Ep. 108 - Rethinking Discovery: Chris Hollowood on Causal Biology and Syncona’s Strategy

This is the Biosentri Show. Brought to you by Biosentri Grand Rounds. Join Biosentri and Regional Host Chair Allen Institute, this June in Seattle, for an R&D forum at the Interface of Industry and Academia. Hello and welcome to the Biosentri Show. I am Simon Fishburn, Editor-in-Chief at Biosentri. So delighted to be joined today by Chris Hollywood, CEO of Sincona Investment Management Limited. And I would say one of the leading voices also in the UK on UK Biotech. Chris became CEO of Sincona in 2023, having been at the firm for over a decade, previously as Chief Investment Officer. His background includes several years in the investment world. Before that, a degree in PhD in Chemistry from Cambridge. For those of you in the know, meaning he's yes in that ski. So we'll see how that plays out during this conversation. You're going to have a backpack or something. I don't know. Alright, Chris, let's start at a pretty. I don't know whether to call this a high level or a deep one. Right? I want to talk about rational target discovery and where the industry is going. So there's just a lot of talk about causal biology being the North Star. But you've got a sort of slightly different take on this, which you discussed last year at our Grand Rounds conference. And I'm going to quote you here, okay? You said if the underlying biology is a premise of the experiment, then it cannot be used as evidence of the causality. T.O. Everyday? Okay. Can you expand on that for the audience and talk about what your concern is here? Yeah, also, firstly, thanks for the invitation to speak today. And I sound very eloquent a year ago. So I hope I can repeat it here. But the fundamental issue I see is part of causality. One of the tests of causality is plausibility. And if you look at the Bradford Hill criteria, that's in there. Actually, you read Bradford Hill. He had concerns about using plausibility as part of that causality proof. And the issue, I think, historic biology has been you start with a great professor that has stowed a piece of biology for 10, 20 years. And they come to you and go, this is a great piece of biology for this disease. And then they run a set of experiments to prove causality. And those set of experiments give you the set of results. And they go, the results will line up. And because the biology is plausible, it must be causal. And that's the issue. You can't have the hypothesis be the proof of causality at the end. And then we're going to get to it. But I see the industry is actually on the cusp of solving that's problem. I say they're exciting future for the industry. Because I think that the tools we have nowadays, we can get round this issue, we'll get much more powerful causality arguments into our experiments than we could before. So I want to just sort of iterate through that for a minute. So let's say somebody finds a gene association with a particular disease. And then they find a pathway that that gene is involved in that's plausible for the disease. Is is that still circular? No, that that as we know that's the pinnacle. Yeah, because genetic evidence as we know is a great predictor of the target. For the point thing, you didn't start saying it's that gene. Right. So you look for a gene that correlated and then you checked its biology and its biology was plausible. That's the right way round. Right. So you've talked a little bit about the importance of an unbiased step. And so that genetic step would be the unbiased step I assume. So maybe you're going to expand now, you know, on what tools the industry is going to be. I don't know if you want to call it a pivot or sort of like the cusp of a new era. It's exciting. Yeah, so it's not a pivot is a natural progression. But when you look at the tools we have available to us like CRISPR light machine learning where you can effectively go into a biological system. And knock out each gene individually in an experiment. And therefore you're not entering that experiment with a biological hypothesis of it's this pathway or that pathway. And then look at the outcome. As to which are the most strongly correlated in that experiment the outcome you wanted. And then check plausibility. Then the plausibility can be used as proof of causality. And because that's a holistic experiment. I mean, right, he'll talk about it that you know where you see associations. You can't rule them out on the lack of plausibility because you are at the frontier. What is known on that day. And we've been in the past. And now because we can do these holistic experiments not only is the experiment on to design more powerful. It covers a lot more biological ground and more likely to find the best target, not just a target that might work. And it's those two elements of it that I think they're going to hugely deal risk novel target discovery and therefore the drug development going forward. So I want to take a tiny tangent here. So this is a personal association of mine somebody that I know who had absolutely no symptoms. And they found a genetic homozygous genetic mutation, such in the eye. Right. No symptoms at all. And they found it when they were screening for something else. Right. So this individual was told, okay, you know, you have this genetic abnormality. But she had no symptoms. And so even though there's a very strong association, all of the people with the disease have this genetic abnormality. There's no information about the number of people with this abnormality who don't have the disease. So this is why I sort of went back to that genetic thing in the first place. For me, it's not necessarily circular, but there's still this tremendous amount of information that we don't have. We, you know, you can have a strong correlation, but you don't know if there's a protective factor or something else. How do you think about that and how biology should be sorted? Yeah, so I think that's a very pertinent question. I think in your example, what you cited as a correlation is an as strong as you thought. Because the penitence of that genetic mutation has been misunderstood because the people that are presented at clinic are the people with the disease. Exactly. Not look holistically across the population is to have that mutation and the disease as well. So it goes to strengthen the correlation. And then if you did see those patients separate out into ones that got the disease and then a clear set that didn't then yes, you would look for a second mark or some of the things you described there as to why is that happening and maybe discover, you know, what is mitigating and maybe that was your idea to treat the disease. So I think you're right. I totally agree with that and that you know, it's the patients who present, right, that the data is from. But what is the solution? Is it the sort of whole scale I was going to get to this later, but we're done. Is it the kind of wholesale genetic kind of screening of populations so that you have just a much full of data set. How do we go about that and do people want to all be genetically profile? Yeah, I think the two questions are there. But look, I think from an experimental design point, you need to make sure that you have done a holistic experiment and it's unbiased. That gives you the greatest confidence, you know, I forceciously think about, you know, biological target discovery, historically as that person feeling that backside of an elephant and trying to figure out what it is. We can move away from that. We can look at the whole elephant now. And that I think is much more powerful than a second question is do people want to know to people want to enter into those kind of studies. I think that's a societal question. Right, right. So just, you know, come back to targets in a minute, but I do want to talk about the way you are approaching this within your companies and how that changes the risk paradigm for you and where it leads at a high level. I mean, is it a tangible difference in the outcomes with this new sort of web looking at it? Well, so right now we don't know. So we're venture capitalist that have a thesis and we're basically love our investments on the back of it. I think all the evidence does point to it. So I mean, AstraZeneca put a paper out. I think it was the mid 2010s that talked about phenotypic screening versus target based discovery. And great to correlations to drug approvals. And I know there's been a lot of opinion on that paper, but I think that is a very interesting set of data that supports the unbiased nature of what we're doing. So there's one evidence set there. And then the holistic piece that we're adding in hard to argue against that police. And then the floor and the holistic piece is what is what is the experiment you're doing and does it replicate disease. So it's one thing doing a holistic experiment across an in vitro assay versus holistic experiment and human being. They are completely different standards or proof. And we know that from all the other work we've done. We do look for holistic and we do look for kind of plausible biology not as the hypothesis, but as the proof. where we can do it in a human, that's the absolute pinnacle. Right, right. No, it's, it's extremely interesting. I want to go back to the point that you made about targets, right? Because this is so often the holy grail and we just published, uh, you know, our analysis of abstracts at AACR where we identified 176 potential new cancer targets, right, that went to our database and hadn't been previously associated. But you, you know, you and I know targets alone do not have first in class make, right? Modality matters. Okay. Um, talk a little bit about that. And I know, you know, you, you pursue that through companies, your companies, your portfolio companies, Yellowstone, Pure Spring, you know, talk a little bit about your approach to modality plus target. That solution. Yeah. So I think the, the, we've had a big paradigm shift in the research tools that allow us to think about target is heavily differently. Um, what we saw over the last 12 years is a huge, um, addition to the set of drug formats we've got, you know, we go back 20 years, we kind of had an antibody in a small molecule. And if it was a target within a cell, you kind of stuck with a small molecule, so chemist, I didn't mind that, but that wasn't a great tool set to have. Um, and now you've got RNA, you've got CRISPR, you've got gene therapy, cell therapy, you've got all of these different modalities and engine inversions thereof. So you've got this really rich set of things to go at targets with, but it also presents jeopardy because now I don't think it's sufficient to be first in class for two reasons. One is, if you're first in class before, no one could come around the side of you because if you had a small molecule, that was the only way of getting at it. Now if you haven't got your modality to match for the target biology you're going after, are you hitting it precisely enough and hard enough? And the disease context doesn't mean that that therapy is enough format for the patient with that disease wants to take. Then given how IP is narrowed, I think you're in real danger of getting overtaken. And we've seen the pace of development now, particularly just in China, really up the pace of development. So you're not safe unless you get all of those things right. So we have a company in our portfolio, which I use an example, it's coming to call pure spring. We've done a lot of investments in gene therapy and been pretty successful at that, particularly in the eye. And really what you're looking for is diseases in term, they differentiate its cells. So we thought, let's look at the kidney. There's a huge number of genetic disorders there. So it's a term, they differentiate its cell. And then we have a view that mechanical delivery can do so much more than biological engineering. So most people out there would have thought, I'm going to engineer an AAD to make it renal traffic. We thought that was a very high bar on a very long road. And actually we looked at what the surgeons do. And so surgeons are able to clamp the renal artery and infuse drug for 20 minutes downstream of that clamp and refuse the kidney. So we took a known surgical procedure and decided that that was the root to deliver it. You're doing that. You don't want to do it very often. And so that may gene therapy and the modality. And in the kidney is a monogenic recessive disorder called all port disease, which is a horrible disease. No disease modified therapies out there, none really in development. And it takes a genetic medicine solution in my view is mongenetic assessor's all tastes of genetic medicine solution to address it. And so there I think we've done an exquisite matching of modality delivery disease in order to get the right therapy into it. And gene therapy is not the answer to everything. Gene therapies for some things like mongenic recessive disorders in other cases that buy specifics in other cases antibodies. You got to get that matching right because if we've gone out with something different, then all we would have done was previous a good target. And that you can get clinical traction in it. And then we would have all these. Welcome back and talk more about selling gene therapies in a minute. Before we go to break, I just wanted to sort of circle back because what you're, you know, what most people do with a gene therapy is they would accept with the eye. They would deliver it systemically and assume that you need a targeting agent to get it to the kidney, let's say, which is very difficult, obviously. So what you're saying is that you actually, it's almost like a local delivery there. Effectively, yeah, that that is a strategic decision. We took very early and we haven't backed off because if you look at the dose saying for kind of a liver based gene therapy and a muscle based gene therapy, they're in order of magnitude different. And the reason they're in order of magnitude different is because of about 10% of the gene therapy doesn't go to the liver. So there's no targeting going on there. What you're doing is cranking the dose to get enough through the liver to get to the muscle. And our view is that firstly, that was difficult from a CMC perspective, but also ran a lot of risk against therapeutic in diets. And why not just do a low rent solution injected directly where it's needed? And that seems to work. Great. We'll take a break and as I said, we'll be back in a minute to continue the conversation. This episode of the BioCentury Show is brought to you by the third BioCentury Grand Rounds in Seattle. Advancing drug development requires more than discovery. It requires the right partners. The third edition of BioCentury Grand Rounds US convenes venture capital, bio-farma decision makers, and academic innovators in Seattle, June 3rd to 5th. This R&D-focused forum brings together leaders at the forefront of translational science to examine the breakthroughs, bottlenecks, and strategies shaping the future of drug and diagnostic development and how to make early stage R&D investable. Discover cutting-edge disease biology and platform technologies, gain insights from emerging biotechs and academic pioneers, schedule partnering meetings with VCs, pharma, and leading academics who can accelerate your path forward. Grand Rounds US is where rigorous science meets strategic capital, and where the right conversations move discovery toward development. Join us in Seattle and discover what's next in bio-farma and who's driving it. Secure your spot. Register at bio-Century Grand Rounds.com. We are back at the BioCentry Show and I'm delighted still to be here with Chris Hollywood CEO of Syncona. So Chris, it has been actually quite a tough time for gene therapies. We talked a little bit about it, you know, your investments there. You had some exits with Nightstar and Gyroscope, those therapies didn't work out. You still are in that space with Beacon, and generally I think people with gene therapies are facing a lot of challenges. Perhaps you can talk about those challenges and how you are evolving a strategy and what you think the field needs to do. Yeah, so I think gene therapy is not a solution to everything. We never thought it was and we never planned to take it to everything. What gene therapy does brilliantly is in a disease term, a differentiated cell changed the phenotype. And there are a lot of genetic disorders in term, a differentiated cells. So then you get to the question of how do I get to the relevant cells? And that's why the eye has been so successful because I can inject in that. And then CNS has been harder because although there's a lot of horrible genetic disease, CNS getting to the right cells and the end points to show that it's working make that harder to attack. And then beyond that, you have to get to doses that are relatively high. And we were always nervous about that. So I would take gene therapy and I would break it down into can I deliver a significant amount to a hopefully monogenic recessive or at least a genetic disorder locally? And if I can, I can really drive therapeutic index. And if I can't, I'm running a lottery as to whether I can navigate between efficacy and toxicity in a modality that you can't reverse. It's not like you can titrate these patients up. And so I think a lot of people took gene therapy into those settings and have had issues as a result. So we never did. We had a very strong focus in the eye. That was the obvious place to go. And we had a great success in night star. And I think if you look at the data in night star, that was absolutely progressible to pivotal trial and bygien to decide not to do that for strategic reasons. So I don't think it's a case of the fails of therapy. The reason we're doing beacon is because it absolutely works in our view. And we want to go about therapy to patients. And then in gyroscope, similarly, the artist took a strategic decision. And I do think that a complement modulator for JAMD is a good gene therapy target because I think those patients that are progressing over 10 years and are asymptomatic at the beginning would appreciate the modality where they don't have to go to clinical every month. So I think there's places you should play gene therapy. And I think there's places absolutely shouldn't. And I think people went beyond that boundary and have struggled. Give you another example. So we have a program in Goucher disease and it's systemic. So we deliver to the liver, liver, sucrease, GBA. And we took a view that in order to get the efficacy, we could do something very clever, which is a good engineer, the protein. An engineer in the protein meant that we have a GBA that was equivalent in activity, but 20-fold half-life. And it's the lowest dose systemic gene therapy in clinical trials anywhere in the world. And so I think you're smart about gene therapy. You can use it in the right settings in the right way, but don't expect it to be something it's not. And so that's spur therapeutic. The one that you were just describing, right, right, right, right, let's just get that name out there. So now let's move to where you've had good news. Well, one of your portfolio companies, or Tolas, if I'm pronouncing it right, or Tolas, I'm never really sure, with approval for the CAR-T cell therapy. Has that sort of ramped up your interest in cell therapies versus this? I'm going to ask another question about cell therapies for the minute, but let's just talk about syncona and how you looking at one modality versus the other. Yeah, so I think, I think all this is a tremendous job. I think Kristen Etonisio there as a force of nature. And we're very, very proud that we got a product to print. It's not work-tiles and investment yet for us. And I think that taught us something about cell therapy, which is decent work and quite clearly you look at efficacy and the safety in particular with that drug. That is something very meaningful for patients, but you need to target it at large markets, because it's only a large market that can actually withstand the infrastructure cost and allow the leverage of that to really make it into a pharmaceutical product. And so we do have, beyond all this, we do have two other cell therapies in the portfolio. One addressing any state liver disease, which is resolution, has some really remarkable early stage data there. And then, Quail, which is looking at autoimmune conditions again, big markets. So we've focused our portfolio down to those two opportunities because I think they work for cell therapies. And I think cell therapy, it's best gets you to an efficacy envelope that no other modality can get to. But you need to go to places where that level of efficacy is needed, because if another modality can do something sufficiently good, people can use the other modality. Right, right. Yeah, I mean, people quite often bundle cell and gene therapy. And for me, the dynamics of each one are really quite different like cell therapies versus gene therapy. Yeah, I'm 100% agree with that. I think it's easy to bundle them together, because they came online around the same time. But I think the diseases you go after the development dynamics, the commercial dynamics are all very different actually between cell therapy and we suddenly think about them very differently. So I will come back to this in a minute, because I want to sort of have some questions. Obviously, one of the big things with cell therapies is the role of China and how they're driving that. But before I go there, you know, you talked about your strategy. I'm very, very interested in how Sincona is moving forward. You announced a pivot last year. You've got a clear message that you guys are open for business. I know you're trading below your net asset value, which I'm sure is not where you want to be and you have a strategy for closing that gap. Perhaps you can talk about your strategy moving forward. Yeah, so during the kind of nuclear winter that would just been through in the bear market. We've all been. We've worked incredibly hard to push our portfolio to late stage. So three years ago when I took over, the portfolio was about 25% clinical stage. It's now over 85% clinical stage and that portfolio will fuel the growth. The beacons in the world will fuel the growth of Sincona and provide the proceeds both to allow us to close the discount gap but also to reinvest in new opportunities. And on the sort of being a London listed entity, the benefit of that is it gives us permanent capital that should think in Europe is a huge differentiator where there is no debt to capital that anyone staged. And so one investor that can connect the dots from university spin out all the way to a late stage therapy. I think is impactful in the market and I actually think it's a unique way to deliver shareholder return. So it allows us to do that but we are an investment trust and the whole investment trust sector, which your American listeners won't know. There's also been a bear market at the same time. So we're all trading at a discount and trying to solve that. The future for us looks like where we start it, which is let's look at these novel ways to target, to get to novel targets that we can address with all the sway the modalities that are now out there. And there's one example of that, which is we started a company, Yellowstone out of University of Oxford. So there's a clinician up there, he's a world leader and a cute mile over the Kemia. He has his patients blood samples pre and post stem cell transplant, thanked for the last 10 years. And within that data set, he has got 15 patients to got a complete cure, the no-graphs of such disease. So if you know that disease, you know that if you don't get graphos of such disease, it means the stem cell transplant didn't work because it's not found anything to graphed onto. So in those unique patients, clearly there was something on the myeloid cells that was found that wasn't found on a healthy cell. And we sequenced all of those and what we found is almost all of us, there's 24 novel targets that haven't been described before. Almost all of those are a single SNP difference between Dunga and patient. And almost all of those are presented on class two. And that goes to the plausibility of that, so where we started, that's a holistic experiment done in the human, that's the best thing about it. Done in a human where we didn't go in saying it's this target of this target, in fact look at all targets, what's the result of the model? The result is an alive human being, that's the greatest result you can get. So the way the experiment sets up is just high veracity, then you go to plausibility, well guess what? One of the escape mechanisms for AML to eventually kill you is down regulation of class two. So it's very, very, very impactful I think is the experiment. So we've got very excited by that. If you also think about the experimental design, we found these 24 targets, because they're affected at the tip of the iceberg with no background noise. There above the water surface, because there's no graph S's host disease. But you now know that if you did a machine learning experiment on that whole data set, looking for single snip differences between donor and patient, and you round the algorithm as what likely to be presented on class two, you're going to find a whole new law. And so that's a really exciting opportunity we think that's just broken up a whole new, not just single target, air is a target and complete over the country. And then you go to medallion see how do you address that? Well, you can do that with a T-cell engaging a few ways to do that. Those T-cell engaging seem a great way to go after it. And so I use that as an example of the sorts of things we look for and the sorts of places that our future capital is going to go into. And you know, I think the very clear question for me from here is to what degree, you know, you talked about this coming out of a university, but what degree is this kind of work enabled by the integration of university discovery science with NHS data sets? Because that of course is a big part we're moving to the UK ecosystem part of the conversation now. Something that, you know, people in the UK are touting. So to what degree is that is that part of the thing? Yeah, so I think that's very real. As you know, we do have universities embedded into hospital systems. Those hospital systems are NHS hospitals. And so they do have access to large data sets. And that integration, I think in this new world, is going to be very important. And I think gives the UK this is placing the industry effectively. So do I think the UK can do what China's doing right now, which is an engineer something to the end of the degree against a known target. It can do that but not as fast. And hopefully we get as fast. And I certainly think there's a niche just when the UK to speed up our whole clinical translation. But with four of the top 10 life science universities and that NHS system and a relatively big ecosystem outside of the US, we have the ingredients here to do something unique in the industry. And we serve our focus on that. I hope other VCs in the UK environment are focused on that. So I see as our advantage. So, you know, I want to end by sort of going down that road a little bit more for Biowecordy Europe, European conference next week. Our scene-seder analysis has looked at clinical trials from clinkortiles.gov in the last, from 2021 to 2025. And you know, we really focus mostly on phase one and that. We do have a little bit of all of that. And we, you know, people in the UK might be delighted to hear. here, there's certainly a tier where we're looking at what clinical trials are done where the US and China are aware ahead. But actually the UK really sits in a tier with South Korea, Australia, Spain for some indications. And so I think about this both in the UK and across Europe where you do have really, really strong science, which we talk about a lot, but we don't talk a huge amount about the hospital strength, the strength for running clinical trials. And the idea of what I think of is creating a flywheel between these, between the academic discovery and the ability of hospitals to do what you want all the time, which is giving you human data, you know. And, you know, so I'm wondering to what degree you think that that will, you know, historically, I guess the physician scientist was much more a part of discovery, like back in the sort of 60s and earlier kind of thing. But to what degree do you think we can really move back towards that closer flywheel from one to the other? Yeah, I think a lot of the people that are state-fold in the UK ecosystem see that and are very aligned by what behind what you just outlined. So I think there's a lot of effort. I mean, you had an interview with the server, the MHRA. Laurence and Laurence had a lot of those same messages, I think. And so I think we can move towards that. I think we have certainly got examples in our portfolio where effectively the MH, engagement with the MHRA has offered a quicker route to clinic than we could get in the US. Ultimately, you need to go into your development in the US because the US is such a big market. It doesn't mean you're using phase one too. And I think that that was really impactful to the success of that company because it meant it could leap for the US competition. And given that we do have a very sophisticated and accessible regulator, that's a key advantage as well. And then you get through that and you get to those physician scientists and the advancement of physician scientists is the hate that they're researching the area they're researching because they're so desperate for something to treat the patients as seeing a clinic. And by definition, that means they know the patient's size as well. And so you have all that connectivity. And I certainly remember some examples of, in our phase one, two trials, our physician scientists found walking down to the pharmacy himself and getting the material to go back to the circle. So you do get that connectivity. And I, you know, it is another UK advantage and we absolutely need to leverage it. Yeah. Well, this has been a great conversation, Chris. We could probably go on for a while, but we have to come to an end. Thank you very much for joining us on the BioCentri show and look forward to next time. So you could thanks to them. I really appreciate opportunity. Brought to you by BioCentri Grand Rounds. Join BioCentri and Regional Host Chair Allen Institute, this June in Seattle, for an R&D forum at the interface of industry and academia. Kendall Square Orchestra provides the music for the BioCentri show. 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