RBC Capital Markets. Today is our great privilege to have Lexeo Therapeutics as part of our 2026 Global Healthcare Conference. Representing the company, we have Nolan Townsend, our Chief Executive Officer, as well as Nani Bhalla, who's the Chief Medical Officer here. We appreciate everyone joining here. I have a long list of questions here, Nolan, but maybe before we go into the specifics, you'll be fantastic if you can maybe just give us a little bit of an overview of what progress has the organization made over the last few months, and maybe most importantly, what's ahead here for Lexeo.
Sure. Thanks for having us. It's always great to be here. Lexeo is a clinical stage gene therapy company focused in genetic cardiac disease. Our most advanced program is treating Friedreich's ataxia, both the cardiac pathology of the disease. We're showing an improvement in cardiac hypertrophy, which is the hallmark of the disease, and several other cardiac biomarkers. We're also showing an improvement in.
Yeah.
The neurologic scales of Friedreich's ataxia as measured by the mFARS scale, which was used to approve the existing commercially approved treatment. We're seeing an effect size in mFARS or the neurologic scale that's similar to the commercially approved treatment. We're also seeing a meaningful improvement in the cardiovascular disease. Taking the two together, we think this therapy that we're developing could change the standard of care in Friedreich's ataxia. We're working towards starting a pivotal study associated with that program within this quarter. We should have a top-line readout next year and then be working towards a BLA. We're in the final stages of aligning with the FDA on that pivotal study protocol, and I, you know, I know we'll probably discuss that. Our next program is in PKP2 arrhythmogenic cardiomyopathy.
We completed enrollment of the phase I/II study last year, so a total of 10 patients treated. We have seven patients treated at the high dose. We reported data associated with that program in January. We showed about a 22% reduction in non-sustained ventricular tachycardia, which is a, you know, very important endpoint in this disease. That 22% reduction in non-sustained VT is roughly similar to the existing standard of care in these anti-arrhythmic therapies. With most of the patients at the earliest time point where we can evaluate efficacy, we're already seeing an effect size similar to the existing, you know, therapies that are out there for patients. The two patients that were at longer time points, so at nine months, we're seeing an average 65%, you know, reduction in non-sustained VT.
In the early data set, we were seeing a deepening effect, you know, over time. For that program, we're working towards a data readout this year. In the second half of the year we should have all of the patients at 12 months. And we're also working towards a regulatory update for that program within 2026. Taking the two together, I think we'll have a picture of the effect size we're observing across key endpoints in the phase I/II study. We'll also have an understanding of what the FDA would like to see in a next study, and I think would set up the program for its future next steps. Those are two of the key, you know, focal points for the company.
We had some interesting data reported at ASGCT associated with one of our preclinical programs in TNNI3 hypertrophic cardiomyopathy. This is a thin filament, you know, a thin filament disease, and we're working with Johnson & Johnson on localized delivery approaches for TNNI3 gene therapy, where we're looking at some novel approaches for that. That's what's coming, you know, potentially in the future.
Gotcha. Gotcha. That's super helpful. Maybe let's go back to Friedreich's ataxia cardiomyopathy. Never a boring day with the FDA these days, right? There's always a lot of moving parts. The fact that Vinay Prasad and Marty Makary gone from the FDA, good or bad for Lexeo?
Yeah. Well, look, I think, the way I'd like to look at this it, you know, things swing. It seems like they swing back and forth.
Sure.
I mean, when Peter Marks and Nicole Verdun were leading CBER, I think we saw a wave of, you know, very supportive approvals and supportive kind of regulatory backdrop that helped accelerate gene therapies through, you know, through to accelerated approvals. We saw under the past leadership of CBER, the most recent leadership, we saw a wave of, you know, frankly, setbacks of gene therapy companies and programs and, you know, a couple of the examples that everyone is familiar with. I think in, you know, we probably are going to see a swing back in the other direction with respect to how the leadership thinks about gene therapy re-regulation.
For us, I think our conversations, we have been, you know, updating the market in terms of where that's headed. I think the study design that, you know, that we've submitted to the FDA is in line with the prior guidance. We've also reflected all of the feedback that we've gotten from the FDA throughout the process. So we think we're likely to land with a study that's of, you know, a reasonable size, length, and risk profile against what we've been working towards over the past period of time. In general, I think it's best not to over-index on one particular, you know, leadership group of the FDA, right? Because we know that things can change over time.
What we want to do is find, you know, the study design and the study structure that can clearly demonstrate the effect size of the drug. We think the things that we've guided to previously, you know, can allow us to do that.
Yeah. Yeah, and hopefully we find some middle ground between Peter Marks on one side and maybe Vinay Prasad on the other side.
Right.
That'd be helpful. Maybe sticking to FDA conversations, it sounds like you have had a meeting with them not too long ago. I think you submitted the SAP, I believe is in February.
In February, yeah.
Have you gotten any kind of formal feedback from the FDA? You're still waiting for it, or are you getting any informal feedbacks? Like what has been the nature of the conversations with the FDA?
Yeah.
Most recently?
Just to, you know, step through it, we had a Type B meeting last year. We also had a CDRP meeting, which is the CMC pilot in the first quarter of this year. We also submitted the protocol, as you mentioned in February for review. We have heard from the agency. We have had some back and forth. We are in communication with them. It has taken longer than what we anticipated. We believed it would be 30 days or potentially 60 days. We're now coming up on 90 days. It's taken a bit longer than we expected. You know, in the meantime, we have a natural history study that we've started recruiting.
This natural history study has an identical inclusion criteria to our treatment study, which means while we are waiting to align with the FDA, we are actively going and finding patients which could be eligible for our treatment study. To the extent we reach this alignment this quarter, which is what we expect, we are in a position to rapidly transition to, you know, launching the treatment study. We have to go out and find the patients and, you know, screen them anyway. We're doing that as we speak, but in the context of a natural history study, where patients can then cross over into the treatment study.
We don't think that this additional, call it, you know, 30+ days that we've been, you know, working to finalize this protocol with the FDA is actually going to impact anything from a broader development timelines perspective. We're still on track for the top-line readout in the timeframe that we have guided to previously, and we're still working towards a BLA in the timeframe we've guided to previously as well, given what I just described.
Gotcha. Is the 30 days going to 90 days, going to 60- 90 days, what's your read? Is that just a function of bandwidth? The FDA has not as much bandwidth or maybe in prior conversations with you had, with the FDA, was there, like, any disagreement between kind of senior leadership and the reviewers? Was everybody on the same page? How should we think about all those dynamics?
Well.
Go ahead.
I'd say, we believe it's bandwidth. That's our belief, 'cause there were some periods, like early on, we didn't hear anything, so it would have reflected that they hadn't even gotten to the file yet. That's what our belief is. You know, Vijay Kumar has been involved in the meetings we've had. He's still there as the interim head, lead of OTP. There's been some consistency, at least at the OTP level. Above that, we're unaware of agreements or disagreements. Vinay Prasad was never in one of our meetings. Neither was Peter Marks. I think we've always the most senior official that's been in any of our meetings has been at the OTP level, whether it was Nicole previously or Vijay now in the role.
Yep, gotcha. That's helpful. Let's maybe talk about the study design at this point. How are you thinking about that study design to potentially get through accelerated approval? Again, you mentioned concurrent natural history. Is there a scenario where the FDA ask for a randomized control trial at this point, or do you think that that would be extremely unlikely and inconsistent with all the feedback that you have heard so far?
Yeah, there's been no discussion of a placebo in this context, I think because LVMI is a objective endpoint. There's no placebo effect of a cardiac MRI that's been observed. There's no spontaneous improvement of cardiac MRI.
Sure.
I think placebo has never been a point of discussion for an endpoint of this profile. I think, you know, at least based on all the feedback and conversations we've had, that's not been a feature, you know, of them. In terms of the study design, I can just give some high-level guidance, and then maybe Nani can speak to some of the details of the endpoints. What we've guided to previously is a study of roughly 20 patients powered on the LVMI endpoint. The FDA's open to time points earlier than 12 months. Those are some of the features that we have guided to previously, which remain intact for the study that we've, you know, that we've submitted to the FDA.
We can talk about LVMI and the relevance of it. We've agreed on this 10% effect size previously.
We're achieving almost a 30% effect size in our phase I and II study.
I would just add that, you know, the LVMI remains the anchor from an endpoint perspective. We know from all the studies and at least two good published data sets that, you know, a 10% change in LVMI reflects a 20% change in mortality for those patients. Definitely an improvement there is helpful. You know, the secondary endpoints can be various biomarkers that we can think of. You know, we've shown the durability of troponin, for example, in the data that we presented earlier this year at ACC, even to patients, some of the patients who are out to three years. We can look at some of the other biomarkers and durability there. We talked about mFARS. We're gonna look at that as well.
Most of our secondaries are gonna be you know, we're looking at powering them to the point where they, if they meet, if they meet the endpoint, then there's significance there.
Gotcha. That's helpful. Can you maybe talk about the evolution of the thinking between expression and LVMI?
Yes.
I think for some period of time, at least I was under impression that maybe you guys were thinking about a co-primary endpoint.
Yeah
Where you're looking both expressions as well as.
That's right.
LVMI versus now I think the conversation has pivoted a little bit more for, to LVMI. Is that because expression requires a biopsy, or is that because expression is maybe not as predictive of a clinical benefit longer term? Like, why has the conversation shifted a little bit away from expression LVMI to just LVMI?
I mean, we'll obviously give the full update on the study design we land on. Just in general, we can say that the group that's at CBER now and OTP probably has less of a focus or emphasis on tissue expression levels. That kind of plausible mechanism of disease that tissue expression can demonstrate is less of a focus for them. LVMI was always the endpoint that we were powering the study on in any case. All of the numbers that we guided to were based on a study powered by LVMI. I also believe that from a cardiologist perspective, for those that are prescribing the therapy to say we're achieving, call it a 30% reduction in LVMI is meaningful.
That probably yields them to say, "This is a therapy that's having effect on the disease," to also say, "Well, you know, we're showing some amount of increase in frataxin," is probably not a major driver to prescription dynamics either. Neither is it probably a major driver to a commercial label. I think it was something that was a feature of the prior group at CBER and OTP that is less of a feature in the group that's leading the regulatory conversations now.
Yeah. Yeah. That's super helpful. Maybe, you know, some of the most recent data for other peers in gene therapy.
Correct
Whether it's Raptor or some of the others maybe has influenced, some of the thinking or the idea.
That may be the case.
Yeah. That makes sense to me. What about high sensitivity troponin? Every time I look at your data set, it feels like troponin. Maybe the endpoint that has the most consistent kind of effect across all different patients that you have enroll. Like, why is that not the go-to endpoint? What's the rationale behind that, I guess?
Maybe, Nani, you wanna comment. I mean, troponin's never been a approval endpoint, but maybe you can comment.
Yeah, and I think that that's the nutshell of it. That it hasn't been an approval endpoint. I would say that we are as intrigued by it as you are, in the sense that, yes, we've seen consistency there. Even in the phase I data in patients who were only had mildly elevated LVMI but had an elevated troponin, we saw that come down. We've seen durability in that response as well.
We think it's probably meaningful, but it's never been anchored to a regulatory approval. I think that's the thing. You know, we are inventing the wheel in some of these things, actually, with Lexeo doing the study. I think as we collect more and more data, could that be something that we could look at in the future? Potentially. It's important to keep on correlating that and measuring that and seeing, you know, where the durability leads from an outcomes perspective down the road. It's definitely something that we're interested in.
If I could also comment commercially. You know, if you look at our phase I/II study, we had patients that had normal left ventricular mass index but had elevated troponin, so they clearly are having some onset of cardiovascular disease probably at the earliest stages. It may be that troponin is a great biomarker to use to diagnose the onset of the cardiovascular disease, so we don't need to rely on cardiac MRIs to evaluate disease onset or evaluate disease progression.
That may be an interesting one to consider for the purposes of underwriting a prescription of a gene therapy in Friedreich's ataxia, having troponin measurements be part of the regular, you know, annual visits that patients would have with their neurologists and cardiologists, and ultimately potentially using troponin as the trigger for prescribing this, a therapy like this one that treats the, you know, comprehensive disease, but also obviously the cardiac component of the disease.
It's almost like a prognostic biomarker.
Correct.
More than actually an endpoint that can be used for approval in this.
Yeah.
Or at least hasn't been used in the past.
We'll look at that. I mean, we need to find the right correlations is the key. I think the natural history data hasn't consistently measured troponin relative to the clinical outcomes, and that's work that, you know, probably we need to do.
Yeah.
To draw those correlations and make the case if we ever want that to be an endpoint that is important in terms of actually looking at disease progression itself. Right now, you're right, it's probably a good way to identify that the disease is beginning to materialize.
Sure. How are you guys thinking about a confirmatory trial? Again, we talk about all accelerated approval and some of the dynamic there, how are you thinking about a confirmatory trial?
Which.
Yes.
For what kind of endpoint, what's the size, what's the big picture thinking on the design of that trial? Any thoughts there?
That work is ongoing right now. We haven't had, you know, formal discussions with the regulators on what the confirmatory design is. We don't necessarily need to have that by the time we start the pivotal. We wanna make sure right now the effort is to get the pivotal going and making sure we have alignment there. As we start to think about what confirmatory designs could look like, you know, certainly one element of that is correlating to the LVMI endpoint itself and what that could look like from a clinical perspective. What are those endpoints that can relate to outcomes that can be hinged upon LVMI, for example?
Also, you know, we've talked about the mFARS as well and what does that look like? This is, you know, the various endpoints that we can consider in a confirmatory over time. That's, as I said, that's the work that's ongoing now, we will, you know, once we get the pivotal up and going, that'll be the discussion with the regulators with these endpoints in mind and trying to understand, you know, where that design and size lands at that point.
Yeah. There's certainly with the endpoints we have in the accelerated approval study, a potential ability to use that study and look at it over longer time points for some of these other endpoints. We're looking at all of those different options, as we work to finalize accelerated approval study. We'll shortly, you know, after begin the discussion on confirmatory.
Will the confirmatory trial be randomized, or that remains to be seen?
I think it depends on the endpoint. It's early enough to say what that would look like. I mean, obviously, if we use the same study, then it could look different if we have to run a separate study. I think just that's a conversation we've not had yet.
Sure. Would that give you more kind of negotiating leverage with the FDA, if you will? Like, "Hey, you know, we're working on accelerated approval, however, we're fully committed to getting to the bottom of this, so we're gonna run a confirmatory trial that is actually randomized, placebo control, you know, primary point is LVMI, or other endpoints that are meaningful." Is that not the right way to think about it?
I.
Is, like, one step at a time, let's get the accelerated approval first, and then let's figure it out later?
I definitely think one step at a time. I don't think needing to randomize or not is really a function of the endpoints. Like, is there, does it require a control group? Does it require is it, does the endpoint have subjectivity associated with it, and therefore it needs that? I You know, it's hard to opine on that now. The other note we'd make is that You know, another 10,000 patients or so in other markets outside of the U.S. such as in Europe. We'd obviously like to pursue a European strategy as well.
In some cases, the accelerated approval studies that are appropriate for the FDA are not the best fit for Europe, which looks more at clinical endpoint. It may be that that study that's both a confirmatory for the FDA needs to serve as the study that allows for an approval in Europe, and we need to understand from the EMA what they would like to see from a study design perspective. I think there's a lot here. We'd be speculating substantially if we try to opine too much on this. I just think there's too much that's up in the air, and we're focused right now just on getting the accelerated approval study started.
Yeah, that makes sense. Maybe two quick questions here. One, maybe any update on manufacturing? Again, it's my understanding that you know, the first patient that we're treating with this therapy were manufactured with HEK cells versus now you have pivoted to Sf9. I believe the FDA required to run a bridging study. I guess where do we stand on that side? Then maybe related, last two questions in one shot in the, in the interest of time, where does the mFARS benefit come from? I mean, obviously, this is a cardiac. You guys have a capsid that has cardiotropism. You know, it's obviously good to see that benefit.
Yeah.
What's the best way to rationalize why we're seeing that?
Starting first with CMC, we agreed with the FDA on a comparability protocol, which we submitted to them in October. We received written feedback that we had met the comparability standard to be able to dose patients in the pivotal study. That requirement has been cleared. We've since had a CMC specific focused CDRP meeting with the CMC review team, no questions about comparability emerged subsequent to that written feedback. We think we're in a good place with respect to CMC. We're also getting very compelling yields out of that process. I think we're at 1E15 vg/L .
So if you know, do the math on that's a substantial number of doses that could supply a meaningful percentage of the total FA, you know, patient population. From a cost of goods perspective, from a commercial supply perspective, we're in a really good place. The vector, the batch has been manufactured, ready to dose patients, you know, at this moment. With respect to mFARS, maybe I'll.
Yeah.
Just.
Yeah. You know, even though you're right, you know, the capsid is cardiotropic, but the promoter we have is ubiquitous promoter on the transgene. As we think about that and when we look at our murine studies and some of our NHP data, you know, we've seen uptake in the dorsal root ganglia. We've seen uptake in muscle. That is likely the rationale for why we're seeing the effect that we're seeing on the mFARS side.
True.
Got you. That's helpful. Maybe if I compare with two PKP2, how does the overall safety of the product compares between PKP2 and Friedreich's ataxia cardiomyopathy? Again, obviously for PKP2 for obvious reasons, it's a structural protein. You're using much higher doses.
Yeah.
To begin with versus Friedreich's ataxia. What can you tell us about the kinetics of the ALT and AST? Are they comparable? Are you seeing materially higher levels? Like, and I know you have a different prophylactic regimen there.
Yeah.
Between the two processes there. Like, well, how should we think about one versus the other in the context of?
Yeah.
I believe the starting dose is 100x higher.
That's right.
Than the dose for Friedreich's ataxia cardiomyopathy.
Yeah. FA we're at 1E12 vg/kg at our highest dose. We saw no elevation in liver enzymes. We saw no complement. In PKP2, we've seen no clinically meaningful complement activation. We did see some elevation in liver enzymes. I don't think it was an amount that's atypical for a gene therapy at that dose. We did not see, you know, like SAEs related to that, no hospitalizations, nothing like that.
I think that that's a reasonable risk-benefit profile to get to an effect size that's at or above the existing standard of care in arrhythmogenic cardiomyopathy, meaning the anti-arrhythmic therapies, but do so with just elevations in liver enzymes that resolved in a transient manner, via the approach we had designed into the protocol already expecting to see that. We think is a risk-benefit profile that the patients would find to be acceptable. You know, I think the enrollment in our trial was a great example of that. We saw I mean, the study enrolled very quickly. Frankly, it's a favorable safety profile, I think relative to some of the other therapies that are developing in this area as well.
True. Got you. That's actually helpful. Are you thinking about, you know, the regulatory path from here? I know we obviously need the data to continue to mature here, but you know, just as much as LVMI maybe is the go-to endpoint for potential accelerated approval for Friedreich's ataxia cardiomyopathy, what is the go-to endpoint for PKP2 arrhythmogenic cardiomyopathy again?
Yeah, sure. You know, you've seen data on both the PVCs and the NSVT. We think the NSVT is the better endpoint here because it's closer to the end result of the disease itself, which is, you know, what leads to the defibrillator shocks and the degeneration into sustained VT and VF. You know, in those patients, unfortunately, who first present with a sudden cardiac arrest or sudden cardiac death. Definitely, you know, that's an area that we're looking at because we think that is the meaningful endpoint, and that's where the discussions will focus as well, you know, when we meet with the regulators to understand a little bit about how are we seeing that endpoint and what that support looks like.
Not just about, you know, measuring maybe just the number of episodes of NSVT, but also what's the character of the NSVT? Are you not just getting fewer episodes, but are you getting slower episodes? Is there less activity from the defibrillator when it comes to the anti-tachycardia pacing algorithms, et cetera? There's a lot that can be looked at within that endpoint other than just counting the number of episodes. Those are the type of discussions we'll engage with as we move towards more data and with the regulators.
Gotcha. Super helpful. I know we're out of time. Maybe Nolan, just to kind of wrap up the conversation here, when you really step back, kind of big picture, what do you think is the most underappreciated aspects of the Lexeo stories that investors should have better appreciation for?
Yeah. I think the effect we're seeing in the FA program, both especially in the cardiac disease, but if you also include neurologic, it's sort of it's almost an undeniable effect. We're seeing the durability out to three years. We see frataxin expression. We see reduction in LVMI. Everything is moving in the right direction, and it is sustained out to, you know, years now. I think that we're looking at a drug that definitely has the treatment effect that we hope for, if not even better. The question now is just, you know, regulatory uncertainty. We all understand that. I think get this protocol aligned with the FDA and get this study started, and I think we're looking at a drug here that has a very high probability of success of being accelerated approved.
I think looking at that picture, is something that maybe has been underappreciated, but I understand the de-risking event is the regulatory alignment itself. We're focused on that within the quarter.
Fantastic. Appreciate your time. Thanks so much. I have a lot more questions, but no more time.
Great.
Thanks everyone for joining, and we appreciate your time. Thank you.
Thank you so much.