Lexeo Therapeutics, Inc. (LXEO) Earnings Call Transcript & Summary

Good afternoon, and welcome to the fireside chat titled: A Clinician's Perspective: Holistic Approach to Managing PKP2-Associated Arrhythmogenic Cardiomyopathy, hosted by Lexeo Therapeutics. As a reminder, this call is being recorded today, Tuesday, December 9. I would now like to turn the call over to Louis Tamayo, Chief Financial Officer of Lexeo Therapeutics. Louis, please go ahead.

Thank you. Welcome to this fireside chat session. Joining us today on the call from DC where they are both participating in the Cardiovascular Clinical Trialists Forum are Dr. Eric Adler of Lexeo Therapeutics; and Dr. Victoria Parikh, Clinician, Scientist and Director of the Stanford Center for Inherited Cardiovascular Disease at Stanford School of Medicine. Before we begin, I would like to remind you that this call may contain forward-looking statements regarding Lexeo's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. Additionally, both Dr. Adler and Dr. Parikh's disclosures are listed on the slide. With that, I would like to turn the call over to Dr. Eric Adler.

Thanks, Lou. I'm really happy to be here today at this session. As you know, at Lexeo, our mission is to change how genetically mediated cardiovascular diseases are treated by research and applying pioneering science. Currently, we have a cardiovascular gene therapy candidate LX2020 that's been evaluated in clinical trials for the treatment of plakophilin-2 arrhythmogenic cardiomyopathy, otherwise known as PKP2-ACM. While a lot is known about ACM, as the treatment landscape evolves, perspectives on how ACM is viewed and managed is also evolving. There's growing evidence both in the literature and from clinical experience that supports approaching complex diseases like arrhythmogenic cardiomyopathy from really a holistic perspective, something we'll discuss more today. And to do that, I'm really excited to have Victoria Parikh with us. Vicki is the Director of one of the largest inherited cardiovascular disease center in the country, the Stanford Center for Inherited Cardiovascular Disease. She's an associate professor at Stanford and just a wonderful clinician and scientist. We're really lucky to have her today. Her center specializes in the care of patients with genetic cardiovascular conditions, including ACM and her clinical experience provides valuable insights into expert level and world-class patient care, and I'm sure we're going to learn a lot today and have a great conversation. So let's dive right in, Vicki. Thanks for joining us today.

Thanks so much for having me, Eric.

Yes. So to start off, give us a little bit of background on your experience in managing patients with arrhythmogenic cardiomyopathy.

As you said, our center is one of the largest in the country in the world. And so we see thousands of patients with inherited cardiomyopathies, families with inherited cardiomyopathies. And one of those, of course, is arrhythmogenic cardiomyopathy. One of the things that we're really focused on and traditionally have been focused on at our center is implementing precision medicine. And as you all know, that is something that is uniquely suited to genetic cardiomyopathy. So not only do we see and diagnose sort of the clinical phenotype of patients with arrhythmogenic cardiomyopathy, but we also are really focused on deploying genetic testing and genetic diagnosis to be able to get to the root cause of those diseases in the clinic.

Great. So with all that being said, let's dive in a little bit to discuss ACM. Can you give us a little bit of background on the disease and its etiology?

Absolutely. So arrhythmogenic cardiomyopathy or ACM, is first and foremost, as it is named, a cardiomyopathy. But clinically, what we see in these cardiomyopathies is that progression toward heart failure is coupled with a particularly arrhythmogenic substrate, meaning that there's a structural change in the heart muscle that is also conferring very high risk of early and life-threatening arrhythmias like ventricular tachycardia. So it turns out that this particular disease is slightly more rare than other inherited cardiomyopathies, but is still present in about 125,000 individuals in the U.S. Of these individuals that have been diagnosed, about 20% on clinical presentation actually come to our attention because they've had a sudden cardiac arrest. So it is a very severe disease. And that sudden cardiac arrest is often caused by ventricular tachycardia or fibrillation. Most of these patients when we do genetic testing, especially those who have their right ventricle involved, have a genetic diagnosis of plakophilin-2, which explains more than 50% of those ARVC ACM subset patients.

Great. Let's dig in a little bit more. How does the mutation of PKP2 gene actually contribute to the development of ACM? What do we know about the kind of the pathobiology?

That is such an important question. The way that PKP2 or plakophilin-2 works is it's a part of the glue that holds heart cells or cardiomyocytes together. And it turns out that just like humans, cardiomyocytes need to talk to each other in order to stay in rhythm and work together. So when you lose PKP2, which is part of that glue, also called the desmosome, you lose those connections. This leads not only to abnormalities in rhythm because those cells can't talk to each other very well, but also to the death of those cells because they are over working and therefore, leading to more arrhythmias and then when they die, to replacement of that section of the heart by scarring or fibrosis. So it's a complex situation with PKP2 ACM, but the bottom line is that mutations or variants in PKP2 and other desmosomal genes lead to significant electrical and structural abnormalities.

Yes. Such an interesting disease with especially this unique infiltration of fibro-fatty tissue. So it's just fascinating. So with that background, talk to me a little bit about your approach to assessing and managing ACM patients.

Yes, it's tough. We don't have a lot of options for them. I think as a clinician, I tend to sort of separate simply each disease into how I diagnose it and then how I follow it and manage it going forward. With respect to actually diagnosing ACM patients, as I mentioned, many of these folks, their first clinical manifestation is a significant ventricular arrhythmia, like ventricular tachycardia. But when that happens, there are a lot of reasons why patients might get ventricular tachycardia. So what we're doing is we're making a systematic evaluation of that patient from the structural disease in their heart, all the way through to electrical changes that might actually tell us a little bit more about the underlying etiology of that VT. So for patients with ACM, we generally, especially in the right-sided ACM, right ventricular ACM, use what we call the Task Force Criteria, which came out a long time ago, but are still really tried and true for defining this disease. Those are complicated because this disease spans both structural and electrical abnormalities. Some salient examples of that are that we're going to take really, really detailed pictures with MRI, imaging and echo of both ventricles to try to understand whether that fibro-fatty replacement that you mentioned is actually disrupting the function of those ventricles and in particular, in certain spots of the ventricle. And then we also do a really thorough electrical evaluation. So that includes an ECG, where we try to understand if the heart is depolarizing, so that means activating, right, normally, but also if it's returning back or repolarizing correctly as well. And then we look for arrhythmia. So the first thing that we look for is this patient having something called nonsustained ventricular tachycardia, is a really, really good sign that, especially we can localize it, that they are developing worsening ARVC or ACM. And then, of course, we also look for PBC count. These can show up a little bit earlier than nonsustained VT. But when those PVC or premature ventricular contraction counts are quite high, that can give us a clue as to whether this is an ACM patient. So importantly, though, you can't base the diagnosis on just one of those. There's a very sort of complicated point system where you have to show that within those structural and electrical categories, multiple of them are actually disrupted in order to make the diagnosis of ACM. So that's the diagnostic criteria, which are quite complicated. But moving forward, right, you look at the management buckets in terms of what's going on with their arrhythmias or their electrical complications and what's going on with their structural disease. So when I'm monitoring these patients, I'm very frequently monitoring their rhythm. The first decision we have to make is whether they are at high enough risk of a sustained ventricular tachycardia or major ventricular life-threatening arrhythmia in order to warrant implantation of a defibrillator, right? And there's a complicated calculus that goes into that. And then, of course, I'm looking for the development of heart failure, which tends to appear a little bit later in this disease, but it's certainly a huge and currently really unmodifiable progression that we see.

Great. Curious, how often do you see cascade patients as well, so family members that just might have a family member with ARVC?

To your point, we, of course, are using genetic testing as part of that diagnostic criteria. As we mentioned, having a known causative variant in, for example, plakophilin-2 is going to get us closer to a diagnosis. And so when we can make those genetic diagnoses, that helps us to screen family members because if they then don't carry that causative genetic variant, we can often release them from screening, which can be lifelong. So we do see those patients. We see folks with very early stages of disease where they carry a PKP2-truncating variant, maybe they're having a run of nonsustained VT, maybe their right ventricle is a little bit big. And so in that diagnostic criteria, we do heavily weight the presence of that genetic diagnosis, that PKP2 truncating variant, for example, because that can really help to tell us how closely we need to monitor those patients in order to catch disease before it becomes a sudden cardiac arrest.

Got it. That's great. Okay. Well, let's transition a little bit to this area around nonsustained ventricular tachycardia, NSVT, and PVCs. There's this clear consensus to look at the components of the diagnostic criteria, but these various parameters need to be looked, as we said, holistically when assessing a patient's cardiac status as well. Do you want to talk about how you look at these 2 parameters in arrhythmias in general?

Absolutely. So I mean, diagnostically, they're actually differentially weighted. So it turns out that nonsustained VT, which is basically a run of rapid extra beats that are coming from the wrong place in the heart, from the ventricle. It should be coming from the atrium and normal beats. So nonsustained VT is something that is heavily weighted in the diagnostic criteria if it seems to be coming especially from the right ventricle. And so it's a major criterion for diagnosis, which gives it more weight in that sort of summative formula that we were talking about, the Task Force Criteria. And then PVCs, if that patient is having more than 500 PVCs or single extra beats from the bottom of the ventricle per day, then that counts actually as a minor criteria, which is sort of 0.5 point. So diagnostically, they're weighted differently, certainly. When we're thinking about following patients going forward, I think of PVCs really as a diagnostic sign of disease. When I start to see nonsustained VT or NSVT, then I'm thinking more about disease progression. Certainly, we see increasing PVC numbers associated with disease progression as well, but it's a little bit of a chicken and an egg there in terms of whether that's actually going to worsen the patient status or whether that is just a diagnostic sign. With nonsustained VT, if that becomes more frequent, longer, faster, those are things that make us worry about the patient then having a sudden cardiac arrest. In fact, when we have developed risk calculators as a community in this ACM population to try to determine who's going to benefit most from a defibrillator, it turns out that nonsustained VT has a really, really big effect on that percentage likelihood of sudden cardiac arrest or sustained VT than the number of PVCs. So in sum, we have to think about both of these things. They're both important. But when I'm following patients in the clinic, I am very, very concerned when I see nonsustained VT. And I think reversing that gets us sort of closer to reversing the risk of sudden cardiac arrest.

Do you think about them differently in terms of kind of the pathology disease like PVCs being a spark and then you have to actually have reentry for an SVT or something like that?

Yes. That's a good point. I think that's probably the underlying reason for my gestalt about NSVT being sort of a heavier sign when I weigh disease progression. So as you're pointing out, nonsustained VT because it's many rapid beats in a row, often it's happening around scar or fatty fibro infiltration in the ventricle that you've described. And so that can sort of tell us that there is a worsening structural disease in addition to those electrical abnormalities. PVCs by themselves can often be a very small number of cells that are not necessarily causing multiple beats around a fibro-fatty scar, but instead are sort of beating out of turn more frequently. So you could, I think, put that together to say, look, nonsustained VT because it's reentrant has the ability to turn in to a longer, sustained, symptomatic, potentially life-threatening VT, whereas a PVC is terminating, right? It's one beat at a time. And so theoretically, it's not going to turn into VT by itself. But there are a lot of complexity that goes into that pathophysiology that makes it an imperfect model.

Got it. Okay. That's great insights. Let's switch gears a little bit and talk about management for these patients. So can you walk through how your -- your current management approach?

Yes, absolutely. Well, I mean I think the first thing to say is that our management approaches are largely trained on the electrical arrhythmias that we see, and that's because we've had some amazing leaders in the field who are, in fact, electrophysiologists and because, as I mentioned, this is the more common presentation of symptomatic diseases to have a sustained ventricular tachycardia or symptomatic nonsustained VT. So for those arrhythmias, the first thing that we try is a beta blocker. It turns out that they are somewhat sensitive to blocking adrenaline, which is what beta blockers do. But in general, for patients that are having those nonsustained VTs, they are going to progress at some point to having a sustained ventricular tachycardia. And so, like I said, we do those risk calculators to make sure that we are understanding the risk-benefit ratio for each patient in terms of giving them a defibrillator, which is, of course, implanted and carry some risk with it. But that's, of course, to prevent sudden cardiac arrest. So that is the second sort of mainstay of therapy is to prevent sudden cardiac arrest with ICDs. And then additionally, as that disease progresses, as their VTs become longer, as they become more symptomatic, there are other antiarrhythmics that can be used. Most recently, flecainide paired with beta blockers has been shown to be relatively safe. There was some concern about that in terms of very old trials with ischemic cardiomyopathy. And then sotalol is another one that can be used, although there's some data to suggest that, that's not as effective. I think in summary, what we're trying to do in ARVC patients is tamp down their arrhythmias and cross our fingers that they're not going to really progress to heart failure because when they progress to heart failure, we do not have good disease-modifying agents. This is a disease with a huge area of need to be able to actually reverse disease and stop -- medically stop the risk of arrhythmia and heart failure.

Sure. And are some of these patients getting ablation like surgical procedures or interventional procedures?

Yes. Thanks for bringing that up. Of course, if the medical intervention of flecainide, for example, fails to control their ventricular tachycardia, these patients absolutely can go for VT or ventricular tachycardia ablation. There are some amazingly skilled electrophysiologists around the U.S. who can provide that service to patients, both from inside of the myocardium and outside, we called that an epicardial ablation. The problem is that in many of these patients, the entire myocardium is affected because the entire myocardium doesn't have enough PKP2, right? So you ablate one VT and then you wait for the next one to happen, and it can turn into a game of whack-a-mole, right? So even ablation is not a cure. So it's a hard disease to take care of in many patients.

And even that doesn't really change the underlying progression to heart figure, right?

Exactly. Exactly.

Yes. All right. Well, that naturally opens up the opportunity and need for novel therapies like gene therapy. So this is obviously a big topic on many people's minds. No gene therapies are currently approved specifically for cardiovascular disease, but there are several investigational gene therapies in clinical trials, and they're getting a lot of attention from clinicians. I noticed this topic all over the agenda, both you and I have been spending some time at CVCT discussing it, highlighting the fact that it's of interest to physicians and investigators, regulators, et cetera, and patients. So where do you think gene therapy could fit in for cardiovascular disease? And how do we move gene therapy forward? Who could be the right candidate, et cetera?

Yes. These are the most critical questions that the clinical community is asking right now. I think in terms of what is the right disease for gene therapy, the first question that we ask as clinicians is who is undertreated, right? What is the disease that we don't have any other answer for? And then also, what is the complexity of that disease? So arrhythmogenic cardiomyopathy is a great example of a disease that, number one, we don't have great options for treatment, especially in terms of progression to heart failure, as you and I just talked about. We have really bad outcomes in this disease that include things like sudden cardiac arrest. And even for patients that we identify early by family screening, we can't always prevent that, right? We have to use a defibrillator to prevent it, which itself is a really -- it carries risk, especially when you're putting a defibrillator in a 35-year-old who's got to have wires in their body until they're 80, right? And then I think once you've talked about area of needs that ACM is -- has huge need as we're discussing, you need to think about sort of which patients with that disease are the right patients to treat. And I think because we've developed so many risk scores and because we have a knowledge of how this disease progresses once it shows up, we're able actually with ACM to find the right patients and tell that patient, I think that you could benefit from a potentially disease-reversing therapy. And that's a powerful thing. So this is, I think, the right disease for this type of precision medicine.

And how about within ACM, is there a sensor you're getting in your mind about which patients might be the right patients?

Yes, I think so. I think that as we talked about, patients present mostly with these pretty severe arrhythmias. And I can tell you from the patients that I've talked to the first time they've had an arrest, the first time they've had a really, really symptomatic fast ventricular VT even if they didn't lose consciousness or the first time they've been shocked, they're telling me, sign me up because I know that this is going to happen again, right? I know I don't want it to happen again. And I also know that there's nothing that you, my physician, can do to stop the progression of heart failure when it comes. So give me something to repair the underlying defect, which is that my body is not making enough plakophilin-2. So I think that as soon as we start to see those first signs of VT, especially symptomatic, especially requiring shocks, that those are the right patients to try to jump in and reverse disease in.

Great. I don't think we got to capture this at all thus far. But can you talk a little bit about what you might be looking for to measure the benefit of gene therapy then signs or signals?

Yes, absolutely. So I think the holy grail here is as somebody who sees a lot of cardiomyopathy to be able to prevent or reverse even progression of that fibro-fatty infiltration, which we can see as an increasing size of the right ventricle as weakness in the right ventricle. But we know that, that will probably take quite a bit of time, especially if we expect to reverse disease, which we all know that replacement of cardiomyocytes is really hard to overcome just based on sort of the biology of the way they don't necessarily divide once they're differentiated, et cetera. I think that really what would be extremely meaningful to my patients would be to see that their heart is less electrically active over time. And so we're thinking about those things like nonsustained VT, which we know is a huge risk factor for having more VT or sudden cardiac arrest. And certainly, looking at how PVC's change can be helpful, too, although as we mentioned, that's a minor criterion and not as predictive of events in the future. So that would be my hope that we would definitely see fewer of those nonsustained and sustained arrhythmias over time. And that in the long term, we would hope to see at least less progression to heart failure, if not repair of existing weakness in the right ventricle.

Great. Well, that's -- thanks so much, Vicki. I think that last point really drives on the key takeaways that we have to look at this holistically. And I think hopefully, by focusing on totality of disease, we can better understand patient needs and the true impact of emerging therapies like gene therapy. So thank you so much for spending some time with us this morning at CVCT. And let me hand this back over to Lou, so we can take some questions from folks.

Thank you, Dr. Parikh and Eric. We'd like to open the call for Q&A. Please note that while we welcome general questions about ACM and today's discussions, we cannot address any inquiries specific to our LX2020 program at this time. We look forward to sharing clinical data related to LX2020 early next year and addressing those questions at that time.

[Operator Instructions] Our first question comes from the line of Geulah Livshits from Chardan.

Good afternoon. Thanks for that really helpful overview. I guess just to better understand the NSVT and PVC component, are there thresholds with respect to levels of NSVTs and PVC that might significantly change management that you would be looking for in terms of degrees of benefit? And just in general, with respect to the efficacy that you see with the antiarrhythmic drugs and the ablation. Is there additional color that you can provide on the kind of degree of benefit that those provide versus what you'd be looking for with a gene therapy approach?

Yes. Of course. So I think the first point to make is that mainly what we want to do is reduce patient symptoms. So that's always the first thing that matters to us in terms of especially PVCs. The threshold of NSVT that we're looking for, it depends on how fast it is and how long it is, and then also on sort of the number of times we see it. Meaningful reductions in NSVT have not been modeled very well in terms of risk of meeting an ICD shock or of having a sudden cardiac arrest. Usually, it's a binary variable is there NSVT or not. That's not to say that clinically, when we see a small reduction in NSVT, we're not happy. It's just that I can't give anybody meaningful changes in outcomes with like a specific threshold change in those two factors.

Our next question comes from the line of Paul Matteis with Stifel.