All right, perfect. My name is Gautam Chukka. For our next session today at the Chardan Healthcare Conference, we have Lexeo, and on the stage with me is Narinder Bhalla, Nani, Chief Medical Officer, and Lou Tamayo, CFO. Thank you so much for joining us.
Thanks for having us.
Absolutely. So we have about 15 minutes or so. I'm going to just jump right into it. So let's start with a quick overview. Tell us about your clinical programs, what are you doing, and what to look out for for the next 12- 18 months.
Yeah. Lexeo is a clinical- stage company focusing on genetically mediated diseases with high unmet need. Our lead program is LX2006 in Friedreich's ataxia cardiomyopathy.
Yeah.
We have a registrational study that we started enrolling at the end of the second quarter of this year. In our phase I/II, we have shown compelling effect size on left ventricular mass index, a variety of different biomarkers, and on the neurological side of the disease through the mFARS scale. Our second program is in PKP2-associated arrhythmogenic cardiomyopathy. That program is LX2020. That program has an ongoing phase I/II, and we have shown a good effect size on non-sustained ventricular tachycardia, on premature ventricular contractions, and with a good safety profile. What to look out for in the next year or so, we have in the FA program, we are expecting a top-line readout on the phase III trial in the second half of 2027 and a BLA filing in the first half of 2028.
As I said on the PKP2 program, we will be reading out data with the majority of our high-dose patients at at least 12 months of follow-up very soon in Q4, alongside a regulatory update as well. In addition to those programs, we have a preclinical pipeline. There is LX2021 and LX2022 for desmoplakin and hypertrophic cardiomyopathy, respectively. We are excited that we just acquired Mantle Therapeutics—
Yes.
—which gives us a portfolio of different neurologically oriented FA programs as well.
Okay. Maybe we will just talk with PKP2, since that is coming up. But before that, maybe just a brief comment on the Mantle acquisition. What was the strategic logic, and how does it fit alongside LX2006?
Yeah. LX2006 has shown an effect in the mFARS scale similar to the commercially approved therapy. But we believe we're reaching the peripheral nervous system and the components of the mFARS scale that are mediated in the peripheral nervous system. For example, skeletal muscle and dorsal root ganglia. But we're not transducing the brain. And we know that there are certain components of the neurological side of FA that are mediated in the cerebellum. So the real strategy around adding the Mantle portfolio is to find a therapeutic that will transduce the brain, so that ultimately we will have clinical trials that include cohorts that have been previously treated with LX2006.
So ultimately, there's a potential there to have a therapeutic package that treats both the cardiac side, where we know LX2006 is showing a good effect, but also to have a component that reaches the brain to treat the totality of FA across both.
Okay, perfect. Okay, let's talk about PKP2. That's coming up in 4Q. Can you just remind us what you've shown in January and how the data's going to be different from this readout?
Yeah. I can speak to that. In January, what we had shown was two effect sizes on PVCs and on NSVT. We had shown a 14% reduction in PVCs and a 22% reduction in NSVT. And particularly in a couple of patients who had actually gone to nine months, we had shown a 65% reduction in NSVT. So as we start to look at the upcoming update, we would want to see many of those patients, I guess maybe one or two would have hit 12 months. So we want to share the data from those patients as they prolong their effect and time in the study, and also hoping to couple that with a regulatory update as well. But we want to see a deepening of the effect size over time, just like we had the hint of in those patients that had reached nine months.
Nani, just remind us, of the seven high-dose patients, will all of them have 12-month follow-up?
Most of them. We should probably have most of them there, except maybe one or two.
What precise endpoint should we be looking out for?
The endpoints, we obviously feel that NSVT. We're looking at both NSVT and PVC, obviously, in our data set, but we feel that NSVT is more clinically meaningful. If you really think about it, that's really what drives disease progression in these patients. This also drives overall arrhythmic events and the clinical decisions that get made in managing these patients. For example, even starting from an implant of an ICD versus changing the settings on an implanted ICD, anti-arrhythmic treatments, monitoring status, all of that is really governed by how much NSVT they have.
Yeah.
That actually is what leads to sustained arrhythmia. We feel that's an important endpoint. PVC obviously is important as well, and we'll take a look at that. Structural changes are important, but just keeping in mind that this is a structural disease at the cellular level with desmosomal disease, and having structural impact is going to take time.
Okay, perfect. In terms of what a clinically meaningful reduction would look like, I believe you've said previously around 35%-40%?
Yeah, and I think that's keeping in If you look at the current care, which is drugs like beta blockers or like sotalol, for example, or flecainide or amiodarone, all these drugs that are not great for long-term treatment for these patients and also have side effects profiles. We're looking at those effect sizes in the 20%-30% range. Given that, I think anything that gets to 35%-40% allows us to beat that comfortably with this potential for attending to a structural issue of the disease and hopefully, leading to a lack of progression of disease toward a heart failure syndrome, I think are all going to be important from an importance perspective from a clinician and a patient perspective.
Great. I know we talked about this a little bit before. What endpoints matters to clinicians and FDA? You have NSVT, PVC burden, structural measures, RVEF, et cetera. What's the best way to think about endpoints that matter to both clinicians and what does FDA care about?
Yeah. Listen, I think NSVT certainly is where we want to focus on just given the discussion that I just had about the fact that clinically meaningful-wise and pretty much all the decisions that get made, and even I think of my own practice, when I was seeing these patients, a lot of the decisions we made were based on NSVT burden, et cetera. So we think that's a clinically meaningful endpoint. From an FDA perspective, yeah, those are the interactions we're having now, and we hope to have some more clarity on that as we come to the update.
Got it. Did you get any indication from FDA that they would accept NSVT as the endpoint?
That's what's still ongoing in the interactions and, as I said, hopefully some direction.
Okay.
We received an RMAT designation in August, and the submission of that package included more contemporary data than what had been previously shared in Q1, but also centered a lot around NSVT.
Okay.
That could be an indication.
Okay, perfect. On the arrhythmia effect deepening, was that going to plateau, or is it going to get better? What remodeling should occur to see any change?
Yeah. I think you want to see deepening of the effect over time. I think that's something that's important, and the question is, when do you anticipate to see that? We think 12 months is a good place to start to anticipate the response to treatment.
Yeah.
From a structural perspective, I think you want to start to see some little changes. We have seen some early deepening with those patients that had hit nine months. We have seen one patient with an increase in their right ventricular ejection fraction as well. I think this is important to keep an eye on, but I think structural changes take time, and the key is going to be going to follow those patients and see where they go. The early indications seem very positive.
Yeah.
The deepening of the anti-arrhythmic or the arrhythmia burden decrease is going to be critical and support safety.
From your experience, how long do you think that structural changes would take?
It depends. I think it depends on where you are on your disease journey and how much fibrosis you have to start with. I would say that we should start to see some assessment of that within the pivotal trial to some degree. Remember, all these patients get followed for five years thereafter, so we may see some happening in that timeframe as well.
Okay, awesome. Then maybe one point on the safety. How comfortable are you with the 6.0E13 dose? It is a higher dose, right? Any changes to the steroid protocol or anything on that front?
No. No changes. Yes, it is on the higher dose side. We would expect, I think at these doses, we would pretty much expect some elevation of liver chemistries. The good news is the ones we have seen have been managed within the protocol. We remained with steroids and sirolimus as our treatment for immunosuppression, and we have not changed that. In the patients who did demonstrate, nobody required any hospitalization, and they were managed within the protocol-dedicated medications, the designated medications, so there was no add-on of different medications or anything like that.
Are these LFT elevations just clinical laboratory measures, or is there an actual clinical significance of LFTs going up?
As I said, there was no clinical meaningfulness in the sense of clinical syndrome related to these elevations. They are transaminitis that occurs on the blood work. It is certainly things that you want to watch for from a levels perspective. Then the question is, how are you managing it? The fact that you can manage it within the protocol-designated criteria because we do expect to see these, but since they are being measured on a regular basis, you make decisions based on those levels to say how are you titrating the steroids, et cetera. The protocol kind of already accounts for that. The key here is not to go outside of the protocolized measures.
Okay, awesome. Maybe quickly then we'll jump into, I think cardiomyopathy. What can we expect from your engagement with FDA, and what should the pivotal look like?
Yeah. When we think about, we want to maximize these interactions, and these meetings aren't obviously very long, so you want to optimize the time that you have with the regulators for each meeting. What we would like to come out with is some understanding of some direction on the endpoint. We've talked about NSVT as being clinically meaningful. We want to come up with some direction over there, and we may have some early signals on what a pivotal design could look like, and that's what we would hope to share at the update.
Okay, awesome. Well, moving on to FA cardiomyopathy, I think the main action's going to be next year in this setting, right? The SUNRISE-FA 2 started in June. Just talk to us about how it's enrolling. What is CLARITY-FA going to do in terms of helping selecting patients? Then maybe, if I may ask a second part to that, the phase I/II showed about 28% in six months, right? What can you think of that you will not be able to replicate a similar effect size in the trial?
I'll take the enrollment part. CLARITY-FA is a natural history study that is now serving as a feeder trial into SUNRISE-FA 2, which is the treatment pivotal study. What it's allowed us to do is to find these patients, and we've seen a very good level of enrollment. We have 19 sites active across eight different countries, and so far we've enrolled 22 patients. In the pivotal study, we're looking for 13 and 13 treated against 13 untreated control. The CLARITY study has an identical inclusion criteria to the pivotal study. As long as those patients do not test positive for neutralizing antibodies, they can roll over into the treatment study so long as the site that they're at has been activated for treatment. So it's giving us a really nice feeder into our trial and helping us to find those patients very rapidly.
Perfect. Maybe let's have one other question, and then we'll wrap it up. What confirmatory evidence is needed for full approval, do you think? Lou, maybe you can talk a little bit about the cash and what the runway supports.
You want to take the first one?
Yeah, I can take the first part. The confirmatory discussions are still going on with the regulators, and I think from our standpoint, the endpoints would be cardiac endpoints to some degree, and also potentially for mFARS, given what Lou talked about, the effect size that we've shown in the mFARS in the phase I, phase II data. We are looking at probably a combination of these endpoints, either cardiac and trying to get mFARS in there as well.
On a cash perspective, our last disclosure at Q2, we had a little over $230 million in cash. We anticipate to burn somewhere in the mid to high 20s per quarter range, so it gives us runway into 2028. We expect that money, excuse me, to fund operations through the filing of the BLA on the LX2006 program, as well as all the CMC work, which we're already manufacturing at a commercial scale. We're starting to make some key hires on the commercial side in terms of marketing, market access. We're expanding our medical affairs team as well.
All right, perfect.