Great. Good afternoon, everybody. Happy to be moderating this panel with Nolan Townsend, CEO of Lexeo , and Eric Adler, Chief Medical Officer and Head of Research. I'm going to ask Nolan to just give a quick overview and update on the Lexeo story, and then we will do Q&A. Thank you guys very much.
Great. Paul, thanks for having us. It's always a pleasure to engage with you and the Stifel team. Lexeo is a clinical stage genetic medicines company. Our most advanced programs are focused on two diseases, two rare diseases of high unmet need. The most advanced is treating Friedreich's ataxia with a gene therapy mediated by the ABRH10 vector, where we're delivering the frataxin gene both to the heart and to skeletal muscle. This therapy is having an effect both on the cardiac pathology of Friedreich's ataxia, but also on certain neurologic endpoints. I think we'll spend some time talking about some of the recent data that we presented around this disease earlier in the year. Importantly, this program is moving rapidly into a pivotal study in 2026.
We're excited to move this program forward and potentially find a way to change the standard of care of treatment in this very, very serious disease. The next most advanced program is treating arrhythmogenic cardiomyopathy. Here we're focused on the PKP2 or plakophilin-2 mutation, which is the most common genetic cause of arrhythmogenic cardiomyopathy. In this program, we have eight patients dosed to date. We're working towards a readout of our Phase I study by the end of 2025, where we'll be looking at both biomarkers but also certain clinical endpoints associated with this disease. In general, Lexeo is a company that's focused on cardiovascular treatments broadly. I think we have a preclinical pipeline that supports other work we're doing in the cardiovascular field.
Excellent. Let's talk about the data you guys have generated to date in FACM. I think the nuance around it is that you see this signal on that left ventricular mass, but in some population that has elevated LVM. Maybe talk about the data and what gives you the confidence that the data here, even in a small end, will de-risk your pivotal study.
Maybe I'll pass it to Eric to say a few words about the data from our Phase I.
I push back a little bit, Paul. The LV mass changes in a subgroup because that would be the only group you would expect to have a change. We don't expect LV mass to move if your LV mass is normal. I wouldn't, and I think you get it. I just want to frame that for others that it's the group we expected to have the change. We learned what we saw was, I would argue it's profound because even though it's a n, if you set the context across thousands of patients in trials for hypertrophic cardiomyopathy who got placebo and hypertrophic cardiomyopathy phenotypes, et cetera, you don't see placebo generally affect LV mass or affect LV mass in any of those trials.
When we talked to KOLs in the space, that's what struck them is this reduction is just generally not seen by chance across now, you know, multiple patients. Finally, the degree of it is, you know, as a practicing cardiologist, it's impressive. You don't see 25% reductions in LV mass with placebo or, you know, just in general practice. I'd say the caveat is unless patients are really at end-stage of disease, and we roll those patients out because the patients whose LV masses go down, those are patients whose ejection fractions drop, their BNPs go up, heart failure. We didn't see any of those others. It's not the kind of, and we're not seeing patients progress to end stage. They're feeling better mFARS score, you know, across the board. Their EFs are not declining. We didn't see any of that.
In general, this looks like a pretty impressive change and I think easy to power statistically to confirm that in our pivotal trial.
Let me just add to that. I think one of the most important parts here is we've reached alignment with the FDA on that endpoint of left ventricular mass index reduction as a co-primary for our pivotal study. The effect size we need to achieve is a 10% reduction in LVMI. As Eric mentioned, we're achieving about a 23% reduction in LVMI in that abnormal LVMI population. I think we're pretty readily clearing the FDA threshold with respect to the n. I would even note that the effect size is even greater than 23% if you focus on the high doses, which is the doses that we intend to take forward into our registrational study and into commercialization.
Do you want to talk to Nolan in a little bit more detail about your engagement with the FDA and what additional dialogues, if any, you need to have with regulators to firm up the nuances of the study and what the ultimate bar is?
Yeah. As Paul's describing, we've aligned with the FDA on the co-primary endpoints of left ventricular mass reduction of 10% and then frataxin expression, which is the missing gene and missing protein, where we need to demonstrate more frataxin post-treatment than we observe pre-treatment. We achieved that degree of frataxin expression in 100% of the patients in our Phase I. I think both co-primary endpoints are de-risked relative to what we need to achieve in the pivotal study. In terms of finalizing the next steps, I think the missing information now is just the final size of the pivotal study. That's work that an engagement we have been having with the FDA to clarify that final size. I say that the size of that future pivotal study will be powered on the LVMI endpoint.
We're looking at that very closely in terms of what incremental data do we need that can help support getting to an approval and powered in that manner. I think that's the primary focus of the conversation with the FDA is to reach final clarity on that size of the study. It would be powered again by the LVMI endpoint.
Are you thinking, Nolan, that what matters is you get a certain percentage of responders or that the mean median is greater than 10%?
I think it's different for each endpoint. I think the LVMI endpoint is certainly likely to be an average or median. I think the frataxin endpoint is likely to be a responder analysis.
How are you guys thinking about selecting the population for the Phase III? You know, how might you be able to enrich this for a higher LVMI baseline?
Maybe Eric, do you want to speak to that?
Can you repeat that? I don't totally understand. How are we going to be able to enrich it?
Yeah, I guess, Eric, right? Obviously, it would seem like the higher the LVMI baseline, the better, right? Maybe you guys have presented, I think, a lot of interesting data on the spectrum of LVMI in this population. Obviously, it's variable. For example, do you think you can enrich the Phase III where the average patient has 30% elevated LVMI at baseline? I'm just throwing out a number.
I think we're going to enrich it by the inclusion criteria of two standard deviations, which that's the criteria that will help us. That's the main thing.
What is that like in terms of the actual amount that it's elevated in this population?
Like what percentage are the actual numbers?
Yeah, given that the effect size is in percentage not standard deviation.
Yeah, I think you're around 20%, 30%.
Okay, that's the target population.
Yeah. Obviously, this disease is not like Danon where these patients are, you know, 4x LVMI, 5x standard deviation. They get heavy, but not quite as heavy. The good news is as we get to two standard deviations or so, you can see profound effects of the drug.
Okay. Before we talk about PKP2, can we just talk a little bit about safety? Maybe talk about the dose level you're at and your comfort, right, in your sort of capsid specific safety margin. Just on frataxin expression and expressing frataxin in the liver, things like that, what gives you comfort that that's not going to show something as more patients are exposed?
I think that, in terms of capsid concerns, which are front and center for folks, we're dealing with logarithmically lower doses than we see in other trials when this comes up. I think we feel comfortable in the fact that we haven't seen it now across 16 patients or so. Obviously, that's a good sign. That's a healthy amount of patients. In terms of frataxin itself, again, we with intention designed this where we're trying to give enough frataxin and not try to get it far above wild type levels, which is where I think other people kind of got stuck when they were initially designing the FA gene therapy. The levels that we're getting, we're not above wild type in our biopsies. That translates to levels in liver, et cetera, that are not going to be significantly high that you would anticipate frataxin toxicity. That played itself out.
People look very closely at this in preclinical models where we never got close to frataxin liver toxicity, even at our highest doses, and have some comfort around that.
Yep. Okay.
I'd add a few things here. I mean, one, we've seen no clinically significant or really meaningful elevations in liver enzymes or in complement. We have a poster we've presented to that effect, in particular for complement. I think that that's a unique sort of attribute of the ABRH10 vector, as it does not appear to result in these increases in complement that you would expect to see with other capsids. What that also then means is we don't need the level of immunosuppression that you may see in other programs. Safety in gene therapy is linked to dose. As Eric described, we're at a 100x lower dose than what you would observe in some of the other systemic programs. Also, by virtue of having this attractive profile with respect to complement activation, we've not needed significant immunosuppression for this program.
We're simply using prednisone, a modest dose, which means that we wouldn't expect to have safety issues associated with immunosuppression either. I think from both perspectives, the lower dose and the existence of a very modest immunosuppression regimen implies a compelling safety profile. For the dose we had to take forward, we intended to take forward into the pivotal study and into commercial, we've not had a single drug-related SAE associated with that dose. This is after a year plus that patients have been on treatment at that dose level.
Okay. Great. If this is approved, what do you see as the early target market in terms of kind of the specific patients, the percentage of total, and how do you see that evolving over the long term?
Yeah. I think from a commercial standpoint, we would see the early adopters being the high left ventricular mass population. These are patients that are the closest to the late stages of the disease, which is ultimately, you know, this heart failure, cardiomyopathy is the cause of death. I think we'd see the early adopters as that high LVMI population. I would also note the effect we're beginning to see in the neurologic disease as well. We're getting improvements in the mFARS, the Friedreich's ataxia rating scale that's roughly similar to the commercially approved treatment. I would expect patients that over time, as they move from earlier stages of cardiac disease to mid and later stages, they begin to seek treatment. I think we'll also have a value proposition for patients that are even earlier in the disease and being able to hopefully stop or improve their neurologic disease symptoms.
I would see this as the continuum, high LVMI population, less advanced heart disease, and then gradually those patients that do not yet have cardiac disease associated.
Makes sense. Anything to add on FA before we talk about PKP2?
Nothing to add beyond that.
Okay. Great. Let's talk about PKP2. I think like the one, maybe just review the thesis and in the context of the kind of gene therapy thesis here, like what are the most bothersome symptoms to patients with this?
I don't know if Eric, you want to start with that.
I can jump in. This is a disease that patients are reminded of every day because they get these ventricular contractions. They get skipped heartbeats, often runs of them. If they have more than three skipped heartbeats in a row, that's non-sustained ventricular tachycardia. They feel that. It's kind of a reminder of your mortality every day because they don't know when they start feeling these skipped beats. They don't know, is this the one that's going to cause me a shock? Especially for those that have had shocks from the defibrillators before, this is torture for them. It's really, really frightening. Patients have high rates of PTSD. You have that element of just this fear of shocks that happens. I talk about patients. I have a patient that carries around a magnet with him because he's so afraid of a shock.
He sits in a chair, puts the magnet on his pacemaker, turns it off. He wants his heart rates to go so fast that he passes out, the magnet drops, and he shocks him. He's willing to risk death to avoid a shock, if that makes sense. That's the first thing. The second thing is they go on to get heart failure. They have a lot of problems with RV failure. 50% at 10 years are going to need a heart transplant. RV failure is terrible because it's not treatable with the drugs that we have. GDMT doesn't work. They get liver failure that precludes them from getting transplants. They get edema, ascites, etc . Finally, for the younger patients, you have this exercise restriction. They're told they can't exercise.
For young folks, that's pretty, you know, they come to see cardiologists who tell them you can bowl and play like non-competitive ping pong. That's like a change in your, especially in our day and age, right? Those three things are front and center for them. If anyone's concerned about how, you know, is this a morbid disease that patients are going to want treatment, look at the patient enrollment across all these. This is a disease with 70,000, 80,000 patients, but this is not a disease in which anyone is struggling to enroll patients in trials. We didn't at all. We're exactly where we are. In this case, having multiple people in it and they're all enrolling on target tells you that patients are coming out of the woodwork. They're coming to the sites and they want this drug because they're willing to be in trials.
What's the right endpoint for both showing real robust proof of concept and then also for potential registration?
I think that's why we're doing the Phase I, right? We're going to look at a totality of data to see. Our first thoughts is PVCs is a very ordinal endpoint, which I know folks like something that they can measure before and after. It relates to, it fits all the criteria because people feel them. They don't like how they feel and it also predicts mortality. It's a field function survive endpoint from the beginning. It's been used in at least two other trials. The FDA's agreed to use it as an endpoint. That being said, we have to look at the data. Other interesting endpoints could be non-sustained and sustained VT. I think that's a really important one. That's more meaningful to patients when they, you know, can you reduce three or more PVCs in a row?
Because that all of a sudden now goes from just a PVC to non-sustained VT. I think that will be very meaningful to patients. Certainly VT when it's 30 seconds or more or, you know, a shock from a defibrillator, that's important endpoints. Finally, we're measuring imaging endpoints like right ventricular function. That's something that no antiarrhythmic is going to affect, right? That's meaningful to patients. Like, are we truly changing the biology of this disease? A lot of, there's a ton of different questionnaires, the PROs that we can lean on, like PROs around anxiety, depression, quality of life, et cetera, which I think are also going to be impactful for patients and regulators.
Can you help set up, Eric, the next data disclosure we're going to get here? On Wall Street, everyone loves to kind of tee up what the bar is for success or for a good outcome. What are we going to get and what are we hoping to see?
I'll let you all on speaker one.
Yeah, maybe I'll take that one. First, I think, unlike Friedreich's ataxia, and probably the case in other genetic cardiomyopathies such as Dan, I think the cardiac biopsies played an important role in those studies. As you know, it's one of the co-primary endpoints of our pivotal for FA. We think the biopsies will play a less important role in PKP2 or arrhythmogenic cardiomyopathy, primarily because this is a disease where the patients have baseline protein anywhere from 20%- 40%. The addition of an increment of protein, it'll be harder to determine what that means from a therapeutic benefit perspective. While we will have biopsies as part of the readout, I think our focus for this readout is more so on the clinical data, the endpoints that Eric described, PVCs, NSVT, EKG measures, imaging measures, and so on.
We're working towards having the majority of the patients that we've dosed to date beyond six months of treatment follow-up, where we can focus on the clinical data that we think is relevant for this disease. Ideally, we see an improvement across more than one clinical measure, and that would be the focus that we'll have for looking at success for this program.
What magnitudes of improvements in this disease would you say are clinically meaningful?
I think it's the totality of the clinical improvement. We couldn't look at any single endpoint and say a certain percentage change ultimately results in an effect. I think there's a criteria for a patient to be diagnosed with arrhythmogenic cardiomyopathy in the first place. There's sort of five domains to that criteria. I think we'd like to see improvement across, call it, two of these domains in order to say we're having an impact on this disease. The specific effect size per domain, I think, would be hard to determine a priority. I think we'd like to see an improvement in more than one in a single patient. You're on mute, Paul.
That makes sense. Thanks, Nolan. How should we think about the competitive dynamics in this disease? I feel like in FACM, it's been a little bit more straightforward to compare across programs. In PKP2, I think there's not really clear consensus out there. How would you frame it?
Yeah, the way I'd frame it is each company's using a different capsid and each company's using a different immunosuppression regimen. I think there are some differences in the doses. Maybe these are, on the scale of gene therapy, relatively small differences. I would say that the success of one program in demonstrating clinical efficacy is likely to be something you could translate to the other programs. I think that the real question in our view is you're developing a gene therapy that you intend to, where you intend to treat or try to treat 60,000 patients. That gene therapy must be safe. I think probably one of the major differences in how this may all play out across the programs is related to safety profile. We have taken the step of giving a safety update for this program and our FA program every single quarter with our quarterly print.
We've talked about, are we observing treatment-related SAEs? We've talked about, are we observing complement, things like that? I don't know that many other companies are doing that. I think that's just a testament to how we think about safety, the importance of safety, and obviously keeping the market aware and being able to follow along with how the safety profile is evolving across this treatment. That's kind of how we see it as that probably the differentiator between the programs ultimately.
I would look at safety, and we're learning this from multiple gene therapy trials, and we saw this in non-gene therapy trials recently as well. It's the totality of safety events, just like, you know, everyone, you know, you can say drug generally well tolerated, but you're looking for patients who are walking around talking, they're having shocks, but they're not on death's door and asking them how much taking immunosuppression, severe significant immunosuppression is associated with adverse events as well. Adding induction therapy, all these things, we know in transplant, and if you put on a transplant cardiologist lens, a lot of the adverse events are not just related to the transplant itself, it's the drugs we use to immunosuppress. I think looking at those and seeing the adverse events in totality is really important.
How fast do you guys see yourselves moving here? If the data later this year are good, what do you see as the next steps with regulatory engagement and potentially starting a pivotal trial?
I think we want to see the data at a sufficient stage of maturity to have robust and credible conversation with the agency. We have eight patients dosed. We intend to have 10 in the trial. I think we'd like to see all of the patients probably beyond six months, so we have a sufficient accumulation. The regulatory engagement is probably a 2026 event. Now we are in our commercial, our Phase I material is in our commercial process. We could theoretically move very quickly to produce the batch for the pivotal study. I think we'd probably be working with a set of the same sites in the U.S. that we're using for our Phase I, so the site startup is probably pretty rapid.
While we can't guide to timelines for the start of the next study, I think we could see a setup here that could allow us to move very quickly following that FDA interaction. I would guide that that interaction is probably a 2026 event.
Yeah. Yep. Okay. Great. We only have a minute left here. Anything else you guys would like to highlight about Lexeo?
I think I would say that, you know, there's obviously been a lot of different positives and negatives that have occurred in the gene therapy field in the last few months. I would say if one were focused on safety, you know, safety in gene therapy is linked to dose. I think Lexeo has and has always been the gene therapy company focused on, you know, treating the diseases of focus, but doing so at the lowest possible dose that we can achieve some clinical benefit in. I think this has resulted in the safety track record of the programs that we've been communicating quarterly, which has actually been pretty compelling for gene therapies. I would say that we're achieving the results and efficacy and so on that we're achieving, but doing so with safe treatments. That's what's important to us here at Lexeo .
Great. Maybe just to finish it off, Nolan, you want to remind everyone of your cash runway?
Yeah. We recently completed a capital raise in May of this year, which gives us a runway into 2028. This should be several quarters beyond when we expect to have the data readout for our Friedreich's ataxia pivotal study. We're well capitalized against the upcoming milestones.
Okay. Great. Thank you guys for taking the time. We appreciate it.
All right. Thank you, Paul. Appreciate you having us on.