RNA. So really this idea about-- unlike using an AAV, for example, our view was we wanted to put the system in, edit, but then it really just to disappear. Because our concern was anything that stays in the cell for an extended period of time is just going to get itself in trouble.
NESSAN BERMINGHAM: So it may just do some off target, and it may take a while for it to do it. But there is a possibility this will happen. So we wanted something that would go in, edit and then disappear. That led us down the RNA avenue also for it. And then the target. TTR was the first target because of that validation that really Ionis and Alnylam had actually shown with their ASOs for Ionis and siRNA from Alnylam.
NESSAN BERMINGHAM: And once we had that validation from a safety tolerability et cetera standpoint, then you really could start to expand into a whole multitude of additional indications that the company's actually doing now.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: The partnerships with Regeneron, and then other things that we did, also was then to allow us to really start expanding to novel targets. And this really led into, not from Intellia to Triplet, but it's this idea about, OK, so you have modalities. And what we're seeing in our industry is these modalities are being commoditized extremely quickly. So if you look at now small molecules, antibodies, ASOs, si's, and we're even not seeing in the editing space, we're seeing the commoditization of these extremely rapidly.
NESSAN BERMINGHAM: So the question now is where are you directing them to? And that's where we started, then to think about how do you identify novel targets? How are they validated as we think about human therapeutic applications? And that led into this whole other area that we actually started thinking about and building up around.
KEVIN DAVIES: I love the serendipity that's involved, sometimes, in putting these companies together. You mentioned John Leonard who succeeded you as CEO. My understanding is you met him in the queue at the salad bar at an Atlas retreat to Florida. He was thinking of retirement, but you obviously saw something differently.
NESSAN BIRMINGHAM: Absolutely. So that's exactly where I met him. And then I flew up to Chicago to meet with an academic up there, and John, graciously, found time to have lunch with me. We sat down and started talking about it. I sent John some papers subsequent to that, it really kind of stimulated his interest. And what was great about John was you had somebody in John or have somebody in John who a lot of experiences when you think about the clinical development aspect, a lot of experience as you think about moving beyond clinical into commercial, as you think about manufacturability, so overall CMC.
NESSAN BIRMINGHAM: And I'd never managed hundreds of people. I'd barely managed five. So I think from an organizational design standpoint, by the time I left, we were over 200 people.
KEVIN DAVIES: Yes.
NESSAN BERMINGHAM: So really, John was very well experienced in managing very large numbers of individuals and how best to actually think about-- we talk about culture a lot. How do you think about that, especially when you're building 200 or 300 people over a two year period? And what people forget, for Intellia was we went from, literally, a sheet of paper in Atlas' offices, all the way through to a publicly listed company in less than two years, multiple rounds of financing, two large pharma deals, TTR already set up in place.
NESSAN BERMINGHAM: So really, we moved extremely fast. And ensuring culture, ensuring direction, ensuring this cohesion across the organization was absolutely critical. And really having people like John, would have that experience in large organizations, was obviously very helpful as we thought about being able to execute appropriately.
KEVIN DAVIES: You've referenced the ATTR amyloidosis target and of course, the results of that very initial clinical trial on a handful of patients were published a month or two ago in the New England Journal of Medicine and received, I mean, ecstatic reviews from pretty much all corners. You were intimately involved in setting up that program. Are you kind of, in any way, pinching yourself at how promising and how good those initial results were?
KEVIN DAVIES: It doesn't always go according to plan like that.
NESSAN BERMINGHAM: This is true. And I think that it was-- I always thought it would be binary. That either you really would see a very limited amount of editing taking place and that frankly, it's not a drug. Or you would actually get this level of editing that you were seeing. And when we look at the non-human primate studies, and I think this is one of the things that really is very helpful for these types of modalities or nucleic acid base drugs.
NESSAN BERMINGHAM: They tend to be directionally, very predictive. So what we were seeing in the NHP's, from a level of knockdown and the durability of that knockdown from a single injection, really was extremely compelling. Now when you talk about an NHP, you're talking about a very small animal that you're dealing with. And then you've got, obviously, increase that as you think about the overall size of a human, the stage that you're going in.
NESSAN BERMINGHAM: But that data, I think, really was what crystallized it for us. And the other aspects that was very helpful was we weren't doing this in a vacuum. So not only were we generating our data, but there's always the potential in the company for sort of bias in data interpretation. You almost pre believe what the data should show you, so you're kind of coming at it with that lens.
NESSAN BERMINGHAM: What was great here was we had all of these other companies out there and all these academics that also were publishing and that was just continuing to increase our overall level of confidence in there. And with the two partnerships between Novartis and Regeneron, they were doing their own work, which also was validating the work that we were doing. So it was reassuring. And it's rare that you have this opportunity that you'd have all of this different data coming through that was validating the data you were building internally also.
NESSAN BERMINGHAM: And that really kind of gave us a sense-- it took us a little longer than I'd hoped, to be honest. And I think for investors, there's always this sort of balance. When do you take a company public and sort of expose yourself to the public markets and the expectations that comes with being a public company? When do you do that knowing, as data is coming out in the timeline, two data, these pre-clinical stage companies, it can take a while to get into the clinic and really generate that meaningful data from a public market standpoint?
NESSAN BERMINGHAM: So we got a lot of push back from investors, over the years, around our approach at the time. But what was very clear, and this was really one of the philosophy that I talked to Atlas about-- I talked to John about, when Tom Barnes was in, Dave Morrissey and the rest of the team-- we were very clear, we're building this for the long-term. We're not looking for a quick entry to human clinical trials, but we're going to build it right.
NESSAN BERMINGHAM: We're going to take the time to do it. And the data now speaks for itself, which is just phenomenal to see.
KEVIN DAVIES: But you're not just building a single company in a way you and CRISPR and Editas, I mean, you're building a paradigm. So I'm curious, is that much kind of-- although, technically, they are competitors of yours, is there, to some extent, some collaboration or some meeting over a beer to just kind of compare and contrast and talk about concerns that are facing the whole industry, not just one company?
NESSAN BIRMINGHAM: Absolutely. I think, that as we look at the venture groups that sit behind all of these companies, they all interact together. They all go all together. And they've been doing this long enough that they actually know the ebb and flows which you think about building a company and a novel technology. From the CEOs and CSO standpoint, on the whole, I wish I could say it was the case for every company, it's not.
NESSAN BIRMINGHAM: On the whole, people do get on very well and they do have conversations. They grab a beer. They will sit down. They'll talk about things, not what's very important. Where we saw the importance of it and the criticality of it really was when CRISPR-Cas9 first came out. The ethical considerations were not minor. And you had ethical considerations and obviously, this is something you've written about and I think it's really important to capture that people not to forget what was going on at that point in time.
NESSAN BIRMINGHAM: And you also had, as you thought about security, biodefense, bioterrorism considerations that were also out there at the time. So collectively, ourselves, Intellia, Editas, CRISPR, we worked to be consistent in our messaging internally and our philosophy, ethically, internally and also externally. So that we were very clear about how we view things, how as companies, we were going to drive this technology and sort of what the line was for us as we thought about not crossing it.
NESSAN BIRMINGHAM: And clearly, there was a lot of discussions from ethicists, from patients-- very important voice to actually hear from. What we classify as disease, others may not classify as a disease and vise versa. So having inputs on that side was absolutely critical. So yes, we see it. I think, though now, as you look at it, we've crossed the rubric somewhat as we think about these technologies.
NESSAN BIRMINGHAM: And it's become now so competitive that I fear that those discussions are becoming less and less. So that cohesion is fraying a little bit. And I think that, in part, is a dearth of targets or applications as you think about these technologies. So you tend to see a lot of them chasing the same targets. So it's effectively, for these types of therapies, whoever gets to market first really is going to be able to take the majority of that patient population, and because we're really not into the zone of thinking about curative medicines, which is a place we've just never had to do before.
NESSAN BIRMINGHAM: So TNF office, you could be the fifth one, if there is an advantage from a dosing paradigm around it or a safety paradigm around it. That's certainly allowed entrance into the marketplace. We're not going to see that, I think, with genome editing and gene therapy.
KEVIN DAVIES: OK, interesting. All right, Alex.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. Listen, let's digress for a minute and look beyond the office and beyond science. In your spare time, as I understand it, you like to do a bit of running.
NESSAN BERMINGHAM: Yes. So there are a few sports I love to do. I love to run, trail running, specifically. I'm a big downhill mountain bike or snowboarder. I've just taken up kite surfing. And I just bought my first dirt bike, which my wife is quite scared of. So yes, I love that. I think there's an element, for the running-- so you ask about the running.
NESSAN BERMINGHAM: There are two aspects to it. Our world, today, is so connected. It's extremely challenging, I find, personally, to be able to step away from it. So your iPhone or your phone is very close to you at all times. You access the computers. I don't wear an Apple Watch, but I watch people who do. It pings during meetings and they look down to see what the text is.
NESSAN BERMINGHAM: So this concept of actually being able to find time to actually let your mind sort of chill out a little bit and mull over some problems, I think, is absolutely critical. So the running really came out from, I would say, over stressed, really starting to see its net impact on me personally, and that I needed to take up some sports to sort of relieve that.
NESSAN BERMINGHAM: Running was one. Boxing, actually, was another one that I took up. And the boxing, the interesting thing, it's very similar to snowboarding or downhill mountain biking. It's 100% concentration on what you're doing at that point in time. There's nothing else can come in when you're doing it or something bad is going to happen. With running, it's the inverse.
NESSAN BERMINGHAM: You can actually get a cadence in place. Your mind, then, can actually start to free itself up. And what I found is that really taking the time to go out and run allows me to actually think about challenges, issues, areas of focus that, then, I come back from and I'll actually look to implement or expand on. So it really allowed me or allows me to actually really just take time to think about things. And the extreme is my wife keeps telling me that I do it, now, to get away completely for days on end.
NESSAN BERMINGHAM: It's now getting into ultra runs. So going out into Patagonia for four or five days. I was supposed to go out to Atacama at the end of September, but that's just been pushed to next year. And I run rim-to-rim-to-rim at the Grand Canyon every year. All of these things, really, to have these really extended periods of time just to really allow yourself to really kind of just think.
NESSAN BERMINGHAM: And I find that, for me personally, it's extremely helpful, both personally and professionally, as I think about my life overall. And one of the themes in every company that I've tried to instill in is work, but play. So this work-life balance is absolutely critical. That this idea of 24/7, no one can maintain that and you're much better and more useful to the organization if you're healthy.
NESSAN BERMINGHAM: You've got that good work-life balance, you're very happy with your personal life overall. That makes you a better person and a better ability to think about what you're doing rather than being an ultimatum where you're just cranking stuff out, regardless of what it actually is.
ALEX PHILIPPIDIS: A few years back, running in Argentina, you came in the top third while half your competitors failed to even finish, which I thought was pretty amazing. So you're still running these ultra marathons and take--
NESSAN BERMINGHAM: I'm trying to. My knees are getting worse as I'm getting older. I think that they and my diet and my expectation from sleeping on the ground is getting harder and harder to do. But yes, I still really enjoy doing that. And again, I think there's back to nature and just having clarity of mind. Personally, I just think is so, so helpful.
ALEX PHILIPPIDIS: But the knees--
KEVIN DAVIES: Kite-surfing might be easier on the knees, I suspect. But let's get back to sort of two of your main occupations. Now let's talk about Triplet Therapeutics. I remember handling some of the first Triplet repeat expansion disorder papers when I was a rookie editor at Nature back in 1990, 1991. These are the sort of mysterious sort of concertina like expansions behind diseases, disorders like fragile X syndrome, myotonic dystrophy and then later, of course, Huntington's disease and spinocerebellar ataxia.
KEVIN DAVIES: I've lost touch with this field. How many of these genetic disorders are there and how is Triplet's-- how do you conceive of a company and an approach that can possibly rein in these and treat these devastating disorders?
NESSAN BERMINGHAM: So the numbers keep growing. It's over 50 right now. Their role in disease, actually, seems to be increasing as we're learning more and more about them. So to back up a little bit, when we think about science and we think about human therapeutics, there's a certain level of arrogance, I think, we all have. I remember when, and you probably call it better than I did, before the Human Genome was sequenced, everybody kind of turned around and said there must be at least 120,000 genes in there to make up how complex we actually are.
NESSAN BERMINGHAM: So if we compare ourselves with nematode, or [INAUDIBLE] fly, right, there's got to be over 100,000 of these things.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: And they go my sequence and they come out and they say, at the time, we think it's between 20 and 25,000. And it was almost like an insult. People kind of do step back. Because there's no way it could be the case. You must have missed 75% of the genes out there.
KEVIN DAVIES: Impossible match.
NESSAN BERMINGHAM: Right. So I think that there are these things that we look at and we have these preconceived notions. CRISPR-Cas9, actually, is another great example. This is the only one-- this is the only system out there. And then once we know what we're looking for, actually, we've seen this whole just portfolio of these systems that are just amazing, that nature has actually built for us. And now we know what we're looking for.
NESSAN BERMINGHAM: So when we think about the repeat expansion disorders-- and again, you're absolutely right. So if I take a cell from you or look at your DNA, and something like Huntington's disease, I'll see about 20 of these repeats. And when we talk about a repeat, it's like a word the repeated 20 times in a row. So most people are going to be somewhere in that sort of 15 to 30 repeat sort of range or 25 repeats. But there are individuals where the repeats are actually longer.
NESSAN BERMINGHAM: So let's say instead of having 20, they've actually got 40 of them. And what that 40 repeats does is it drives disease. And for a long time, we'd assumed that each one of these indications of things like myotonic dystrophy, Huntington's disease, fragile X syndrome, again, over 50 of these, that each one of these genes, with this repeat expounded in there, actually was a single disease-- a single driver of the disease.
NESSAN BERMINGHAM: And that as we think about treating it, we need a bespoke therapy on an indication of medication basis. So that was our assumption. And that was the assumption stood for a long time. So you're right, since the 1990s, we'd assume this. But we had data out there that when we looked at patients-- and I'll talk about Huntington's disease, but it's not just Huntington's disease.
KEVIN DAVIES: Yeah, yeah.
NESSAN BERMINGHAM: When you look at patients, you actually can identify two patients that were born with the same number of repeats. So let's say it's 40, and then you track them over time. And one patient-- excuse me-- has a age of onset of 20 years of age and the disease very rapidly progresses. And then the second individual is an age of onset of 60 years of age, and the disease does not progress particularly well.
NESSAN BERMINGHAM: So even though same DNA effect or impact, different rates of onset, different rates of progression. So we knew background here was absolutely critical. The genetic background that you have was absolutely critical. Some beautiful work done by a number of academics out there, Vanessa Wheeler being one of those, Jim [? Kassala, ?] multitude of others. And what they looked at was what is doing that? And what these people found or these investigators found was, well, if I take a cell out of the body from the reaches of the brain that are impacted, for example Huntington's disease, and look at that gene, what I see is that even though they were born with 40 repeats, when they actually died that repeat now has grown to, for example, over 1,000 repeats.
NESSAN BERMINGHAM: So over the life of that individual, that DNA actually is quite unstable and that repeat is getting longer and longer and longer. So then they did a lot of work to figure out what's actually driving this. They published all of this data. And it's a pathway called the DNA Damage Response Pathway that basically is driving it. And as Triplet, we stepped in or what became Triplet, we stepped in and actually looked at the pathway.
NESSAN BERMINGHAM: And said, OK, let's look at the number of genes that are associated with this. What's the right point of intervention? What's the right therapeutic modality? What's the right indication as we think about targeting it? Now what actually ended up happening was from a mechanistic standpoint, the system actually is very, very simple. So if you think about DNA, DNA is transcribed, makes RNA, RNA then into the protein.
NESSAN BERMINGHAM: And when you think about one transcription is taking place, you've got double-strand DNA that basically opens up, it gets read and then it refolds. Well, when it closes or makes double-strand DNA again, if you have a length of repeats that are, let's say, 20 repeats, its ability to actually become double-stranded exactly correctly is relatively straightforward. Think of two pieces of Velcro, very short. You lay one on top of the other one, they'll bond together flat.
NESSAN BERMINGHAM: But when it goes above a certain length, when that DNA goes to [INAUDIBLE] and becomes double-stranded, it actually doesn't do it properly, and you see these kinks form. Very similar down, again, to two very long pieces of Velcro that you're trying to put together, you'll see these little bleb that form out of them. And that's really what's happening. These bleb form.
NESSAN BERMINGHAM: The DNA Damage Response System goes to repair them. And basically, it cuts the flat piece, pulls that bleb flat or straight and then fills it in. So whatever's in that DNA and that bleb, has now been actually added to the DNA. And over time, this accumulates, accumulates and it increases the rate at which it does it over time. So at Triplet, we looked at antisense oligonucleotides and siRNAs, depending on the tissue we wanted to targeted.
NESSAN BERMINGHAM: We looked at a multitude of genes within our targets, within this pathway, multiple mRNA models and then ultimately, that led us to and nominate a compound called TTX-3360, which is moving into IND studies or clinical trials. And next year, on Huntington's disease, we've started natural history study in Huntington's disease and also [INAUDIBLE] to specifically look at this aspect of it.
NESSAN BERMINGHAM: And unfortunately, again, with Triplet, there was a lot of work that other people were doing that validated this target and validated this pathway, which was great to see. But I think this is probably the first time or one of the first times that patients, themselves, actually identified the mechanism. So really going back to those two patients, one 20 years old who got the disease and one was 60 years old, if you build enough of those individuals, enough numbers in both of those groups, you actually can look to see what's difference in the genome between them, between the groups, and the same within the group.
NESSAN BERMINGHAM: And really it was that work in those patients and then validation with animal studies that identified this pathway and ultimately, led us to this point. So it's really just phenomenal human genetics at its finest.
KEVIN DAVIES: Yeah, yeah. How are you going to-- most of these disorders, certainly Huntington's and many of the others that we briefly mentioned, are neurodegenerative disorders. What are the added challenges of-- you've identified a very plausible mechanism, you've still got to deliver it to the brain or wherever. So how are you going about that?
NESSAN BERMINGHAM: So that's a great question. I mean, delivery-- people, I think, underestimate some of the challenges of getting a drug to the right side at the right point in time. When we look at other treatments that are very similar to this approach or other ones that are in clinical development today-- so Spinraza already approved, spinal muscular atrophy. And then there's a multiple ones for Huntington's disease in clinical trial too, which recently failed clinical studies.
NESSAN BERMINGHAM: They basically, injected into the spinal cord. And it's called intrathecal delivery. So it's basically inject the drug in spinal cord. And for those of you that might know, in the brain of the spinal cord, you've got this fluid. And basically, that fluid is just flowing and bathing the whole system. So the thinking being if you inject it in, the flow will pick it up.
NESSAN BERMINGHAM: It'll disperse through the fluid, and that flow of the fluid will, actually, deliver it to the cells. Great in concept. Practically speaking, that's not what actually happens. So there are some real challenges as you think about the actual flow of the CSF. And in addition, in some of these patient populations, specifically, the flow gets challenged or it's not as a regular flow because of the nature of the disease itself.
NESSAN BERMINGHAM: So we took a slightly different approach. So since the 1960s, people have actually been just injecting drug directly into the brain. So there are systems in there that you can put a very small device that is it sits just underneath the scalp. It's a bit like a little rubber balloon, tiny. It's about the size of a quarter or a dime. Out of it is, effectively, this little-- thing of it is a straw-- that goes down into the CNS and delivers your drug to where you need it to go.
NESSAN BERMINGHAM: So when you think about delivering it, all you're doing is injecting through the scalp into this reservoir, and then the drug itself then goes down through the catheter and into the actual CNS. So we effectively opened up that as a delivery avenue for antisense oligonucleotides. So we've done a tremendous amount of work in it. We've identified the right ICD devices from a delivery standpoint, the delivery metrics now, which we've actually published around.
NESSAN BERMINGHAM: So really, we started looking at IT because everybody else was doing it. But we found that it wasn't doing what we needed it to do. That led us into ICV and other avenues. ICV really shows to be very effective as we think about delivery. And when we talk to patients-- so there's always a concern. If you're talking about putting a device in, and it's a very simple device-- but when you talk about putting a device in, you need to talk to patients and understand, as they think about their lives and their considerations, concerns, how will they respond to it.
NESSAN BERMINGHAM: And what became very clear, quickly, was two things. One, IT delivery is just a painful, uncomfortable thing for a patient to have done to them. So here you've got this disease. You're going to take this route of administration because the disease is terminal, effectively. But it's not a good way to deliver a drug from the patient standpoint. And then secondly, when you looked at the actual ability to deliver at home, this opened up the opportunity to actually potentially do that.
NESSAN BERMINGHAM: And that meant, as you think about the impact on your life, it has a lot less impact on life versus having to go to a facility where are you going to get this IT and delivery. But before we had the conversation, it really was a very big concern of ours. How were physicians and patients respond to ICV? And we spend a lot of time working through that and educating, also, as we think about the application here.
KEVIN DAVIES: All right, Alex.
ALEX PHILIPPIDIS: OK. Thanks, Kevin. Just checking on something I think you said a couple of minutes ago. Lead candidate TTX-3360-- I know the company's talked about preparing to submit an IND by the end of the year. Did I hear you right that the clinical trial is set for next year to start? If that would be--
KEVIN DAVIES: Right. So--
ALEX PHILIPPIDIS: OK.
KEVIN DAVIES: I think that there were a couple of things in consideration around that. As I mentioned, there were two drugs that failed effectively in human clinical trials recently for Huntington's disease. And it was a real disappointment, I think, to the community as a whole as we looked at target-- they were targeting actually the HTT gene or the HTT RNA in its own right. And for all of us, I think, we took a step back and said, OK, what do we learn from this?
KEVIN DAVIES: So one was from Roche who had partnered with Ionis and the second one was with Wave. And when we looked at some of the considerations around it, there were elements from a biomarker standpoint that they were looking at. There were elements from an imaging standpoint that we were looking at. And back to that drug distribution and time of intervention, when do you actually intervene in these patients?
KEVIN DAVIES: So there was a lot of data, and there's more we believe that that Roche would likely be putting out over the next few weeks into the next couple of months, to actually help us think about how do you run a clinical trial here? How do you think about these class of drugs from an intervention standpoint? Triplet, very different target, very different mechanism. But we would be foolish to not look at that data and actually listen to what it's telling us.
KEVIN DAVIES: And that's really, in part, what the company did. So we took a step back and said, OK, a lot of data has come through. We need to actually process it. We need to talk to advisors around it. We, frankly, need to talk to the FDA and the regulatory authorities about it and how they think about the implications around this. And there's more data that's yet to come out.
KEVIN DAVIES: So when we think about our patients, one of the things we want to be absolutely clear is that the drug that we're bringing into the clinic, from a safety, tolerability, and potential for therapeutic intervention, that we've done as much as we can. So I look at and say, if I'm not willing to give it to a member of my family or myself, that I should not be taking this drug into the clinic.
KEVIN DAVIES: So that sort of made us take a step back and say, OK, we're delaying. We're delaying by two quarters to ensure that we've ticked all the boxes. And again, different mechanism, different sequencing, different route of administration, but you're delivering a nucleic acid to the CNS. So let's ensure that before we get into human clinical trials that we've actually done what we need to do from a safety and tolerability and frankly, dosing paradigm also as we think about moving into human clinical trials.
ALEX PHILIPPIDIS: Mm-hmm. Beyond the challenge of delivery, which you've got into, how do you prioritize one disorder over another when there are dozens of related disorders?
NESSAN BERMINGHAM: So great question. There's almost-- it's like you look at it and say, to your point, this mechanism looks like it may be involved in, and if not, all 50 plus repeat expansion disorders, at least a large number of them, sponsored by [? Taxius, ?] myotonic dystrophy, multiple ones. So there are a number of criteria that when we founded the company, we sort of put in place and said, OK.
NESSAN BERMINGHAM: As we think about that first in human clinical study, that is the determinant. It's a bit like the TTR discussion for Intellia, you get one kind of shot when you start talking about these sort of platform approaches or these targets. And really, if you don't maximize the probability of success for that, then your ability to go into these additional indications become more and more challenged.
NESSAN BERMINGHAM: So you're balancing your first indication, but also you don't want to be just a single indication company. You want to make sure, too, that you've got other indications that are actually coming behind it, that you will continue to learn from or optimize around. So Huntington's disease was chosen for a number of reasons. Excuse me. The amount of data out there, on Huntington's patients as you think about progression, as you think about this mechanism from a disease standpoint, as you think about the sheer knowledge-base of the patients that have this disease is unprecedented.
NESSAN BERMINGHAM: So as we looked at it, that patient population, the depth of data, the depth of experience from a clinical standpoint, the depth of patient education and awareness of disease really made it a very clear, first clinical application. Very close behind it, frankly, is myotonic dystrophy. And then you're getting into the spinocerebellar ataxias. So that was the reason why, from a Huntington's disease standpoint, that was the first one.
NESSAN BERMINGHAM: Now you're right, it did bring its challenges from a delivery standpoint. Whereas as you think about things like myotonic dystrophy, you've got groups like Avidity and others that have are utilizing systems, now, for delivering into the muscle. And [INAUDIBLE] Therapeutics is another great example of it as you think about that delivery. But as we think about that patient population, disease progression, size of the repeats, Huntington's disease made the better sense as first in human clinical study for us.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thanks, Alex. In the last few minutes, Ness, that we have you, we'd love to talk about one of your other new and current ventures, Korro Bio, an RNA editing company. It doesn't get much hotter than this, does it? RNA is halts and gene editing or variations, thereof, is also incredibly hot. The company's tagline, I looked it up this morning, is "edit the message, rewrite the future". I like that.
KEVIN DAVIES: What sets this company apart? And did your kids named this company as well?
NESSAN BIRMINGHAM: No, one of the other co-founders, Andrew Fraley, named us. We're back to this question about understanding disease mechanism and targets. And what's become very clear is genetic background is a critical driver. Frankly, the environment in which you live can be a critical driver also, if you think about disease, disease onset, disease progression.
NESSAN BIRMINGHAM: So as we think about permanent modifications, I'm reluctant to do permanent modifications on genes that actually you don't know if there would be a detrimental impact on these patient populations. So as we think about one aspect of what Korro does is it's transient. And there's a lot to be said for that. We figure out a lot about drugs in phase four clinical studies because you've now opened up to a much larger-- when you think about a clinical trial, you've got enrollment criteria.
NESSAN BIRMINGHAM: People got to fall within that enrollment criteria. Whereas in a phase four or once it's approved, there are really no hard and fast criteria. We leave it to physician's discretion as they think about prescribing a drug. So when we think about it, you really want to go in and do something that's transient that you can switch off. You can start to see everything associated with it.
NESSAN BIRMINGHAM: But then you start to look at some of the things that we'd hoped you could do with CRISPR-Cas9. So when we started Intellia, when CRISPR started [? medi tasks, ?] you may recall, we talked a lot about the Swiss army knife from a therapeutic modality. And that really-- this is you could do everything with it. But the reality is it's a bit like a hammer. You've got the claw and then you've got the face of the hammer, but that's kind of it.
NESSAN BIRMINGHAM: It could do two things, pull a nail out, knock a nail in. That's kind of it. It's very effective at doing that, but it does two things. When you look at a lot of the disease driving mutations or variants driving disease, they really are single-base changes. So now you're back to, well, how do you actually modify that? And how do you rescue it? So really you want to go in and be really precision medicine.
NESSAN BIRMINGHAM: Go in and actually make one change at one target site, no halo effect. Korro, the technology, it uses a system that's actually already in your cell, which I love. So we're using something that's already in your cell that does this, co-opting it to do where we want it to actually do it. So that's one thing that it does. And then there are other aspects that they're working on around endowing functionality as you think about super proteins functions or making them more effective at doing what you want them to do.
NESSAN BIRMINGHAM: Or getting rid of them if that's what you want them to do. So the way the company has been built is thinking about expanding beyond what we thought about as sort of rare orphan diseases into much, much larger patient populations that allows us to actually, then, be very specific and very targeted in our treatment. With, again, a nucleic acid that from a manufacturability standpoint, cost of good standpoint, delivery standpoint is a lot easier as we think about delivery on those factors than some of the other approaches that are being utilized today or are being explored in the clinic today.
KEVIN DAVIES: Can you think of this technology as base editing on RNA rather than DNA?
NESSAN BERMINGHAM: Yes, I mean, that's a great way to do it. And I think, as we think about more and more targets coming through, the speed at which you can actually design these and direct them is extremely fast. So unlike, we go back 20, 30, 40 years ago, that if you've got a target and you wanted to validate that target from a disease standpoint, you're making a small molecule against at that point in time. Right now you might talk about moving into other systems. But it took a very, very, very long time to actually design and validate.
NESSAN BERMINGHAM: If we think about what we did in Triplet, we moved from again a piece of paper to our development candidate in, I think, it was less than two years. Triplet was great execution, don't get me wrong. But really, it was around the flexibility of these systems, the vendors that are right there to allow you to actually build these sort of, think of them as being LEGO blocks that you're putting together, that are there to allow you to do this.
NESSAN BERMINGHAM: You do it extremely fast. Your screens are fast. And from a cost standpoint, on a relative basis, they're actually very cheap to manufacture and to actually then go and test in animal models. So our speed is much, much better than it's ever been before. Now its target. How do we identify novel targets?
NESSAN BERMINGHAM: How do we think about being able to actually walk our way through with them to identify what's the most appropriate one from a safety, tolerability, and efficacy standpoint?
KEVIN DAVIES: Are you going to answer your own question? What are your really telling us?
NESSAN BERMINGHAM: So I think we're at a fascinating point now. So we're back to how do we think about genome sequencing, patient records, medical records, disease tracking, backgrounds under which these genetic backgrounds are being expressed on to us to be able to glean and manipulate them. So you look at all of the groups out there, the UK Biobank, all the big population sequencing studies that are going on right now and computational power.
NESSAN BERMINGHAM: So if we think about of the binary computational structures that we've had historically, they really were limited in the complexity of what you could actually ask and the data that you could actually put into them. We're now moving beyond that into things like quantum computing. And what that allows us to do is you've got patient data that's coming in and population data that's coming in.
NESSAN BERMINGHAM: So cost of sequencing has come down, screening times is a lot faster. So you've got all that data coming in. We've got all of these computational systems now, as we think about quantum computing, as we think about machine learning, artificial intelligence. We've got these therapeutic modalities that we can build extremely fast and that are very specific and as we think about the modifications around them.
NESSAN BERMINGHAM: And then we're getting better as we think about what are we looking for in animal models or in vitro as we think about cellular systems. So we're back to-- again, when CRISPR-Cas9 came out, it came out at the perfect time. We've got these all now coming together. We're starting to get real, new insight into disease and pathways that actually are directly impacted.
NESSAN BERMINGHAM: So what do I think this is going to go? I'm going to ask my own question, right. If we think about things like TNF alpha, inhibitors or some of the systems that were-- Humira, great example. When we think about when that was first approved, it was approved in an environment where there was not enough manufacturing capability in the world to actually meet the need.
NESSAN BERMINGHAM: And when you thought about actually getting the treatment, you had to go into a physician's office. Fast forward, whatever it is, x number of decades. And now you have it delivered to your door. We have overcapacity. We have beyond Humira into now others like Cosentyx as we think about novel targets and novel areas within pathways. Delivered to your door, self inject, you're done.
NESSAN BERMINGHAM: So when we think about these distribution systems, when we think about these fill finish, these manufacturing, the simpler the modalities get, the more practical it is to actually start building these systems in place. So I think we're going to get to, maybe not in my lifetime, but I think we're going to get to a point whereby genome sequenced, we do the analytics around as we think about the environment in which you live, what diet, how you live your life and we start to actually now really design and develop drugs specific to you.
NESSAN BERMINGHAM: That's similar to a book, we can print in real time, fill finish it and ship it to your door and it's a self injector. And if you think about all of the disparate components you need to enable you to that, they're actually there already. It's now just which targets. And to me, that's what it comes back to. Target, target, target.
KEVIN DAVIES: Yeah. How do you make this a commercial success? Ness, you had a good series A, I think, it was last year raising just a little over $90 million. Are you looking for more of the same or do you start to think about going public? Or there was a company, in your space, Shape Therapeutics, just hot off the press announced a major deal with big pharma companies. So which of those options might you explore?
NESSAN BERMINGHAM: I think that pharma deals are important because of the capability and skill sets, the bandwidth that that provides you. And when you're building a company in real time, it can be very difficult for you to really span the full gamut of applications, especially when you're talking about platforms. So when you look at the partnerships, I think that they are actually pretty important around doing that.
NESSAN BERMINGHAM: When you think about the capital, it always takes more capital than you think. I remember when we did the $15 million series A for Intellia and we had the Novartis upfront payments. And I was like, oh, this is going to give us capital for, I kind of [INAUDIBLE],, but let's say next five years. I think we burnt through it in like 18 months. So the reality is these are very expensive because of the verticals that you actually need to put in place.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: The issue that you have is those capital needs are really huge for these platform companies, and you need to build extremely fast. So you're constantly thinking about those capital raises, the milestones that actually justify bringing in new capital. And you're balancing bringing new capital in with valuation. Because obviously, your investors are looking for a rate of return that you just need to be very conscious of, but you also don't want get over your skis on that.
NESSAN BERMINGHAM: So there's a lot of work that's put into that and-- excuse me-- fortunately we have Ram, CEO of Korro, Vineet, CFO there, who are constantly thinking about this and looking at the trajectory of the company, the use of proceeds and how we think about the market. And I think you've got to think about the market both from a fundamental standpoint and also a technical standpoint. When I started my career, it was very much fundamentals.
NESSAN BERMINGHAM: Fundamentals are the driver that's already you need to focus more on. But what's become very clear is the technicals within the macro market are critical. So as you think about that timing, you also have to look at the experiences that we've all had where the market has provided a lot of capital to biotech and then sucked out a lot of capital from biotech, and then it's back in and it comes back out.
NESSAN BERMINGHAM: So it's really thinking about it and understanding the metrics around those sort of ebbs and flows in the marketplace, and building your company and also trying to time that so that you are actually able to raise the capital that you need to see yourself through. And that obviously, can come from BD, private financing, public. But I think people have rushed to go public now and that's great because you can access capital.
NESSAN BERMINGHAM: But back to the comment about being a pre-clinical stage company, the valuation you're going out with and just the sheer time sink when you were thinking about the reporting, the dealing with the investors and everything else, it should not be taken lightly because there are a lot of considerations as you're trying to build your company also.
KEVIN DAVIES: Excellent, Ness. Fascinating conversation, thanks so much. Alex, I'll you sign off.
ALEX PHILIPPIDIS: All right, thanks, Kevin. And just like that, we've run out of time for today's show. Thanks to Nessan Bermingham for joining us on Close to the Edge and I enjoyed the conversation as well. So meantime, please check out GEN Edge for exclusive news, interviews and analysis as well as the entire series of Close to the Edge videos. For Kevin Davies, I'm Alex Philippidis. Thanks for watching and goodbye for now.
ALEX PHILIPPIDIS: Take care.
KEVIN DAVIES: Bye-bye, everyone.
NESSAN BERMINGHAM: Thank you.
Segment:0 .
KEVIN DAVIES: Hello, everyone. Welcome to Close to the Edge, the new show from GEN Edge, the premium subscription service from GEN: Genetic Engineering News magazine in which we interview chief executives and, in some cases, executive chairpersons of pioneering biotech and pharma companies. We're really looking forward to this episode. I'm Kevin Davies, editor at large with GEN and the author of Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing.
ALEX PHILIPPIDIS: And I'm Alex Philippidis, senior business editor with GEN. We're up to episode seven of this series. Do you believe that? Our special guest today is Nessan Bermingham, a serial entrepreneur and veteran of venture capital who is executive chairman and former CEO of Triplet Therapeutics, executive chairman of Korro Bio, co-founder of both and chairman of F-star. Howdy, Nessan, and thank for coming on at Close to the Edge.
NESSAN BERMINGHAM: Hi. Thank you for the invitation.
KEVIN DAVIES: Nessan, serial entrepreneur seems to be a pretty handy description for your career. We're going to talk in depth about your past and present activities in the rest of the program. Your career began in a way with a PhD at St. Mary's Hospital in Paddington, which by sheer coincidence is where I did my PhD, perhaps a couple of years ahead of you before moving to the US. What prompted you to shift from biomedical research to the business side of the industry?
NESSAN BERMINGHAM: Well, within academia, a lot of discoveries were being made as we think about biology and our understanding, mechanistically, of some of the key drivers of disease. I think the actual conversion from basic science to actually human therapeutic applications really captured my attention very early on. And this real concept of being able to take very granular observations and think about how do them apply from a therapeutic application, therapeutic modalities as we think about what's the most appropriate therapeutic modality and what's the most appropriate patient population to go into.
NESSAN BERMINGHAM: So really, very quickly it moved from, after my post-doc at Baylor College of Medicine in Houston, Texas, moved into industry and starting to actually understand how do you convert these observations, actually, into human therapeutics.
KEVIN DAVIES: Right. The biotech companies you founded or co-founded, over the years, run the gamut from small molecule drugs and biologics to medical devices, diagnostics, gene editing. What, if anything, did these entities have in common or do you just simply seize exciting opportunities as they arise?
NESSAN BERMINGHAM: Really, many of them, I think-- a consistent theme across many of them are really around cutting edge technologies or cutting edge observations. And when we think about it, I think Intellia is, for example, a great example of that. Since around 2000, I've been looking at editing approaches such as zinc fingers, TALENS, meganucleases that have been out there. And in parallel to that, watching technology such as lipid nanoparticle delivery systems as we utilized for siRNA and ASOs in addition to overall chemical modifications for nucleic acid deliveries into human cells.
NESSAN BERMINGHAM: The challenge from an editing standpoint was probably twofold. So one, was very much, as we think about the right editing tool, what is the one that's most appropriate as we think about overall size, deliverability, overall effectiveness, when we think about the edit we're actually looking to do. And then secondly, as we think about the actual application of it.
NESSAN BERMINGHAM: So it's great to have a tool. But if you don't really have the application for it, there is nothing really that you can do. And I think the CRISPR-Cas9 system was discovered at a point in time where, really, there was this interface of a lot of different data systems out there, so a tremendous amount of work done by companies like Alnylam, like Ionis, at the time, now Isis Pharmaceuticals-- or sorry, I meant Ionis Pharmaceuticals.
NESSAN BERMINGHAM: And I really started to understand this concept of how does the cell respond to nucleic acid that's been delivered to it, how do we think about packaging it. And then we had this very effective cutter with the CRISPR-Cas9 based system that allowed us, really, to be very specific in targeting. So then from a therapeutic application standpoint, and this is one of the differentiators, I think for Intellia, was very much this idea about if we're going to make a permanent modification, we need to be sure that the target we're actually going after, once we modify it, that is going to be safe and very well tolerated.
NESSAN BERMINGHAM: And that really allowed us down to targeting initially TTR because there have been a tremendous amount of data from Ionis, from Alnylam around actual knocking that down above 85% to 95% over an extended period of time. That really addressed the disease and was not associated with deleterious impacts on patients, not from a target standpoint. It was absolutely critical as we thought about that systemic first in human clinical trial.
NESSAN BERMINGHAM: And we've seen this consistently across the company's-- Triplet, it's the same example. An observation made by multiple academics-- which we'll talk a little bit more about that. Korro, the same thing. Tal Medical, from the device standpoint, really cutting edge observations made by academic or researchers that were published and really then building on that for human therapeutics.
KEVIN DAVIES: Yeah. So you've been the CEO of several companies. You're not currently holding that role. But would you take it on again if the right opportunity arose?
NESSAN BERMINGHAM: I think for the right opportunity, absolutely. I think the area that excites me the most is really thinking about the strategic-- the concept for the company, the overall building the strategy, recruiting in the people into it. And I've been very fortunate with the people I've been able to work with over the past 20 plus years, and then really the initial execution of that strategy.
NESSAN BERMINGHAM: But there is a point, and again, Intellia is a great example of it, were really the strategy is built in and now it's really the execution of it. And when you think about-- a lot of people talk about entrepreneurial spirit versus sort of a maintenance and execution CEO. They're very distinct roles. And it's very rare that you can get a CEO, I believe, that really can actually cross that gamut.
NESSAN BERMINGHAM: I certainly cannot. I'm on the entrepreneurial side-- start the company up, get it up and going, strategy, first couple of business development deals, financing. But there's a point, really, where I am not the right person to be running that company anymore.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: And really that's where we see, in our industry, where you start to then see the CEO cycling through as the company itself actually evolves and needs different capabilities to enable them to execute.
KEVIN DAVIES: Yeah. He might have some advice for other executives about knowing when to hand over the reins. But we'll come back to that a bit later. Alex, over to you.
ALEX PHILIPPIDIS: Thanks, Kevin. Nessan, you mentioned the spectrum of specialties you've worked in. Is it more rewarding to work in therapeutics as opposed to diagnostics? Which area do you find more challenging and why?
NESSAN BERMINGHAM: So the reason why I rotate into therapeutics more than diagnostics is we've seen great and tremendous developments in the area of diagnostic. And I think we're on the cusp of seeing a lot more. So as we think about genomes being sequenced, the cost of the genome sequencing coming way down, as we think about snippets association or variant association with disease on very specific genetic backgrounds, we're learning a tremendous amount around that.
NESSAN BERMINGHAM: And I think we're really at the tipping point as we actually think about being able to actually pre-diagnose the potential for certain diseases-- cardiovascular, neurodegenerative and others. And so we're going to see a significant shift in that over time, I believe. The challenge, from my standpoint, is diagnosing something, for example, like Huntington's disease and not having a therapeutic there for that patient.
NESSAN BERMINGHAM: It clearly is important money, for instance, for the patient or the individual to know what may lie ahead of them. But once it's diagnosed, there's absolutely nothing you can do. And you, effectively, are sitting there watching that patient or that individual deteriorate over time and the actual common impact it has on their families, their friends, society overall. So really, as we think about the diagnostic aspect, it really is ensuring that we have therapeutics that we can very quickly bring to bear that are either, in some respects, chronic, palliative therapies or curative, which is where I believe we're moving to now as we think about these diseases.
NESSAN BERMINGHAM: And ideally, getting into these diseases, that what you're diagnosed, you're actually treating immediately or hopefully, curing it immediately. So that the actual long-term impact is not really being realized. And the actual continued deterioration, which leads to additional effective indications in those individuals that are not actually realized also.
ALEX PHILIPPIDIS: Wow. You've had two stints with Atlas Venture. You returned, the second time, in 2018 as a partner and you were a managing partner at Omega Funds. What are some of the challenges and rewards of working in venture capital? What brought you to the field and what made you step back from that kind of work more recently?
NESSAN BERMINGHAM: So I've been tremendously fortunate to work with Atlas for many years, off and on. And they really have backed all the companies or nearly all of the companies that I've been involved with. When we think about venture capital as a whole, it's a tremendously challenging and highly stimulating job. So when you think about the exposure that you have for novel discoveries, for the people that you get to meet, the companies you get to build and actually as you think about the growth and frankly, the death of some of those companies, we talk a lot about the successes, but the failures are actually equally as important as you think about what you learned from them and how that actually educates you as you think about additional indications or additional avenues to explore.
NESSAN BERMINGHAM: Atlas, from day zero, really, have been very much focused on starting companies and building those companies up to certain points. And they're not afraid of blue sky science and novel areas of exploration. A great example, companies like Alnylam, companies like deCODE and Exelixis. Just this concept of being able to-- and these, obviously, are older companies, that really at the time, absolutely, cutting edge and that really hasn't changed over the history of Atlas, over time.
NESSAN BERMINGHAM: I think that really speaks to a willingness in the venture, especially the seed venture community, to really go after these discoveries and actually figure out how best to actually utilize them. So you have a piece of a puzzle, but it's one piece of a multi-piece puzzle that you need to build. So really, it's how do you build that and that's the capability and the expertise and the challenge and the fun.
NESSAN BERMINGHAM: And rather than the difference from a venture standpoint to an operating standpoint is, at the venture, you have a portfolio of companies or ideas that you're actually working with. So your day can be extremely varied, and you can be moving from oncology into inflammation into neurodegeneration in the space of a 12 hour period or a 24 hour period. In operations, you're dealing with a very, in some respects, a very linear, strategic initiative or imperative within that organization.
NESSAN BERMINGHAM: And unlike venture, while it's linear from an application or a focal component within the organization, you then are dealing with the actual stratification or multilayered elements within that linear structure. So you obviously have your pipeline. So you've got basic research. You've got translational research. You've got clinical research, potentially, in there.
NESSAN BERMINGHAM: You've got, then, IP. You've got corporate, legal. You've got finance. If you're at fundraising, if you're a public company, obviously, you've got governance-- a very different governance structure publicly versus privately. You're dealing with independent or public market investors. So really, there's a tremendous breadth you have to deal with, but there's a central focal point that research and key tenant of that company in its own right.
NESSAN BERMINGHAM: So both are extremely challenging, but in very, very different ways.
ALEX PHILIPPIDIS: Mm-hmm. OK, Kevin, over to you.
KEVIN DAVIES: Thanks. We wanted to spend a bit of time talking about Intellia because, of course, hugely in the news in the last few weeks for all the right reasons. So you, obviously, saw the promise of genome editing, as you touched on a few minutes ago, pretty early on. What stands out when you think back about how you pulled the company together? There was a lot of jockeying, it seems, as some of the other big names in the field were getting ready to launch companies like Editas and CRISPR Therapeutics.
KEVIN DAVIES: So how did Intellia emerge from this morass?
NESSAN BERMINGHAM: Well, it was interesting. We spent a lot of time, prior to Atlas and also while I was in Atlas, looking at the editing technologies that were out there. So you had people like Keith Young, with the [INAUDIBLE],, really interesting discovery. The modularity of it was actually very intriguing as we looked at actually thinking about that application for human therapeutics. You had the meganucleases and clearly, had its own IP considerations and fraught with its own complexity as you thought about who owned the IP for that.
NESSAN BERMINGHAM: And you had [INAUDIBLE],, really the leader for editing overall with the zinc fingers. So we've been watching it for a very long time. But I think our challenge, very much, was they were not as-- either efficiency were a challenge, manufacturability, specificity. So really we were constantly looking to see what is the next sort of evolution of it. And obviously, Emanuelle and Jennifer's publication came out, which was just phenomenal to see that come through, and not a surprise.
NESSAN BERMINGHAM: It was a surprise at the time. In hindsight's, it's a wonderful thing. Bacteria, [INAUDIBLE],, very complex as you think about just the breadth that's actually in these systems. And to actually see an immune system come out from that was just wonderful to see. But really, then, it was like, well, how do you think about turning that into a drug?
NESSAN BERMINGHAM: And I was fortunate enough to know Shaun Foy and get [INAUDIBLE] Rodger Novak, which ultimately became CRISPR Therapeutics, and start looking at and evaluating opportunities with them and thinking about the development technology. But ultimately, myself and Atlas made the determination to start our own company which ended up becoming Intellia. My kids named it. So it became Intellia.
NESSAN BERMINGHAM: And really the difference between Intellia, CRISPR Therapeutics and Editas, it's like different flavors of ice cream. There are multiple different ways you can think about building a drug and how you actually want to go after things. And I think our concept, myself and Atlas, was very much-- we want to build a modular system that once you validate it in one indication, you can then very quickly just change your glide sequence.
NESSAN BERMINGHAM: And within that organ or in that system, that really allows you, then, to very quickly build a very broad pipeline across it. So unlike the sort of approach-- and we wanted to do that, I'm sorry, systemically. So really, it wasn't worth pulling cells out of the body, modifying and putting them back in, but actually, we were just injecting the drug into your body.
NESSAN BERMINGHAM: And this may give you a little bit of insight into how I think all of this is ultimately going to go, which I'll be happy to share with you in time. So that was the concept. So we looked at it and said, for us to be able to do that, there are elements we need to bring into the organization. So obviously, the people we hired were very fortunate, John Leonard, Dave Morrissey, Tom Barnes, Jennifer King-- as we think BD, just really as we think about overall execution, just was great from an execution standpoint.
NESSAN BERMINGHAM: But as we thought about delivery vehicles, bringing in lipid nanoparticles from a delivery standpoint, which Novartis have been working on and was part of our partnership with them, that really was a game changer for us. Because it gave us this packaging system, or think about it like your car. It gave us a car that we could fill with stuff, deliver it to the body and that would hone in to the right cell type for us.
NESSAN BERMINGHAM: So that was really important. The other aspect was really around the manufacture identity modifications and the concept of using RNA. So really this idea about-- unlike using an AAV, for example, our view was we wanted to put the system in, edit, but then it really just to disappear. Because our concern was anything that stays in the cell for an extended period of time is just going to get itself in trouble.
NESSAN BERMINGHAM: So it may just do some off target, and it may take a while for it to do it. But there is a possibility this will happen. So we wanted something that would go in, edit and then disappear. That led us down the RNA avenue also for it. And then the target. TTR was the first target because of that validation that really Ionis and Alnylam had actually shown with their ASOs for Ionis and siRNA from Alnylam.
NESSAN BERMINGHAM: And once we had that validation from a safety tolerability et cetera standpoint, then you really could start to expand into a whole multitude of additional indications that the company's actually doing now.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: The partnerships with Regeneron, and then other things that we did, also was then to allow us to really start expanding to novel targets. And this really led into, not from Intellia to Triplet, but it's this idea about, OK, so you have modalities. And what we're seeing in our industry is these modalities are being commoditized extremely quickly. So if you look at now small molecules, antibodies, ASOs, si's, and we're even not seeing in the editing space, we're seeing the commoditization of these extremely rapidly.
NESSAN BERMINGHAM: So the question now is where are you directing them to? And that's where we started, then to think about how do you identify novel targets? How are they validated as we think about human therapeutic applications? And that led into this whole other area that we actually started thinking about and building up around.
KEVIN DAVIES: I love the serendipity that's involved, sometimes, in putting these companies together. You mentioned John Leonard who succeeded you as CEO. My understanding is you met him in the queue at the salad bar at an Atlas retreat to Florida. He was thinking of retirement, but you obviously saw something differently.
NESSAN BIRMINGHAM: Absolutely. So that's exactly where I met him. And then I flew up to Chicago to meet with an academic up there, and John, graciously, found time to have lunch with me. We sat down and started talking about it. I sent John some papers subsequent to that, it really kind of stimulated his interest. And what was great about John was you had somebody in John or have somebody in John who a lot of experiences when you think about the clinical development aspect, a lot of experience as you think about moving beyond clinical into commercial, as you think about manufacturability, so overall CMC.
NESSAN BIRMINGHAM: And I'd never managed hundreds of people. I'd barely managed five. So I think from an organizational design standpoint, by the time I left, we were over 200 people.
KEVIN DAVIES: Yes.
NESSAN BERMINGHAM: So really, John was very well experienced in managing very large numbers of individuals and how best to actually think about-- we talk about culture a lot. How do you think about that, especially when you're building 200 or 300 people over a two year period? And what people forget, for Intellia was we went from, literally, a sheet of paper in Atlas' offices, all the way through to a publicly listed company in less than two years, multiple rounds of financing, two large pharma deals, TTR already set up in place.
NESSAN BERMINGHAM: So really, we moved extremely fast. And ensuring culture, ensuring direction, ensuring this cohesion across the organization was absolutely critical. And really having people like John, would have that experience in large organizations, was obviously very helpful as we thought about being able to execute appropriately.
KEVIN DAVIES: You've referenced the ATTR amyloidosis target and of course, the results of that very initial clinical trial on a handful of patients were published a month or two ago in the New England Journal of Medicine and received, I mean, ecstatic reviews from pretty much all corners. You were intimately involved in setting up that program. Are you kind of, in any way, pinching yourself at how promising and how good those initial results were?
KEVIN DAVIES: It doesn't always go according to plan like that.
NESSAN BERMINGHAM: This is true. And I think that it was-- I always thought it would be binary. That either you really would see a very limited amount of editing taking place and that frankly, it's not a drug. Or you would actually get this level of editing that you were seeing. And when we look at the non-human primate studies, and I think this is one of the things that really is very helpful for these types of modalities or nucleic acid base drugs.
NESSAN BERMINGHAM: They tend to be directionally, very predictive. So what we were seeing in the NHP's, from a level of knockdown and the durability of that knockdown from a single injection, really was extremely compelling. Now when you talk about an NHP, you're talking about a very small animal that you're dealing with. And then you've got, obviously, increase that as you think about the overall size of a human, the stage that you're going in.
NESSAN BERMINGHAM: But that data, I think, really was what crystallized it for us. And the other aspects that was very helpful was we weren't doing this in a vacuum. So not only were we generating our data, but there's always the potential in the company for sort of bias in data interpretation. You almost pre believe what the data should show you, so you're kind of coming at it with that lens.
NESSAN BERMINGHAM: What was great here was we had all of these other companies out there and all these academics that also were publishing and that was just continuing to increase our overall level of confidence in there. And with the two partnerships between Novartis and Regeneron, they were doing their own work, which also was validating the work that we were doing. So it was reassuring. And it's rare that you have this opportunity that you'd have all of this different data coming through that was validating the data you were building internally also.
NESSAN BERMINGHAM: And that really kind of gave us a sense-- it took us a little longer than I'd hoped, to be honest. And I think for investors, there's always this sort of balance. When do you take a company public and sort of expose yourself to the public markets and the expectations that comes with being a public company? When do you do that knowing, as data is coming out in the timeline, two data, these pre-clinical stage companies, it can take a while to get into the clinic and really generate that meaningful data from a public market standpoint?
NESSAN BERMINGHAM: So we got a lot of push back from investors, over the years, around our approach at the time. But what was very clear, and this was really one of the philosophy that I talked to Atlas about-- I talked to John about, when Tom Barnes was in, Dave Morrissey and the rest of the team-- we were very clear, we're building this for the long-term. We're not looking for a quick entry to human clinical trials, but we're going to build it right.
NESSAN BERMINGHAM: We're going to take the time to do it. And the data now speaks for itself, which is just phenomenal to see.
KEVIN DAVIES: But you're not just building a single company in a way you and CRISPR and Editas, I mean, you're building a paradigm. So I'm curious, is that much kind of-- although, technically, they are competitors of yours, is there, to some extent, some collaboration or some meeting over a beer to just kind of compare and contrast and talk about concerns that are facing the whole industry, not just one company?
NESSAN BIRMINGHAM: Absolutely. I think, that as we look at the venture groups that sit behind all of these companies, they all interact together. They all go all together. And they've been doing this long enough that they actually know the ebb and flows which you think about building a company and a novel technology. From the CEOs and CSO standpoint, on the whole, I wish I could say it was the case for every company, it's not.
NESSAN BIRMINGHAM: On the whole, people do get on very well and they do have conversations. They grab a beer. They will sit down. They'll talk about things, not what's very important. Where we saw the importance of it and the criticality of it really was when CRISPR-Cas9 first came out. The ethical considerations were not minor. And you had ethical considerations and obviously, this is something you've written about and I think it's really important to capture that people not to forget what was going on at that point in time.
NESSAN BIRMINGHAM: And you also had, as you thought about security, biodefense, bioterrorism considerations that were also out there at the time. So collectively, ourselves, Intellia, Editas, CRISPR, we worked to be consistent in our messaging internally and our philosophy, ethically, internally and also externally. So that we were very clear about how we view things, how as companies, we were going to drive this technology and sort of what the line was for us as we thought about not crossing it.
NESSAN BIRMINGHAM: And clearly, there was a lot of discussions from ethicists, from patients-- very important voice to actually hear from. What we classify as disease, others may not classify as a disease and vise versa. So having inputs on that side was absolutely critical. So yes, we see it. I think, though now, as you look at it, we've crossed the rubric somewhat as we think about these technologies.
NESSAN BIRMINGHAM: And it's become now so competitive that I fear that those discussions are becoming less and less. So that cohesion is fraying a little bit. And I think that, in part, is a dearth of targets or applications as you think about these technologies. So you tend to see a lot of them chasing the same targets. So it's effectively, for these types of therapies, whoever gets to market first really is going to be able to take the majority of that patient population, and because we're really not into the zone of thinking about curative medicines, which is a place we've just never had to do before.
NESSAN BIRMINGHAM: So TNF office, you could be the fifth one, if there is an advantage from a dosing paradigm around it or a safety paradigm around it. That's certainly allowed entrance into the marketplace. We're not going to see that, I think, with genome editing and gene therapy.
KEVIN DAVIES: OK, interesting. All right, Alex.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. Listen, let's digress for a minute and look beyond the office and beyond science. In your spare time, as I understand it, you like to do a bit of running.
NESSAN BERMINGHAM: Yes. So there are a few sports I love to do. I love to run, trail running, specifically. I'm a big downhill mountain bike or snowboarder. I've just taken up kite surfing. And I just bought my first dirt bike, which my wife is quite scared of. So yes, I love that. I think there's an element, for the running-- so you ask about the running.
NESSAN BERMINGHAM: There are two aspects to it. Our world, today, is so connected. It's extremely challenging, I find, personally, to be able to step away from it. So your iPhone or your phone is very close to you at all times. You access the computers. I don't wear an Apple Watch, but I watch people who do. It pings during meetings and they look down to see what the text is.
NESSAN BERMINGHAM: So this concept of actually being able to find time to actually let your mind sort of chill out a little bit and mull over some problems, I think, is absolutely critical. So the running really came out from, I would say, over stressed, really starting to see its net impact on me personally, and that I needed to take up some sports to sort of relieve that.
NESSAN BERMINGHAM: Running was one. Boxing, actually, was another one that I took up. And the boxing, the interesting thing, it's very similar to snowboarding or downhill mountain biking. It's 100% concentration on what you're doing at that point in time. There's nothing else can come in when you're doing it or something bad is going to happen. With running, it's the inverse.
NESSAN BERMINGHAM: You can actually get a cadence in place. Your mind, then, can actually start to free itself up. And what I found is that really taking the time to go out and run allows me to actually think about challenges, issues, areas of focus that, then, I come back from and I'll actually look to implement or expand on. So it really allowed me or allows me to actually really just take time to think about things. And the extreme is my wife keeps telling me that I do it, now, to get away completely for days on end.
NESSAN BERMINGHAM: It's now getting into ultra runs. So going out into Patagonia for four or five days. I was supposed to go out to Atacama at the end of September, but that's just been pushed to next year. And I run rim-to-rim-to-rim at the Grand Canyon every year. All of these things, really, to have these really extended periods of time just to really allow yourself to really kind of just think.
NESSAN BERMINGHAM: And I find that, for me personally, it's extremely helpful, both personally and professionally, as I think about my life overall. And one of the themes in every company that I've tried to instill in is work, but play. So this work-life balance is absolutely critical. That this idea of 24/7, no one can maintain that and you're much better and more useful to the organization if you're healthy.
NESSAN BERMINGHAM: You've got that good work-life balance, you're very happy with your personal life overall. That makes you a better person and a better ability to think about what you're doing rather than being an ultimatum where you're just cranking stuff out, regardless of what it actually is.
ALEX PHILIPPIDIS: A few years back, running in Argentina, you came in the top third while half your competitors failed to even finish, which I thought was pretty amazing. So you're still running these ultra marathons and take--
NESSAN BERMINGHAM: I'm trying to. My knees are getting worse as I'm getting older. I think that they and my diet and my expectation from sleeping on the ground is getting harder and harder to do. But yes, I still really enjoy doing that. And again, I think there's back to nature and just having clarity of mind. Personally, I just think is so, so helpful.
ALEX PHILIPPIDIS: But the knees--
KEVIN DAVIES: Kite-surfing might be easier on the knees, I suspect. But let's get back to sort of two of your main occupations. Now let's talk about Triplet Therapeutics. I remember handling some of the first Triplet repeat expansion disorder papers when I was a rookie editor at Nature back in 1990, 1991. These are the sort of mysterious sort of concertina like expansions behind diseases, disorders like fragile X syndrome, myotonic dystrophy and then later, of course, Huntington's disease and spinocerebellar ataxia.
KEVIN DAVIES: I've lost touch with this field. How many of these genetic disorders are there and how is Triplet's-- how do you conceive of a company and an approach that can possibly rein in these and treat these devastating disorders?
NESSAN BERMINGHAM: So the numbers keep growing. It's over 50 right now. Their role in disease, actually, seems to be increasing as we're learning more and more about them. So to back up a little bit, when we think about science and we think about human therapeutics, there's a certain level of arrogance, I think, we all have. I remember when, and you probably call it better than I did, before the Human Genome was sequenced, everybody kind of turned around and said there must be at least 120,000 genes in there to make up how complex we actually are.
NESSAN BERMINGHAM: So if we compare ourselves with nematode, or [INAUDIBLE] fly, right, there's got to be over 100,000 of these things.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: And they go my sequence and they come out and they say, at the time, we think it's between 20 and 25,000. And it was almost like an insult. People kind of do step back. Because there's no way it could be the case. You must have missed 75% of the genes out there.
KEVIN DAVIES: Impossible match.
NESSAN BERMINGHAM: Right. So I think that there are these things that we look at and we have these preconceived notions. CRISPR-Cas9, actually, is another great example. This is the only one-- this is the only system out there. And then once we know what we're looking for, actually, we've seen this whole just portfolio of these systems that are just amazing, that nature has actually built for us. And now we know what we're looking for.
NESSAN BERMINGHAM: So when we think about the repeat expansion disorders-- and again, you're absolutely right. So if I take a cell from you or look at your DNA, and something like Huntington's disease, I'll see about 20 of these repeats. And when we talk about a repeat, it's like a word the repeated 20 times in a row. So most people are going to be somewhere in that sort of 15 to 30 repeat sort of range or 25 repeats. But there are individuals where the repeats are actually longer.
NESSAN BERMINGHAM: So let's say instead of having 20, they've actually got 40 of them. And what that 40 repeats does is it drives disease. And for a long time, we'd assumed that each one of these indications of things like myotonic dystrophy, Huntington's disease, fragile X syndrome, again, over 50 of these, that each one of these genes, with this repeat expounded in there, actually was a single disease-- a single driver of the disease.
NESSAN BERMINGHAM: And that as we think about treating it, we need a bespoke therapy on an indication of medication basis. So that was our assumption. And that was the assumption stood for a long time. So you're right, since the 1990s, we'd assume this. But we had data out there that when we looked at patients-- and I'll talk about Huntington's disease, but it's not just Huntington's disease.
KEVIN DAVIES: Yeah, yeah.
NESSAN BERMINGHAM: When you look at patients, you actually can identify two patients that were born with the same number of repeats. So let's say it's 40, and then you track them over time. And one patient-- excuse me-- has a age of onset of 20 years of age and the disease very rapidly progresses. And then the second individual is an age of onset of 60 years of age, and the disease does not progress particularly well.
NESSAN BERMINGHAM: So even though same DNA effect or impact, different rates of onset, different rates of progression. So we knew background here was absolutely critical. The genetic background that you have was absolutely critical. Some beautiful work done by a number of academics out there, Vanessa Wheeler being one of those, Jim [? Kassala, ?] multitude of others. And what they looked at was what is doing that? And what these people found or these investigators found was, well, if I take a cell out of the body from the reaches of the brain that are impacted, for example Huntington's disease, and look at that gene, what I see is that even though they were born with 40 repeats, when they actually died that repeat now has grown to, for example, over 1,000 repeats.
NESSAN BERMINGHAM: So over the life of that individual, that DNA actually is quite unstable and that repeat is getting longer and longer and longer. So then they did a lot of work to figure out what's actually driving this. They published all of this data. And it's a pathway called the DNA Damage Response Pathway that basically is driving it. And as Triplet, we stepped in or what became Triplet, we stepped in and actually looked at the pathway.
NESSAN BERMINGHAM: And said, OK, let's look at the number of genes that are associated with this. What's the right point of intervention? What's the right therapeutic modality? What's the right indication as we think about targeting it? Now what actually ended up happening was from a mechanistic standpoint, the system actually is very, very simple. So if you think about DNA, DNA is transcribed, makes RNA, RNA then into the protein.
NESSAN BERMINGHAM: And when you think about one transcription is taking place, you've got double-strand DNA that basically opens up, it gets read and then it refolds. Well, when it closes or makes double-strand DNA again, if you have a length of repeats that are, let's say, 20 repeats, its ability to actually become double-stranded exactly correctly is relatively straightforward. Think of two pieces of Velcro, very short. You lay one on top of the other one, they'll bond together flat.
NESSAN BERMINGHAM: But when it goes above a certain length, when that DNA goes to [INAUDIBLE] and becomes double-stranded, it actually doesn't do it properly, and you see these kinks form. Very similar down, again, to two very long pieces of Velcro that you're trying to put together, you'll see these little bleb that form out of them. And that's really what's happening. These bleb form.
NESSAN BERMINGHAM: The DNA Damage Response System goes to repair them. And basically, it cuts the flat piece, pulls that bleb flat or straight and then fills it in. So whatever's in that DNA and that bleb, has now been actually added to the DNA. And over time, this accumulates, accumulates and it increases the rate at which it does it over time. So at Triplet, we looked at antisense oligonucleotides and siRNAs, depending on the tissue we wanted to targeted.
NESSAN BERMINGHAM: We looked at a multitude of genes within our targets, within this pathway, multiple mRNA models and then ultimately, that led us to and nominate a compound called TTX-3360, which is moving into IND studies or clinical trials. And next year, on Huntington's disease, we've started natural history study in Huntington's disease and also [INAUDIBLE] to specifically look at this aspect of it.
NESSAN BERMINGHAM: And unfortunately, again, with Triplet, there was a lot of work that other people were doing that validated this target and validated this pathway, which was great to see. But I think this is probably the first time or one of the first times that patients, themselves, actually identified the mechanism. So really going back to those two patients, one 20 years old who got the disease and one was 60 years old, if you build enough of those individuals, enough numbers in both of those groups, you actually can look to see what's difference in the genome between them, between the groups, and the same within the group.
NESSAN BERMINGHAM: And really it was that work in those patients and then validation with animal studies that identified this pathway and ultimately, led us to this point. So it's really just phenomenal human genetics at its finest.
KEVIN DAVIES: Yeah, yeah. How are you going to-- most of these disorders, certainly Huntington's and many of the others that we briefly mentioned, are neurodegenerative disorders. What are the added challenges of-- you've identified a very plausible mechanism, you've still got to deliver it to the brain or wherever. So how are you going about that?
NESSAN BERMINGHAM: So that's a great question. I mean, delivery-- people, I think, underestimate some of the challenges of getting a drug to the right side at the right point in time. When we look at other treatments that are very similar to this approach or other ones that are in clinical development today-- so Spinraza already approved, spinal muscular atrophy. And then there's a multiple ones for Huntington's disease in clinical trial too, which recently failed clinical studies.
NESSAN BERMINGHAM: They basically, injected into the spinal cord. And it's called intrathecal delivery. So it's basically inject the drug in spinal cord. And for those of you that might know, in the brain of the spinal cord, you've got this fluid. And basically, that fluid is just flowing and bathing the whole system. So the thinking being if you inject it in, the flow will pick it up.
NESSAN BERMINGHAM: It'll disperse through the fluid, and that flow of the fluid will, actually, deliver it to the cells. Great in concept. Practically speaking, that's not what actually happens. So there are some real challenges as you think about the actual flow of the CSF. And in addition, in some of these patient populations, specifically, the flow gets challenged or it's not as a regular flow because of the nature of the disease itself.
NESSAN BERMINGHAM: So we took a slightly different approach. So since the 1960s, people have actually been just injecting drug directly into the brain. So there are systems in there that you can put a very small device that is it sits just underneath the scalp. It's a bit like a little rubber balloon, tiny. It's about the size of a quarter or a dime. Out of it is, effectively, this little-- thing of it is a straw-- that goes down into the CNS and delivers your drug to where you need it to go.
NESSAN BERMINGHAM: So when you think about delivering it, all you're doing is injecting through the scalp into this reservoir, and then the drug itself then goes down through the catheter and into the actual CNS. So we effectively opened up that as a delivery avenue for antisense oligonucleotides. So we've done a tremendous amount of work in it. We've identified the right ICD devices from a delivery standpoint, the delivery metrics now, which we've actually published around.
NESSAN BERMINGHAM: So really, we started looking at IT because everybody else was doing it. But we found that it wasn't doing what we needed it to do. That led us into ICV and other avenues. ICV really shows to be very effective as we think about delivery. And when we talk to patients-- so there's always a concern. If you're talking about putting a device in, and it's a very simple device-- but when you talk about putting a device in, you need to talk to patients and understand, as they think about their lives and their considerations, concerns, how will they respond to it.
NESSAN BERMINGHAM: And what became very clear, quickly, was two things. One, IT delivery is just a painful, uncomfortable thing for a patient to have done to them. So here you've got this disease. You're going to take this route of administration because the disease is terminal, effectively. But it's not a good way to deliver a drug from the patient standpoint. And then secondly, when you looked at the actual ability to deliver at home, this opened up the opportunity to actually potentially do that.
NESSAN BERMINGHAM: And that meant, as you think about the impact on your life, it has a lot less impact on life versus having to go to a facility where are you going to get this IT and delivery. But before we had the conversation, it really was a very big concern of ours. How were physicians and patients respond to ICV? And we spend a lot of time working through that and educating, also, as we think about the application here.
KEVIN DAVIES: All right, Alex.
ALEX PHILIPPIDIS: OK. Thanks, Kevin. Just checking on something I think you said a couple of minutes ago. Lead candidate TTX-3360-- I know the company's talked about preparing to submit an IND by the end of the year. Did I hear you right that the clinical trial is set for next year to start? If that would be--
KEVIN DAVIES: Right. So--
ALEX PHILIPPIDIS: OK.
KEVIN DAVIES: I think that there were a couple of things in consideration around that. As I mentioned, there were two drugs that failed effectively in human clinical trials recently for Huntington's disease. And it was a real disappointment, I think, to the community as a whole as we looked at target-- they were targeting actually the HTT gene or the HTT RNA in its own right. And for all of us, I think, we took a step back and said, OK, what do we learn from this?
KEVIN DAVIES: So one was from Roche who had partnered with Ionis and the second one was with Wave. And when we looked at some of the considerations around it, there were elements from a biomarker standpoint that they were looking at. There were elements from an imaging standpoint that we were looking at. And back to that drug distribution and time of intervention, when do you actually intervene in these patients?
KEVIN DAVIES: So there was a lot of data, and there's more we believe that that Roche would likely be putting out over the next few weeks into the next couple of months, to actually help us think about how do you run a clinical trial here? How do you think about these class of drugs from an intervention standpoint? Triplet, very different target, very different mechanism. But we would be foolish to not look at that data and actually listen to what it's telling us.
KEVIN DAVIES: And that's really, in part, what the company did. So we took a step back and said, OK, a lot of data has come through. We need to actually process it. We need to talk to advisors around it. We, frankly, need to talk to the FDA and the regulatory authorities about it and how they think about the implications around this. And there's more data that's yet to come out.
KEVIN DAVIES: So when we think about our patients, one of the things we want to be absolutely clear is that the drug that we're bringing into the clinic, from a safety, tolerability, and potential for therapeutic intervention, that we've done as much as we can. So I look at and say, if I'm not willing to give it to a member of my family or myself, that I should not be taking this drug into the clinic.
KEVIN DAVIES: So that sort of made us take a step back and say, OK, we're delaying. We're delaying by two quarters to ensure that we've ticked all the boxes. And again, different mechanism, different sequencing, different route of administration, but you're delivering a nucleic acid to the CNS. So let's ensure that before we get into human clinical trials that we've actually done what we need to do from a safety and tolerability and frankly, dosing paradigm also as we think about moving into human clinical trials.
ALEX PHILIPPIDIS: Mm-hmm. Beyond the challenge of delivery, which you've got into, how do you prioritize one disorder over another when there are dozens of related disorders?
NESSAN BERMINGHAM: So great question. There's almost-- it's like you look at it and say, to your point, this mechanism looks like it may be involved in, and if not, all 50 plus repeat expansion disorders, at least a large number of them, sponsored by [? Taxius, ?] myotonic dystrophy, multiple ones. So there are a number of criteria that when we founded the company, we sort of put in place and said, OK.
NESSAN BERMINGHAM: As we think about that first in human clinical study, that is the determinant. It's a bit like the TTR discussion for Intellia, you get one kind of shot when you start talking about these sort of platform approaches or these targets. And really, if you don't maximize the probability of success for that, then your ability to go into these additional indications become more and more challenged.
NESSAN BERMINGHAM: So you're balancing your first indication, but also you don't want to be just a single indication company. You want to make sure, too, that you've got other indications that are actually coming behind it, that you will continue to learn from or optimize around. So Huntington's disease was chosen for a number of reasons. Excuse me. The amount of data out there, on Huntington's patients as you think about progression, as you think about this mechanism from a disease standpoint, as you think about the sheer knowledge-base of the patients that have this disease is unprecedented.
NESSAN BERMINGHAM: So as we looked at it, that patient population, the depth of data, the depth of experience from a clinical standpoint, the depth of patient education and awareness of disease really made it a very clear, first clinical application. Very close behind it, frankly, is myotonic dystrophy. And then you're getting into the spinocerebellar ataxias. So that was the reason why, from a Huntington's disease standpoint, that was the first one.
NESSAN BERMINGHAM: Now you're right, it did bring its challenges from a delivery standpoint. Whereas as you think about things like myotonic dystrophy, you've got groups like Avidity and others that have are utilizing systems, now, for delivering into the muscle. And [INAUDIBLE] Therapeutics is another great example of it as you think about that delivery. But as we think about that patient population, disease progression, size of the repeats, Huntington's disease made the better sense as first in human clinical study for us.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thanks, Alex. In the last few minutes, Ness, that we have you, we'd love to talk about one of your other new and current ventures, Korro Bio, an RNA editing company. It doesn't get much hotter than this, does it? RNA is halts and gene editing or variations, thereof, is also incredibly hot. The company's tagline, I looked it up this morning, is "edit the message, rewrite the future". I like that.
KEVIN DAVIES: What sets this company apart? And did your kids named this company as well?
NESSAN BIRMINGHAM: No, one of the other co-founders, Andrew Fraley, named us. We're back to this question about understanding disease mechanism and targets. And what's become very clear is genetic background is a critical driver. Frankly, the environment in which you live can be a critical driver also, if you think about disease, disease onset, disease progression.
NESSAN BIRMINGHAM: So as we think about permanent modifications, I'm reluctant to do permanent modifications on genes that actually you don't know if there would be a detrimental impact on these patient populations. So as we think about one aspect of what Korro does is it's transient. And there's a lot to be said for that. We figure out a lot about drugs in phase four clinical studies because you've now opened up to a much larger-- when you think about a clinical trial, you've got enrollment criteria.
NESSAN BIRMINGHAM: People got to fall within that enrollment criteria. Whereas in a phase four or once it's approved, there are really no hard and fast criteria. We leave it to physician's discretion as they think about prescribing a drug. So when we think about it, you really want to go in and do something that's transient that you can switch off. You can start to see everything associated with it.
NESSAN BIRMINGHAM: But then you start to look at some of the things that we'd hoped you could do with CRISPR-Cas9. So when we started Intellia, when CRISPR started [? medi tasks, ?] you may recall, we talked a lot about the Swiss army knife from a therapeutic modality. And that really-- this is you could do everything with it. But the reality is it's a bit like a hammer. You've got the claw and then you've got the face of the hammer, but that's kind of it.
NESSAN BIRMINGHAM: It could do two things, pull a nail out, knock a nail in. That's kind of it. It's very effective at doing that, but it does two things. When you look at a lot of the disease driving mutations or variants driving disease, they really are single-base changes. So now you're back to, well, how do you actually modify that? And how do you rescue it? So really you want to go in and be really precision medicine.
NESSAN BIRMINGHAM: Go in and actually make one change at one target site, no halo effect. Korro, the technology, it uses a system that's actually already in your cell, which I love. So we're using something that's already in your cell that does this, co-opting it to do where we want it to actually do it. So that's one thing that it does. And then there are other aspects that they're working on around endowing functionality as you think about super proteins functions or making them more effective at doing what you want them to do.
NESSAN BIRMINGHAM: Or getting rid of them if that's what you want them to do. So the way the company has been built is thinking about expanding beyond what we thought about as sort of rare orphan diseases into much, much larger patient populations that allows us to actually, then, be very specific and very targeted in our treatment. With, again, a nucleic acid that from a manufacturability standpoint, cost of good standpoint, delivery standpoint is a lot easier as we think about delivery on those factors than some of the other approaches that are being utilized today or are being explored in the clinic today.
KEVIN DAVIES: Can you think of this technology as base editing on RNA rather than DNA?
NESSAN BERMINGHAM: Yes, I mean, that's a great way to do it. And I think, as we think about more and more targets coming through, the speed at which you can actually design these and direct them is extremely fast. So unlike, we go back 20, 30, 40 years ago, that if you've got a target and you wanted to validate that target from a disease standpoint, you're making a small molecule against at that point in time. Right now you might talk about moving into other systems. But it took a very, very, very long time to actually design and validate.
NESSAN BERMINGHAM: If we think about what we did in Triplet, we moved from again a piece of paper to our development candidate in, I think, it was less than two years. Triplet was great execution, don't get me wrong. But really, it was around the flexibility of these systems, the vendors that are right there to allow you to actually build these sort of, think of them as being LEGO blocks that you're putting together, that are there to allow you to do this.
NESSAN BERMINGHAM: You do it extremely fast. Your screens are fast. And from a cost standpoint, on a relative basis, they're actually very cheap to manufacture and to actually then go and test in animal models. So our speed is much, much better than it's ever been before. Now its target. How do we identify novel targets?
NESSAN BERMINGHAM: How do we think about being able to actually walk our way through with them to identify what's the most appropriate one from a safety, tolerability, and efficacy standpoint?
KEVIN DAVIES: Are you going to answer your own question? What are your really telling us?
NESSAN BERMINGHAM: So I think we're at a fascinating point now. So we're back to how do we think about genome sequencing, patient records, medical records, disease tracking, backgrounds under which these genetic backgrounds are being expressed on to us to be able to glean and manipulate them. So you look at all of the groups out there, the UK Biobank, all the big population sequencing studies that are going on right now and computational power.
NESSAN BERMINGHAM: So if we think about of the binary computational structures that we've had historically, they really were limited in the complexity of what you could actually ask and the data that you could actually put into them. We're now moving beyond that into things like quantum computing. And what that allows us to do is you've got patient data that's coming in and population data that's coming in.
NESSAN BERMINGHAM: So cost of sequencing has come down, screening times is a lot faster. So you've got all that data coming in. We've got all of these computational systems now, as we think about quantum computing, as we think about machine learning, artificial intelligence. We've got these therapeutic modalities that we can build extremely fast and that are very specific and as we think about the modifications around them.
NESSAN BERMINGHAM: And then we're getting better as we think about what are we looking for in animal models or in vitro as we think about cellular systems. So we're back to-- again, when CRISPR-Cas9 came out, it came out at the perfect time. We've got these all now coming together. We're starting to get real, new insight into disease and pathways that actually are directly impacted.
NESSAN BERMINGHAM: So what do I think this is going to go? I'm going to ask my own question, right. If we think about things like TNF alpha, inhibitors or some of the systems that were-- Humira, great example. When we think about when that was first approved, it was approved in an environment where there was not enough manufacturing capability in the world to actually meet the need.
NESSAN BERMINGHAM: And when you thought about actually getting the treatment, you had to go into a physician's office. Fast forward, whatever it is, x number of decades. And now you have it delivered to your door. We have overcapacity. We have beyond Humira into now others like Cosentyx as we think about novel targets and novel areas within pathways. Delivered to your door, self inject, you're done.
NESSAN BERMINGHAM: So when we think about these distribution systems, when we think about these fill finish, these manufacturing, the simpler the modalities get, the more practical it is to actually start building these systems in place. So I think we're going to get to, maybe not in my lifetime, but I think we're going to get to a point whereby genome sequenced, we do the analytics around as we think about the environment in which you live, what diet, how you live your life and we start to actually now really design and develop drugs specific to you.
NESSAN BERMINGHAM: That's similar to a book, we can print in real time, fill finish it and ship it to your door and it's a self injector. And if you think about all of the disparate components you need to enable you to that, they're actually there already. It's now just which targets. And to me, that's what it comes back to. Target, target, target.
KEVIN DAVIES: Yeah. How do you make this a commercial success? Ness, you had a good series A, I think, it was last year raising just a little over $90 million. Are you looking for more of the same or do you start to think about going public? Or there was a company, in your space, Shape Therapeutics, just hot off the press announced a major deal with big pharma companies. So which of those options might you explore?
NESSAN BERMINGHAM: I think that pharma deals are important because of the capability and skill sets, the bandwidth that that provides you. And when you're building a company in real time, it can be very difficult for you to really span the full gamut of applications, especially when you're talking about platforms. So when you look at the partnerships, I think that they are actually pretty important around doing that.
NESSAN BERMINGHAM: When you think about the capital, it always takes more capital than you think. I remember when we did the $15 million series A for Intellia and we had the Novartis upfront payments. And I was like, oh, this is going to give us capital for, I kind of [INAUDIBLE],, but let's say next five years. I think we burnt through it in like 18 months. So the reality is these are very expensive because of the verticals that you actually need to put in place.
KEVIN DAVIES: Yeah.
NESSAN BERMINGHAM: The issue that you have is those capital needs are really huge for these platform companies, and you need to build extremely fast. So you're constantly thinking about those capital raises, the milestones that actually justify bringing in new capital. And you're balancing bringing new capital in with valuation. Because obviously, your investors are looking for a rate of return that you just need to be very conscious of, but you also don't want get over your skis on that.
NESSAN BERMINGHAM: So there's a lot of work that's put into that and-- excuse me-- fortunately we have Ram, CEO of Korro, Vineet, CFO there, who are constantly thinking about this and looking at the trajectory of the company, the use of proceeds and how we think about the market. And I think you've got to think about the market both from a fundamental standpoint and also a technical standpoint. When I started my career, it was very much fundamentals.
NESSAN BERMINGHAM: Fundamentals are the driver that's already you need to focus more on. But what's become very clear is the technicals within the macro market are critical. So as you think about that timing, you also have to look at the experiences that we've all had where the market has provided a lot of capital to biotech and then sucked out a lot of capital from biotech, and then it's back in and it comes back out.
NESSAN BERMINGHAM: So it's really thinking about it and understanding the metrics around those sort of ebbs and flows in the marketplace, and building your company and also trying to time that so that you are actually able to raise the capital that you need to see yourself through. And that obviously, can come from BD, private financing, public. But I think people have rushed to go public now and that's great because you can access capital.
NESSAN BERMINGHAM: But back to the comment about being a pre-clinical stage company, the valuation you're going out with and just the sheer time sink when you were thinking about the reporting, the dealing with the investors and everything else, it should not be taken lightly because there are a lot of considerations as you're trying to build your company also.
KEVIN DAVIES: Excellent, Ness. Fascinating conversation, thanks so much. Alex, I'll you sign off.
ALEX PHILIPPIDIS: All right, thanks, Kevin. And just like that, we've run out of time for today's show. Thanks to Nessan Bermingham for joining us on Close to the Edge and I enjoyed the conversation as well. So meantime, please check out GEN Edge for exclusive news, interviews and analysis as well as the entire series of Close to the Edge videos. For Kevin Davies, I'm Alex Philippidis. Thanks for watching and goodbye for now.
ALEX PHILIPPIDIS: Take care.
KEVIN DAVIES: Bye-bye, everyone.
NESSAN BERMINGHAM: Thank you.
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