How Evox Therapeutics is targeting CNS diseases with exosomes

0:05Hello, and welcome to Beyond Biotech, the weekly podcast from the Biotech. I'm Dylan Kassane, and this is episode 213 for the podcast. Gene therapy has largely stayed out of the brain, and the blood-brain barrier has been the reason why. It protects the brain from harm, but it also blocks most advanced medicines from ever reaching it. That's now beginning to change. The recent FDA approval of a brain-penetrant enzyme therapy for Hunter syndrome showed that biologics can cross the barrier and work. The next question is whether gene editing can do the same. My guest today is Dr. Pear London, co-founder and CEO of Evox Therapeutics, a UK biotech using engineered exosomes to deliver genetic medicines directly into the brain.

0:56evox is now extending their platform from rna and biologics into gene editing targeting the genetic drivers of diseases like huntingtons and als where treatment options remain extremely limited pair also brings a background as a european patent attorney and repeat biotech founder we'll talk delivery pipeline and what a commercially scalable genetic medicine for the brain might actually look like. But first, a word from our friends at Inside Biotech.

1:34Dr. Per Lundin: Hi everyone, my name is Karish Manjigani and I am the co-host of Inside Biotech, the official podcast of Biotech Connection Los Angeles or BCLA. For those who may not know, BCLA is a non-profit organization dedicated to inspiring, educating, and connecting emerging scientists, students, and entrepreneurs to help grow and diversify the biotech ecosystem in Los Angeles. On Inside Biotech, we invite you to get a behind-the-scenes look at one of the fastest growing biotech hubs in the country. Each month, we sit down with scientists, founders, investors, and industry leaders to talk about the cutting-edge science inside their companies and the personal journeys that brought them there.

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2:45Per, welcome to Beyond Biotech. Thanks, Dylan. Good to be here. Per, you've been involved in founding five biotech companies. What keeps pulling you back to starting something new rather than just staying inside and growing something over 10, 20 years? Well, yeah, it's a good question, actually, Dylan. And to some extent, with this company, I have stayed for 10 years. But I do like new things, right? I think it's ultimately one thing that I think brings people to biotech more broadly. And I think that's, you know, hopefully making a difference for patients. Right. And so, you know, I've been mostly engaged in companies working on advanced modalities, but it tends to be about unmet medical need, you know, patients going through a really difficult time with a given disease and then trying to find a solution to that.

3:32And I think that brings a lot of people to biotech. But, you know, the other thing that I think brings people to biotech is that the science is exciting. right so you know we work on gene editing i worked on cell therapy gene therapy rna therapeutics you know these are exciting things to work with and you know you know that you're working on important things and at the same time it's you know intellectually stimulating so i think i guess that's the thing that brings me back but i've certainly tried the corporate job as well but i find the biotech to be a bit more uh dynamic and and exciting in many respects yeah as i understand minute you were a qualified patent attorney that's not a typical CEO background for biotech how has that actually shaped the way that you build and develop a company like Evox yeah it's a good question I mean I actually think it's a background that's more common than people believe because it's such a useful useful toolkit right you know when you are when you're an IP attorney you know you often represent small biotech companies you might be representing pharma companies, I think it gives you a really good understanding for how you create and protect the secret sauce of a company.

4:38And it's all intangibles, right? The work that we do, it's all about innovation. And so being an IP attorney, I think, is very helpful in that regard, because it brings together value creation, protection, commercialization. And so in many respects, I think it's a really useful background. I think the way that it impacts the way I think about kind of science and medicine and developing programs, I think is to some extent about making sure that we make good decisions now, because those decisions are going to stay with you, you know, in the lifetime of a patent, right? You make a decision when you find the patent, and that decision is going to be with you for 20 years.

5:16Somewhat the same in biotech, the decision we make today about a given guide RNA targeting a given gene, well, that's going to be with us for a long time. So we want to make good decisions. But we also want to make sure that we think about what the end game is, because I think you have to think about that a lot as an IP attorney. It's not so much where the company's at today, where this patent is going to go, but where is it going to be in 20 years' time or in 10 years' time when you're commercializing this? So I think it gives you a few interesting kind of lenses to drug development and to biotech more broadly.

5:48Now, let's talk a little bit about Evox. You founded Evox back in 2016 with a couple of partners. You took over as CEO in 2024. What made you want to step into that role? Yeah, it's a good question. I mean, you know, I think, as you say, we started Evox in 2016. Myself, a professor here in Oxford, Matthew Wood, and a professor at the Kerlinske Institute in Stockholm, who's one of my old friends and grad school colleagues, I guess. You know, when we started the company, we really built it right into what initially was a big platform play. You know, 2016, when we spun out the company, There was lots of companies working across many different application areas.

6:30And we worked on delivery of RNA therapeutics, gene therapy, gene editing, different aspects of delivery. And, you know, we came to a point throughout that journey, you know, and I was always part of the leadership team here as COO and CBO. But we came to a point in 2023 when I think we felt in the management team and more broadly, the board and our shareholders that we needed to be a bit more focused. And so we did a kind of a restructuring and a real kind of strategic pivot, if you will, in 2023, 2024. And I felt that was the right time for me to take over and run the company again and essentially try to really make sure that we became a bit more asset centric, a bit less scientific.

7:15And I think that suited me pretty well. So, you know, the first step that we took there in that kind of strategic pivot was to license in the gene editing technology that we have an exclusive license to. And, you know, that's kind of a skill set that I have to try to understand how we build these things. And it's back to your question about being a patent attorney. I think I'm good at putting together the pieces that create a viable long term strategy. And so, yeah, I stepped back into this in 24 and I think it's been a good run since then and we're making some good progress. So how would you describe the field that Evox is in right now?

7:50You know, it's exosome, but, you know, where are you actually locating yourself? Where do you see yourself fitting in? Yeah, you know, it's funny, right? Because I think as humans, we have this tendency to use categorization to simplify the way that we think about things. And to some extent, we work on exosomes as a delivery system, as an enabler for genetic medicines and specifically gene editing. So I think more about exosomes and about Evox as an enabler for gene editing. And for that reason, I mostly see us as a gene editing company. We happen to use exosomes as the delivery modality because we think that gives us the ability to address challenges that you perhaps cannot really fully address with other types of technologies.

8:39And so I think about positioning us somehow in between where LMPs are and, you know, I've had a fantastic impact on liver directed genetic medicines, right, with editing, for instance, but also with other types of genetic medicines. and where I guess AAV is as it relates to protein replacement. And I think we have a bit of a unique sweet spot in between where we have a non-viral delivery modality that is super safe and can take you into new tissues like the central nervous system. And so I think we're really a CNS-focused gene editing company. And that's a pretty unique position to have. As you know, Dylan, most gene editing companies focus on liver applications, ex vivo applications, maybe some in vivo CAR T applications.

9:28I think we try to really unlock what I think is a super important medical, but of course also commercial opportunity, right, which is the central nervous system. Yeah, well, central nervous system, so CNS, delivery there has always been a challenge. It's always been a bottleneck. But pretty recently, Denali got themselves an approval for Hunter syndrome. And that's been described elsewhere as just this turning point for brain penetration medicines. Is that approval significant for a company like you, even though you're using a different delivery approach? Yeah, I mean, I think it broadly is, right?

10:04I think it just goes to show how much more we understand about the BBB, about how we can effectively deliver drugs into the brain. Obviously, it doesn't read directly on what we do. You know, for our Huntington's program, we're using a direct route into the central nervous system. So we're kind of circumventing the BBB, right, and avoiding the challenge of crossing the BBB. But certainly, I think this is very important. And, you know, as we know, when you make progress in one part of the field, that tends to unlock other aspects of it. And so I think some of the progress we've seen on crossing the BBB from Denali, but from other companies as well, right, I think is impactful for newer generation more broadly because it just means that it's perhaps easier to finance studies in this area as we have seen success before.

10:50We might be developing better biomarkers and better ways of looking at measuring outcomes in clinical trials. And so, yeah, broadly speaking, I think it's possible, or positive, although it doesn't directly read on the work that we do. You know, this BBB, the blood-brain barrier, that stopped a lot of really promising science from actually reaching patients. You know, how can you describe what makes it so hard to solve? Why is it such a challenge? Yeah, I mean, I think there are a few kind of holy grails of drug development, right? I mean, one is targeted delivery. You know, we've talked about targeted delivery for many decades, right?

11:28And that is a tricky one just because it is, you know, you're kind of trying to fight against the body's own kind of distribution system for drugs and for substances. With the BBB, first you need to target the BBB and then you need to cross this barrier, right? And the barrier is there for a reason. It's there to keep out substances that can be harmful for the brain. And so you're really fighting against, I guess, two waves of the body's defense systems. And I think that just makes it quite tricky. Then, you know, as with the brain, it's difficult to study. It's been difficult to study the composition of the BBB and then finding the sweet spot for how you identify shuttles.

12:09You know, we worked on transferring for many, many years in this industry. Right. And I think we now have a good understanding for how you balance the avidity that you need in some of these ligands. And so I think it's just one of those things that most things in science takes a lot of time. And now we've spent 20 years trying to get through the BBB, and I guess we're making some good progress finally. But again, there is much more work to be done, right? And we have seen some positive examples of success, but there is much more to be done in that space also. but you say now you're taking a direct approach so you're sort of bypassing the bbb explain what you're actually doing yes so for our huntingtons program for instance we are using something called convection enhanced delivery um so essentially we go directly into the brain using a device so we're essentially uh for for huntingtons we we utilize our exosome delivery system as a way to ensure that we maximize the spread of our gene editor in the context of the striatum.

13:14So this is done through a neurosurgical procedure where you go in with a device and then deliver the drug product into the striatum directly. And this really gives you maximum exposure to the key brain region, which is important in Huntington's. But it also is really suitable for a modality like a gene editor or for a gene therapy because we are doing essentially a single dose. This is done once. And so, you know, if you think about that, you know, it's of course an invasive approach to do neurosurgical procedures and you prefer to take a pill or do an IV infusion. But if you're only going to do it once and you know that you want to have maximal efficacy, well, then going directly into the brain is a very, very helpful way of thinking about central nervous system diseases.

13:59And I think we're increasingly seeing this. So in the context of Huntington's, for instance, the company called unicure is about to get the drug approved um in huntington's using the same type of approach using the same type of delivery device and so we think this is a really de-risked and increasingly clinically very feasible approach uh to delivering drugs into to key parts of the brain and so that's where huntington's intra-parenchival administration with als which is our other program uh we do uh what's called intra um interest is done a magna administration so administration into the cerebrospinal fluid.

14:35So that's again a direct route into the CNS, but not directly into the parenchyma, but into the CSF. So we're trying to make sure that we are avoiding the challenges of crossing the BBB, and we want to make sure that we have as maximum exposure as we can possibly get when it comes to getting to these key brain regions and the key cell types that you want to get to in Huntington's and ALAS. Now this program of yours for Huntington's. You're targeting MSH3. Can you explain what MSH3 actually does and why editing it is potentially changing the course of the disease? Yeah, that's a really good question, Dylan.

15:12So, you know, Huntington's is an interesting disease, right? We've known about the HDT gene for probably 30 years by now. And really, HDT, which is kind of the genetic course, if you will, of Huntington's is a gene in which you have something called CAG repeats. These repeats are essentially expanding throughout the lifetime of a patient, and that's something called somatic expansion. And what has been shown in the last 10 years or so is that in Huntington's, the real key driver of pathology, in fact, is this expanding repeat. Because when the repeat reaches a certain threshold, you start to see a work neurotoxicity of these medium-spine neurons in the straight that are first impacted in Huntington's.

15:54And so what we really want to try to do is to stop this repeat from happening or stop the repeat from accelerating. And so we're trying to address this by knocking out a gene called MSH3. This is a DNA damage response gene, which is, you know, in the normal context, very important for maintaining the integrity of DNA, right? But in the context of Huntington's and specifically in the context of these repeats in the HDT gene, MSH3 really speeds up this somatic expansion. So by knocking out this protein, we believe that we have a really good opportunity here to stop the expansion fully and really kind of stop it in its tracks so that we can have a really transformative impact, we think, on patients from a kind of pathophysiological standpoint.

16:42So essentially, our intervention, as I just described as a direct intraparenchymal infusion of an editor delivered using an exosome that knocks out MSH3. And we think the knockout of MSH3 is really important because it really drives a very deep protein reduction. And we know from all the preclinical and also the clinical genetic data that if you're really going to have a substantial impact on somatic expansion, you want to get a very deep knockdown of the target. And we think gene editing is probably the best way to do that. You know, with CRISPR-Cas9, you can completely ablate the given protein.

17:18And that's very, very difficult to do with any other modality. So, yeah, the plan really is to knock out MSH3. And we think that that is going to stop somatic expansion and for that reason have a very positive impact in Huntington's. So we plan to test this. We're going into the clinic next year, second half of next year. And so we're looking to go into Huntington's patients in stage two and hoping to have a big impact on these patients over, hopefully a relatively short time period. So we're pretty excited by that. So Huntington's ALS, you've also opened a collaboration with the Rett Syndrome Research Trust to explore how you might address Rett Syndrome.

17:55How are you as a CEO, as an executive in the team, deciding which disease to go after next with this platform of yours? Yeah, it's a good question. It's always, I think, interesting with platforms, right? Because it really puts you in a position where making a good decision as to which indication you pursue becomes one of the most critical decisions that you make throughout the lifetime of a company, right? And so with both ALS and with Huntington's, I think we felt that we have some really good targets here where a gene edit can have a uniquely impactful kind of approach to those targets. And if you can utilize gene editing, you can really change the course of these diseases.

18:39It's the same with RET, really. I mean, with the Rett Syndrome Research Trust that we collaborate with, you know, they have spent many years trying to understand Rett as a disease because it's obviously, you know, a rare disease with relatively few patients. But they've also spent a lot of time trying to develop different modalities that could potentially address this disease. And so one of the things that they have thought about for many years is can they develop a gene editing approach to Rett syndrome, but preferably a gene editor that then could be delivered using a non-viral delivery system.

19:13And so, you know, there aren't that many companies having compelling non-viral delivery data of gene editors in the central nervous system. And so I think we have a bit of a meeting of the mind here in the sense that, you know, we think gene editing is a really great modality for addressing genetic diseases of the central nervous system. But the key thing that you need to try to get to the bottom of is how can you deliver them effectively? And so we're doing work with the RET Syndrome Research Trust team to try to understand distribution, to try to understand exposure, and then ultimately, hopefully, deliver a base editor that can address the MECP2 gene and the mutations that you have in that gene for RET patients.

19:52So we're excited about this. It's early stage, but, you know, it's obviously a disease with huge on that medical need. And we're, you know, very grateful to work with the RET team on trying to move this forward. You know, I think as you mentioned before, a lot of these gene therapies and gene editing therapies today are really bespoke. They're one patient, one at a time processes. What does it actually take to get a genetic medicine for the brain that you can manufacture and, you know, produce at commercial scale? Yeah, that is a good question. As you see, there's lots of interest in end-of-one diseases, ultra-rare diseases, right?

20:29And these can be, in some respects, really good starting points for drug development efforts. You have a monogynetic basis of disease. Patients might be relatively homogenous. You have a huge unethical need, et cetera. You know, in our case, with Huntington's, with ALS, and also with RAT, you have, you know, relatively sizable patient populations. So you have, in addition to a huge unethical need, you also have a significant commercial potential. and I think in those areas it's easier than it is if you have an ultra rare disease with say 5 000 patients globally right that puts you in a difficult position from a development standpoint but still in the end I think the same the same fundamental parameters are at play right you need to try to make sure that you have a drug that's really clinically impactful and you need to be able to commercialize it and then of course make it at a reasonable cost and I think that last point right we've really been trying to invest in a manufacturing process that gives us the ability to scale really effectively and to do so at a very attractive cost of goods profile and i think we've got to a point where certainly we know that that can be done with our exosome delivery technology and i think that of course puts you in a position where you know you can think about also looking at diseases which are you know relatively rare but at the same time you know with huntingtons with day last you have a big commercial opportunity and we're trying to start there where we think we have a good sweet spot between a genetic basis for disease there is significant unmet medical need that we can hopefully have a positive impact on but then also you know diseases where we have an ability to manufacture and then actually sell drug and have a commercial business in the end because you know this is how this business works you know in reading and preparing for a discussion today i saw that at one point you described yourself as having a dominant ip position in exosome based delivery how deliberately did you build that portfolio of ip and how much of a moat does it actually give you against others yeah that's a really good question um you know since we were one of the early companies in the exosome space i think we we were able to to really carve out some extremely broad and important ip right when we when we spun out this company from Oxford and from the Karolinska Institute in 2016.

22:46We put together IP coming from Oxford that we licensed in. We acquired IP from the Swedish university. We put that together. And at some point in time, I think we were really protecting almost the entire exosome space from a kind of delivery standpoint. So when it comes to delivery of RNA therapeutics, delivery of proteins, targeted delivery, but also manufacturing inventions. And to some extent, although we have a focus that is today a bit more narrow. Many of those patents and a lot of those IP assets are still extremely relevant. The manufacturing IP, the ability to load cargos into exosomes, the ability to target exosomes to different tissues.

23:26I think it gives us a really, really strong position. And certainly throughout the years here at Evox, we have done a few different business development transactions and IP always plays a big role in that, right? And I think that's a testament to the ip position that we have um you know now as we focus in on gene editing we're building out a proprietary position also in the editing space you know composition of matter patterns focused on the products how we modify the guide rnas how we deliver this effectively into certain parts of the brain etc so i think we we have a really strong competitive position and I think, you know, looking just at the track record of financing and business development, I think it has clearly played an important role in the value creation story.

24:15In that business development sector right now, do you see a lot more interest in deals that are involving these CNS therapies or delivery platforms just generally? I think there is a lot of interest in the central nervous system, in neuroscience, in neurogeneration. I think there are certain things that are driving more interest than other things. you know you think about having genetic targets for instance genetic validation having good biomarkers i mean with us working on msh3 and attacks in two you know we're essentially trying to go upstream of the pathology right so we're upstream of hdt and huntingtons we're upstream of tdp43 and alas i think there is a lot of interest in that and certainly the ability with a technology whether you call that the platform or not but the technology that enables you to pursue more than one thing, I think is always attractive for partners.

25:06You know, people are investing sometimes in a single asset, but you know, if you can have a basically repeatable technology that you can deploy against different applications and different problems, I think that is very attractive. So that combination of genetic targets in the CNS and ability to run effective studies and then having technologies that can be kind of iterated around, I think is very attractive. And I think certainly we are having a lot of good conversations with strategics in those areas. And are we talking here about partnering or is this more about keeping programs in-house, letting the pipeline mature a little bit more?

25:45You know, as always with these things, Dylan, with biotech, right, it's really a long game. And so you kind of have to try to think, okay, who's the best person to take a program to a given stage, right? I think where we are right now, you know, we are uniquely positioned, I think, to move these programs forward. We have a lot of experience and expertise around how we develop these drugs. But at some point in time, there will be a point where, you know, it's going to make sense for us to perhaps work with a big pharma company on commercialization or clinical development or what have you. And so, you know, we're always talking to people and it's always about trying to understand, you know, when is the right time to engage and when are we better off running on our own.

26:27And, you know, at this point in time, I think we have programs at different stations. And so we're talking to folks about different ways of engaging. And is a company like Evox also talking to patient groups in certain countries or certain regions? Yes. Yeah, indeed. Indeed. I mean, we, you know, like, for instance, I was just out in China three or four weeks back. And we had a good meeting with the Chinese Huntington's Disease Network. we have an ongoing dialogue with CHDI which is a big international huntingtons organization so so absolutely and of course the work that we do with the red syndrome research trust I guess is a is an indicator of this too right we are engaging a lot with patients because in rare disease it's it's so important to try to make sure that you understand what's really really critical for patients from a clinical development standpoint but but ultimately also from a standpoint of the payer and for what's really going to be meaningful for patients so So, yeah, we're engaging with different stakeholders, patients, regulators, etc., to try to make sure that we build the best drug development programs that we can build.

27:34Per, let's take a look forward here. If your approach is, imagine it works, these trials continue, they go well. If it works out the way that you hope, what does this mean for a Huntington's or an ALS patient in five years, ten years from now? yeah you know i hope uh dylan that with if i take our huntingtons starting point you know i i hope with knocking out msh3 we are one of the first few companies doing that and i think the genetic data and the preclinical data that supports that target is super strong and if the clinical data is consistent with what we've seen pre-clinically i think we can have a hopefully a really big impact on huntington's disease and so you know looking at the timelines i mean we're starting our clinical study at the back end of next year and so if i look out 10 years hopefully we can be at the point where this is a drug that is actually in the clinic and is used on a routine basis right and you know we're certainly excited by that hopefully that can have a um a really transformative impact on on the disease course in huntingtons at this point in time we're going into stage two patients you know they have started having symptoms but over time i think you want to try to move earlier and earlier.

28:43And so if you could go in even pre-symptomatically, that'd be fantastic. But of course, that's a long road ahead, right? But certainly just having an impact initially in stage two and perhaps then in stage one, I think would be fantastic. And hopefully we can be there in 10 years' time. So maybe thinking a little bit closer then, what's the next big milestone for EVOX that listeners should be watching out for? Yeah, so essentially, as I say, we're looking to be in the clinic by second half of 27 so roughly 12 months from now first half of next year we're running a gf toxicology study which of course is important and then between now and then we have several regulatory interactions lined up we're right now preparing the briefing book for a pre-ind meeting with the fda for instance we've already been to the uk regulator the mhra and had a very positive meeting with them and then we have a few european scientific advice meetings coming up so we're really trying to engage with different regulatory authorities ahead of entering the clinic so as I say those are kind of the real near-term things and then as we look into 28 29 you know we're looking to generate the initial clinical data coming out of those those first first studies so so that'll be exciting.

29:56Where can people go to learn a little bit more about what you're doing to follow your progress and just stay in touch? Yeah we are We're active, of course, on LinkedIn. We have a website. We are typically attending conferences. I know I'm going to Poland to attend a big Huntington's conference in October, for instance. So I think people can find us in different settings like that. And then, of course, we're always at partnering meetings and industry conferences. So I think we're in all the standard forums that you'd find biotech companies, and certainly with the focus on the central nervous system.

30:30Perfect. Per, thanks for joining us today on Beyond Biotech. Thank you, Dylan. Pleasure. That's it for this episode. Don't forget to check out all the latest news and analysis at labiotech.eu. I hope wherever you are in the world, you have a great week ahead. Thanks for listening, and I hope you'll join us again next time for another Beyond Biotech.

31:01Thank you.