Name:
Front Row - Dr. Townsend
Description:
Front Row - Dr. Townsend
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Duration:
T00H24M45S
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Upload Date:
2023-10-19T00:00:00.0000000
Transcript:
Language: EN.
Segment:0 .
[MUSIC PLAYING]
MALORYE BRANCA: Thank you, Mr. Townsend. It's such a pleasure to talk to you about this very exciting new endeavor. And what we wanted to start with is to-- because this Alzheimer's disease has been such a difficult topic for so many companies. So challenging and yet there's been so much research in it. What is the background for the research behind your approach? And where did it come from? And how has it evolved?
R. NOLAN TOWNSEND: Thank you for asking. So LEXEO, as a company, is a spin out from Ronald Crystal's lab at Weill Cornell. Ron Crystal was one of the early pioneers in the gene therapy field. He was involved with dosing the first patients with gene therapy utilizing a virus in the early 90s, and has been involved in several other milestones in the field since then. And the basis of the company was really a technology source from Ron Crystal's lab, including this program.
R. NOLAN TOWNSEND: And he had done a significant amount of preclinical research focused on the APOE4 gene and also delivering the APOE2 gene to into the CNS of mice and non-human primates in order to advance his program. There was a very strong preclinical data package that supported a successful IND that then moved this program into the clinic. It was around that point in which LEXEO, as a company, was launched and this program was then licensed from Ron Crystal's lab into the company.
R. NOLAN TOWNSEND: And we've since advanced the program through clinical development over the last 12 months. But the basis of the technology, the thinking, the science was from Ron Crystal's lab at Weill Cornell.
MALORYE BRANCA: Can you tell us a little bit about the background for why APOE? What brought that to light? I think I believe that this was long standing target and nobody's been able to do anything with have they?
R. NOLAN TOWNSEND: Yeah. There's a lot behind it. I think there's just the fundamental epidemiology. There's highly enriched in terms of APOE4s that end up developing Alzheimer's disease. There's a 15 to 20 times higher likelihood of developing Alzheimer's disease if you have the APOE4 gene. This is higher likelihood than normal. Normal being APOE3 of which most of us are.
R. NOLAN TOWNSEND: And interestingly, APOE2s have a lower likelihood of developing Alzheimer's. But most interestingly, for E2/E4 heterozygotes, the existence of E2 removes the E4 risk. So this is basic fundamental thinking behind the program. Let's say the genetic validation behind it is that the existence of E2 removes that E4 risk. APOE4 is known to be involved in a number of different processes associated with Alzheimer's disease.
R. NOLAN TOWNSEND: Nerve death, the formulation of tau tangles, amyloid depositions, and a number of other inflammation, so a number of processes involved with Alzheimer's disease. I think the addition of APOE2 is meant to be in some ways protective against the disease. So this is the basic formulation, basic formula behind the program in terms of the thinking. But I think from there, it was about how can you successfully deliver the APOE2 gene to the CNS of APOE4 homozygotes to confer to patients that same protected benefit that a natural E2/E4 heterozygote has.
MALORYE BRANCA: Does this address any of the heterogeneity that we see in Alzheimer's? Will this be directed at a certain subset of patients or will have a broader reach?
R. NOLAN TOWNSEND: The current clinical program, the inclusion criteria is focused on patients with mild cognitive impairment. These are all APOE4 homozygotes above 50 years of age. They have both tau and amyloid pathology from a biochemical perspective. So that's the target of the existing clinical program. I could see once we demonstrate that the treatment is safe for patients broadly, there could be a potential of addressing earlier patients, potentially pre-symptomatic patients, and potentially addressing patients that are at a more advanced stage of disease.
R. NOLAN TOWNSEND: But today's treatment, the phase I study is focused on patients with mild cognitive impairment with the other criteria that I mentioned.
MALORYE BRANCA: Will your results be based mainly on their testing, their cognitive testing or do you have biomarkers that you're also using?
R. NOLAN TOWNSEND: Yeah. It's a phase I study. It's a safety study, dose escalation, five patients per dose in three doses, which is common for a phase I study in gene therapy. However, we are also looking at the biomarkers that are commonly associated with Alzheimer's disease. So this is amyloid beta, tau, and phospho-tau, and some others. So I think we are looking to determine whether the addition of E2 does have an impact simultaneously on these different biomarkers.
R. NOLAN TOWNSEND: The study is not powered to show a benefit in cognitive decline. However, we are looking at some of the cognitive decline measures that are common for any Alzheimer's study.
MALORYE BRANCA: There's a lot of new companies in gene therapy now. It's a very active field. What do you bring that's new to it?
R. NOLAN TOWNSEND: I would say a few things. I'd say just taking a step back as a company. I think the research legacy that we have in gene therapy goes back decades. So a lot of the learning that was developed at Cornell in Dr. Crystal's lab is ultimately made its way into the way the company thinks about developing its programs. It also makes its way into the targets that we ultimately advance as a company.
R. NOLAN TOWNSEND: I think we've been very selective, especially in the CNS side of things, as to the diseases we target, where we feel that we can actually have a meaningful impact for patients and diseases of high unmet need. The APOE4 is a great example. As you know, the existence of APOE4 and its link to Alzheimer's disease has been well understood.
R. NOLAN TOWNSEND: The protective benefit of E2 has been well understood. But as you suggested, no other company has really gone after this target. I think this bold thinking that's gone into us pursuing this APOE4 target in Alzheimer's disease is also something that we plan to do across other indications. So I think what we bring new is just a very bold approach to addressing some of the diseases that have high unmet need today.
R. NOLAN TOWNSEND: Beyond this, we're building a really high quality team. All of the senior team here has some prior experience or track record in the gene therapy space, coming both from pharma and from other gene therapy biotech companies. So I think the two together is something new and unique for the gene therapy space. And hopefully, we're able to demonstrate benefit for patients.
MALORYE BRANCA: And how are investors and prospective employees responding to this?
R. NOLAN TOWNSEND: I think responding very positively. I think as we look at the profile of LEXEO, we are a post-Series A company with multiple clinical stage programs. It's a very mature product pipeline for a company at our stage. And I think investors recognize that. I think potential employees of LEXEO recognize that as well. I also think our location is relatively unique. When we formed the company, we chose to continue to locate the company in New York City.
R. NOLAN TOWNSEND: This is a somewhat unique location for a clinical stage. Gene therapy company most are and a couple of other biotech ecosystems that exist across the US. So we have a number of different colleagues that have come to us from large pharma companies that are in the area that have felt they've always wanted to work in biotech, but they've not wanted to move to Boston or San Francisco in order to do that. So I think we've had a unique positioning for ourselves in respect to attracting talent.
R. NOLAN TOWNSEND: And this also happens to be where a number of our investors are located as well. So I think the geographic location of the company has been an advantage for us as well.
MALORYE BRANCA: Is there a technological tweak that something that makes your gene therapy delivery different?
MALORYE BRANCA: So there's I think two elements for these particular indications we're mainly focused on now. I think we are applying a known capsid serotype in different ways and others are applying it. So this is the AAVrh10 serotype. It has not been traditionally used for treating cardiac diseases. However, some of our data suggests that this could be the most cardiotropic vector amongst the commonly used vectors today.
MALORYE BRANCA: And it has allowed us to transduce the heart at doses that are low for systemic gene therapy, but still achieve protein expression that has allowed us to correct Friedreich's ataxia and some of our preclinical models. And so I think this new application of a known vector is something that is unique and different for what we're focused on. I also say we've made unique expression cassette modifications in some of the indications we're focused on.
MALORYE BRANCA: We think that modifying and enhancing expression cassettes could have real advantages in improving the expression profile of some of the gene therapies that were focused on. So those are I'd say two of the key differences in our approach relative to maybe some of the other companies that are [INAUDIBLE].
MALORYE BRANCA: With the Alzheimer's disease though, is there anything technologically different or are you using the tried and true [INAUDIBLE]??
R. NOLAN TOWNSEND: Well, the capsid itself is known. It has been used in CNS diseases previously. So I'd say there's a benefit to that, and that it has a known safety and efficacy profile. In fact, it was used in our phase I study for our CLN2 Batten disease program, demonstrated both safety and efficacy there reaching clinical proof of concept. So I think using a known capsid has significant advantages when you're moving into the clinic.
R. NOLAN TOWNSEND: For the construct of the Alzheimer's, the actual expression cassette itself, there are some pieces of that we've not fully disclosed publicly. But I do think there are some unique elements to it. But moreover, I think for gene therapy now and where it's headed, a lot of the constructs that we're pursuing in terms of expression cassette and vector on the margin, improve the expression profile of whichever gene therapy we're focused on.
R. NOLAN TOWNSEND: I think today, it's about some of the clinical development aspects of drug development for gene therapy. It's finding the right dose, finding the right target patient population, designing the studies correctly. I think this is where gene therapy is, from a development perspective, is that some of the modifications that we can make in the early science could play a role in improving the profile of the gene therapy incrementally. But I think the real gains are going to be made by successfully moving these programs to the clinic and getting them to patients faster.
MALORYE BRANCA: What do you see as the biggest hurdles for your programs in Alzheimer's?
R. NOLAN TOWNSEND: First, the most simply, it is finding and enrolling patients into the clinical study. There are a lot of patients that obviously have Alzheimer's disease in the United States, but they don't all know whether they have the APOE4 gene variant. And I think that this is something that gradually, more neurologists are beginning to become aware of that.
R. NOLAN TOWNSEND: Actually, doing this genotyping work could be beneficial for patients, because it would help to understand their eligibility for certain clinical trials such as ours. But obviously, there are others out there focused on APOE4. So I think the first challenge is just ensuring we can find patients that are eligible for the study based on the inclusion criteria and are aware that they are APOE4 homozygotes.
R. NOLAN TOWNSEND: Beyond this, once we're able to demonstrate that adding the E2 gene can have this impact on these biomarkers that we're tracking. We'll be designing a phase II or phase II/III study that can demonstrate a benefit in cognitive decline as well. And that obviously, for any Alzheimer's program, is a big step to take.
MALORYE BRANCA: Does it change your horizon at all that one drug has already been approved and it looks like there's another one in the transom there for Alzheimer's? Does the therapeutic environment effect what you're doing? Or do you think what you're doing is fundamentally different enough that it will not be impacted?
R. NOLAN TOWNSEND: I don't see any direct impact. I would, in general, say that over time, we'll see this probably more clearly. I don't think a patient that is being treated with an antibody would be ineligible for a gene therapy, fundamentally ineligible for a gene therapy. So I don't necessarily see the approaches in conflict with one another by any stretch. I actually think bringing more treatments into the Alzheimer's area for patients and making these treatments available is generally a positive thing, both for the Alzheimer's field, but also obviously, for patients.
R. NOLAN TOWNSEND: But it also I think just brings more investment in capital to the Alzheimer's disease area more generally. Today, you've seen the majority of Alzheimer's treatments are being developed by some of the large pharma companies with deep pockets. You've seen a lot less of this with smaller biotech companies. I think this is related to the perceived, let's say, risk profile of Alzheimer's drug development. And maybe some of the earlier stage, venture, and public market investors a little bit more risk averse when it comes to this area.
R. NOLAN TOWNSEND: And therefore, it has been mainly the pharmas that have been focused there. I think this approval may change that and subsequent approvals may change that even further. So I think that this is all positive for the Alzheimer's field.
MALORYE BRANCA: Excellent. And when you look back at the history of Alzheimer's, has that created any kind of a cloud? People are always wondering how can these drug developers keep being optimistic about this field and what made you guys dive into Alzheimer's as one of your first indications?
R. NOLAN TOWNSEND: I think that this challenge of Alzheimer's is very, I don't know, I'd say fundamental to the substance of the risk in return of drug development more generally. I think it's exactly the kind of research that society wants from the biopharmaceutical industry is that we try to tackle diseases of high unmet need despite the risks associated with them. I think that that's why you've seen a number of companies despite the failures that continue to work in this area, because they understand that there's a significant return for this in terms of just being able to address a disease that has such high prevalence and presumably growing prevalence over time with aging populations in most countries.
R. NOLAN TOWNSEND: So I think we will continue to see companies that are advancing development programs in Alzheimer's. And interestingly, with each failure, I think we begin to understand what does not work. And therefore, we begin to focus on areas of science that do have, let's say, more promise to them and presumably produce a greater benefit for patients. So interestingly, with each failure, the probability that the next treatment will work increases.
R. NOLAN TOWNSEND: Because we now know that the failed areas do not. So for those reasons, I think a number of the pharma companies have continued to invest in this area. The companies that obviously we're aware of. And I hope to see and I expect to see more of the earlier stage biotech companies focused in this as well.
MALORYE BRANCA: Have the number of targets in Alzheimer's increased or have they been pretty steady over the last few years?
R. NOLAN TOWNSEND: I think there's been a pretty steady number of targets that have been considered in Alzheimer's. I think what's changing is that the understanding of those targets is becoming more sophisticated and more advanced than before. I know that there are really two different camps out there. There are those who believe that the tau pathway, the tau is the one of the drivers of the disease, and the other one is amyloid beta.
R. NOLAN TOWNSEND: Interestingly, it's our view that both will play a role in the pathogenesis of the disease. And that the way to truly address Alzheimer's disease is to go upstream, treat the genetics of the disease, which then should have a downstream impact on multiple different pathogenic mechanisms, including amyloid beta, tau, and others. So this is fundamental to the approach that we're taking is that actually we're going upstream and treating the genetics of the disease, which doesn't have us taking a view as to whether it's amyloid beta or tau that's driving the pathogenesis.
R. NOLAN TOWNSEND: We're addressing both via the genetics.
MALORYE BRANCA: But you said earlier that you're starting with the people who have the earlier development.
R. NOLAN TOWNSEND: That's correct.
MALORYE BRANCA: Correct. And is there any idea now whether it reaches a point where there's no intervention possible or does it-- I thought you mentioned that you might be able to use it later.
R. NOLAN TOWNSEND: So I don't think the answer to that is known. So what you're describing is that there's a cascade associated with the disease and has it gone too far to be stopped or reverse. I don't think the answer to that is known. I think for us today, it's just with this earlier patient population, first demonstrate safety, but secondly, demonstrate that introducing the E2 gene can have this impact on multiple different biomarkers associated with the disease.
R. NOLAN TOWNSEND: I think once we're able to demonstrate that, I could envision future studies that look at patients that are pre-symptomatic and a primary prevention indication. And potentially, look at patients that are a little bit more advanced. I think we'll have to see the results of those studies before we have a clear view on whether we can stop this progression if it's a bit further along.
MALORYE BRANCA: So it was interesting that you're doing both CNS and cardiac. Those are very different fields. What's the reasoning behind that?
R. NOLAN TOWNSEND: I think we have legacy capability in both areas. I think that legacy capability has generated learnings that we can clearly apply to future programs in the area. That's really the key driver behind our interest to focus in both. I think we see that our capability set from a manufacturing, clinical development, regulatory strategy, all of that will apply across both areas equally.
R. NOLAN TOWNSEND: And some of the main differences between CNS and cardiac are related to the routes of administration, the dosing, some of the vector design, expression cassette design, and so on, which are really on the discovery and preclinical research side. Today, LEXEO is primarily focused on a handful of clinical stage programs. And therefore, adding more clinical stage programs of a similar type into that picture will leverage the learnings that we're generating today.
MALORYE BRANCA: But does the Alzheimer's program lead to any other diseases? Or do you think that it will be onto its own? And any other-- for example any other related dementias would have to have their own program.
R. NOLAN TOWNSEND: I would say it the reverse actually. So we have a CLN2 Batten disease program that has a completed phase I. And a lot of the learnings we've developed with that program, we are applying to the Alzheimer's program. So some of the results we've gotten in the CLN2 program and that we continue to get via some of the more recent work are a good read through for what we may expect in the Alzheimer's program. So I think it just increases our probability of, let's say, technical success with the Alzheimer's program, because we've advanced our CLN2 Batten disease program to the state-- to the place it's been advanced to.
MALORYE BRANCA: Excellent. Is there anything else that you'd like to add about LEXEO and your programs and your prospects?
R. NOLAN TOWNSEND: Yeah. So we focused a lot on the APOE4, the clinical stage APOE4 program. This is the one where we're adding the APOE2 gene to the CNS of APOE4 homozygotes. And the idea being we can hopefully alter their CNS to become E2/E4 heterozygotes and give the same protective benefit that APOE2/4 heterozygotes have naturally. But we have two other programs that are in pre-clinical development.
R. NOLAN TOWNSEND: One we're simultaneously adding the APOE2 gene but also suppressing E4. So the idea there is that if the clinical stage program shows some benefit to patients, the preclinical second generation program should show an even more dramatic benefit. We're also doing some research around what's called the Christchurch mutation, which is an interesting genetically validated target as well that's focused in the APOE region.
R. NOLAN TOWNSEND: And that's another interesting approach with the very similar strategy to what we're doing today. So it's really a portfolio of approaches focused on the genetic drivers behind Alzheimer's disease. So I think with these programs advancing, we'll have one of the most sophisticated understandings of the genetics behind Alzheimer's disease. And we're excited to bring these learnings to the Alzheimer's community, both scientifically and to ultimately benefit patients.
MALORYE BRANCA: And do you see yourselves as going this alone for now or partnership is an option and something you're actively exploring?
R. NOLAN TOWNSEND: For now, I think we're staffed and structured to be able to move forward and complete the phase I study in APOE4. We're certainly staffed and structured to be able to pre-clinically advance the two programs that I mentioned. So for the foreseeable future, we'll likely to go it alone. I know that a large pivotal study in Alzheimer's is a heavy lift for a small company.
R. NOLAN TOWNSEND: So at some point, it may be something we consider. But I think for the next couple of years, we're likely to go it alone here and hopefully deliver value and benefit for patients. So we're really excited about that.
MALORYE BRANCA: Well, thank you so much for your time. This has been fascinating. We're going to be watching you guys closely. [LAUGHS]
R. NOLAN TOWNSEND: Absolutely. Look forward to being in touch and thank you for the conversation. [MUSIC PLAYING]