also has limited dorsal ganglia toxicity, leading to less safety events in CNS gene therapy. But I think overall, we're a company that's focused on larger rare diseases or non-rare diseases, which I think is unique relative to other gene therapy companies out there.
Got it. Well, let's, we'll dive into both programs, but just to kind of take a step back here, I wanted to ask you about recent developments in the regulatory environment space for gene therapies and rare diseases. Have these influenced or impacted your development or commercial planning? I mean, you know, given FDA's seemingly more open environment here.
Yeah. So historically, and let's focus first on the cardiovascular disease area, there are fewer than 10 precision medicines approved, and several of these are treating the same disease. This is very different from oncology, where you see 50%-60% of the treatments are precision medicines. Now, there's a reason for this difference, and the primary reason has been historically, the FDA's required required cardiovascular outcome studies or hard endpoints like mortality, to support the approval of CV therapies. But this has been changing. Up until recently, the approval of mavacamten was based on function, symptom, and biomarker-based endpoints, and then there was alignment reached with the FDA for Danon disease cardiac gene therapy program, using two biomarkers as co-primary endpoints in a 11-patient pivotal study.
This is a major shift in the regulatory landscape for cardiovascular therapies, which we think yields the opportunity set for the introduction of a broad range of rare disease treatments in the CV area. I don't know, Eric, if you want to add anything to that.
Yeah, I think, this is a really exciting time where you're seeing guidance from regulators, like Peter Marks, saying: "Give us your, give us your data, give us your trials. Work with us." As opposed to trying to push them, they're actually pushing the companies that, where there's a consensus that they're... The longer we wait, the more patients we lose, that there's an opportunity, and there's... So I think it's a, a very exciting time. We talk about it in the scope of like a Gleevec moment, where you're seeing the just the, the first few of these therapies signaling that we're gonna have a transformative way of approaching cardiovascular disease.
This evolved landscape can be applied to what are potentially dozens, if not hundreds, of genetic cardiomyopathies that today have no existing therapies.
Got it. Well, I think that's a great segue here into... Let's talk about the cardiac pipeline. It's, it's very broad. You have programs in Friedreich's ataxia, arrhythmogenic cardiomyopathy, and DSP. What were some of the key considerations playing into the decision to pursue these particular indications? You know, why were the targets ideal?
Maybe, Eric, you want to touch on the myocyte?
Yeah. I mean, I think if you look broadly at our pipeline, you can see that we are targeting all aspects of the cardiomyocyte, which is the fundamental or the primary cell in the heart, and that's because now you can successfully deliver genetic payloads with the capsids we're using, so that's transformative. And that opens up multiple different diseases with different pathology. So in some of our programs, you see we're targeting the desmosome, which is the part of the cardiomyocyte that connects cells to each other, and those are the arrhythmogenic cardiomyopathies, and you're seeing a lot of interest in that. Our lead program in Friedreich's ataxia targets a protein that is found primarily in the mitochondria, and so we can successfully treat that, and it's a sign that we can treat other mitochondrial diseases.
Then finally, we have programs that are focused on the sarcomere. So kind of, if you think about it, all aspects of the myocyte can now be treated with gene therapies. At the same time, I think you really have to think about the each disease, the unmet need, the endpoints that you're going to be examining. Can you see those in a time period, so that is conducive for a clinical trial? So thinking about the end at the beginning, as soon as you think about a discovery, you're really thinking about what a trial would look like, and that's the key to speeding up these whole processes.
I think these are also relatively large diseases on the rare disease scale. I mean, we're looking at Friedreich's ataxia, it's about 5,000 patients in the U.S. Arrhythmogenic cardiomyopathy is 60,000 patients in the U.S. There may be some undiagnosed patients in that picture. We're also looking in both cases at potentially a first-in-class therapeutic option for patients in that disease area. So I think from a commercial potential standpoint, we're also working, you know, working against indications that have a lot of potential there as well.
Great. Well, let's dive into the Sunrise. So this is the LX2006, the phase I/II. It's ongoing. Where do things stand? How is enrollment, and do you think you'll need that third cohort?
Maybe, Eric, you...
Yeah. So this trial is actively ongoing through our second cohort, and we have a decision framework to evaluate that data. We'll be sharing data mid-year to decide about a third cohort or not. I think that, you know, we've already disclosed some of the very initial data when, as part of our initial public offering and our subsequent financing round, where you can see that we've already shown clinically interesting and significant improvements in cardiac biomarkers, cardiac functional potential cardiac functional endpoints. So that makes the decision around dose escalation interesting and weighing the potential benefit of a higher dose with obvious risk of that as well, when you go into higher doses and risk of toxicity.
Maybe I'll add there, you know, it appeared from that early data that the clinical translation was running ahead of the preclinical models, that at the 2e11 per kilogram dose, we did not see substantial improvement in cardiac output function in the preclinical studies, yet in the clinical trial for the first two patients. We saw this pretty dramatic reduction in left ventricular mass index, of which both patients almost returned to normal. And this was at the lower dose. Now we're in the higher dose, where we're delivering 5 times more protein. So the question is: Will we see an effect size at the current dose that would be sufficient to take forward into the next study? This will really govern the decision on whether or not we need to go up to the third dose.
Yeah. I would just add, and I think Nolan brings up a good point, the effects we're seeing are not effects typically seen with placebo. Like, you just don't reduce the, the mass of your heart. You just don't reduce these biomarkers, so that's why they're particularly exciting for us.
Great, and then maybe from a practical administrative standpoint, can you describe your recent deal with Weill Cornell Medicine? How quickly do you expect it to accelerate development?
Yeah, so the agreement we reached with Weill Cornell was, in effect, licensing the data from the same drug candidate that's being studied in a very similar patient population. The studies were set up as parallel studies from the beginning. The Cornell organization was able to access a grant in order to advance their portion of the study, and we've since licensed the data that Lexeo can now utilize for regulatory purposes. It will also be part of the midyear readout as well. But what this does is brings the total number of patients dosed with this drug candidate now to 11 patients. I think that's a pretty substantial substrate of data to bring to the FDA to have a discussion about the future of the program and the future, you know, the future endpoints.
So that acceleration is a function of just the larger end that we're able to bring to the FDA to facilitate those types of discussions. We're not yet guiding on when we will be offering this feedback, you know, externally, but I think we're, you know, moving in the right direction on that front.
Great. Cameron from my team had a few questions. Cameron?
Yeah, so maybe moving on to LX 2020, you know, designed to increase desmosomal PKP2 protein levels, and also in the clinic for arrhythmogenic cardiomyopathy. Could you maybe touch on the status of enrollment and when you expect to have the first update?
So I'd say all of our milestones are on track for the program. We intended to initiate the phase I study in the first half of this year, which we have done. We're on track for a readout of our low-dose cohort by the end of the year. This will be primarily focused on the cardiovascular, you know, biopsies associated with the program. I don't know if there's any words you'd like to say about the disease itself and just some background.
Sure. Yeah, and I think as you mentioned before, this is what we would call a common rare disease, affecting between one in 2,000 and one in 5,000 Americans. It's been well known in and studied in Europe as well, so it makes it probably the largest target in all of striated muscle, skeletal muscle, and cardiac muscle for gene therapy. The preclinical data from this is extremely compelling. The disease is very morbid. Patients are getting shocks to their heart all the time at unknown to them when that's going to occur, so they have very poor quality of life. It's associated with a high risk of death and a high risk of heart transplant. So it kind of checks. We talked earlier about how we select diseases.
This is the one that checks all the boxes, and we're really excited to share data forthcoming.
Great. Well, I certainly did wanna touch on your neurology programs here. Could you walk us through sort of the design of lead? You know, especially when considering, you know, it can take quite a bit of time for the symptoms of Alzheimer's to even appear or progress. How does that factor into your clinical development plans?
Yep. So just taking a step back, for this program, we're treating APOE4 homozygotes with an APOE2 gene therapy. Here we're looking for, in the clinical trial, mainly biomarker-based endpoints, so, the E2 expression relative to E4 in the cerebrospinal fluid. We're also looking at the biomarkers that are commonly associated with Alzheimer's disease: amyloid beta, tau, phospho-tau. And the thesis being that by adding the APOE2 gene, you have this downstream impact on several different pathogenic mechanisms simultaneously. So we need to need to look at a range of biomarkers in order to, you know, prove out that, you know, that thesis. So I'd say for the study, it's primarily biomarker-based endpoints that we're looking at from an efficacy standpoint. We have CSF, amyloid beta, tau, phospho-tau. We're also doing amyloid and tau PET scans.
We have cognitive decline data as part of the study, but at, you know, a study of this size, it's not powered to show a benefit in cognitive decline, so there will be more directional trends that we'll be looking at. I'd note that, we did read out data from our lowest dose cohort at CTAD in 2022. This was three patients that had reached a 12-month time point, at that particular point in time. We did see reductions in tau, amyloid, and phospho-tau, in that readout, and this was at our lowest dose. Now we have the three higher doses, which we've since enrolled, and that's the readout that we're, you know, working towards at the end of the year.
How do these data inform your next two assets of the program, which you're actively not only adding in the APOE2 gene, but also targeting the APOE4 products?
Yeah, I think they're really interesting. All are progressive improvements on the existing, on the existing therapy. So if I take Christchurch, the Christchurch mutation as an example, we've already reported, you know, mirroring data suggesting that the Christchurch mutation can have a greater effect in reducing tau than the wild type, the wild type construct. So you would see a Christchurch mutated APOE2 is a more effective therapeutic option than the wild type version. So I think there'll be more to come on a development decision in terms of taking those forward, but our, our strategy all along was a life cycle strategy that, that allowed us to introduce one therapy and then progressively improve on it over time. And as we're looking at a population of, of this size, 900,000 patients, the incident population is also large.
The incident population will probably be growing as society ages. This market can support multiple therapies and multiple gene therapies, that seek to treat this disease over time.
Perfect, and thus far, you've got three programs entering clinical development, a few preclinical and discovery phases. I guess, how do you look at resource allocation? You know, at what point do you start to prioritize clinical development, and at what point do you start thinking more about the pipeline?
That's a good question. I'd say at current, two of our three clinical programs are in the cardiovascular space. We've completed enrollment of the lead study in Alzheimer's, so at the moment, the majority of our spend is being allocated to the cardiovascular disease area. I think as our pipeline advances, and you rightfully pointed out, you know, discussion around the preclinical studies in the Alzheimer's programs, we will be considering resource allocation very carefully. I'd say on balance, we probably would see more of our aggregate spend going into the cardiovascular disease area, but that's our current thinking, you know, at this moment in time.
Got it. And when does it start to make sense to think about partnerships?
So I think on the Alzheimer's side, that's probably the place we're more open to partnerships. I'd see Alzheimer's as a larger, very capital-intensive, disease area, both from the clinical development standpoint, but frankly, also from a commercial launch standpoint. I'd say on the other end of this data readout, on the other end of regulatory interactions, we'd probably see ourselves more open to partnerships on the Alzheimer's programs.
Well, got it. Very exciting times for Lexeo. Thank you so much for a very intriguing and interesting discussion.
Thank you so much for having us. Really appreciate it.