Okay. Hi, everyone. Yeah, it says, it's, it's, it's on. Are we not? Is this better? Yeah? Okay. Okay. Sorry about that. Hi, everyone. My name's Nicole Martucci. I'm an associate here at TD Cowen. Thank you all for joining us this afternoon. With us right now, we have Faraz Ali, who is the CEO of Tenaya Therapeutics. He'll be providing a corporate update. Following the presentation, we're gonna have some question-and-answer sessions, so please take it away.
Great. Thanks, thanks for being here, and thanks for the opportunity to tell the Tenaya story. We are a publicly traded company, so we'll be making some forward-looking statements, and these are our standard disclosures. Tenaya, many of you may know this, but we are 100% focused on heart disease. Have come a very long way since the company was founded in 2016, and three clinical stage programs that are very exciting that we'll talk about today, with deep, just unparalleled expertise at the intersection of rare diseases, genetics, and cardiology. For the purpose of today's presentation, we'll really focus on the gene therapy programs. We have an exciting portfolio. Something that puts Tenaya apart is, in addition to the focus on heart disease, is the fact that we're modality agnostic.
In our earlier pipeline, you can see both gene therapies and small molecules, and we go after both rare and prevalent forms of heart disease. The gene therapies are targeted at rare, severe genetic forms of cardiomyopathy, while the small molecule is targeted at a prevalent indication called HFpEF. In the interest of time for today's presentation, I'll focus on TN-201 gene therapy and TN-401 gene therapy programs, which are the ones that are actively dosing and for which there's some important data catalysts in the coming months. Just to put into perspective what it means for us to be a clinical stage company, we at this point have, for these two gene therapy programs alone, 45 sites activated in eight countries, and at this point, we've already enrolled hundreds of patients in our natural history studies. We think that's, you know, meaningful and important.
Partly, we've built the clinical engine that is really moving these programs forward. That sheer number of patients that have enrolled in our natural history studies gives you a sense. It's a surrogate marker for the patient severity and the interest in what we're doing. It also means that they're feeding in the study recruitment for these interventional studies that will supply both the current studies as well as future pivotal studies. Last but not least, we know that the FDA is gonna require natural history data to approve us in pivotal studies. We're already accumulating hundreds of patients' worth of retrospective and prospective data that will fuel those pivotal studies. Also, at the same time, it has never been a better environment on the regulatory front for AAV gene therapies.
In short, what all these logos on the right-hand side of this screen share in common is that all of them have, with a modest number of patients with sufficiently good clinical data, been able to get alignment with the FDA on going either converting their existing phase I-II studies into pivotal studies or to launch pivotal studies. The most true relevant examples for us are Rocket and Lexeo, both AAV gene therapies going after genetic cardiomyopathies, and both, with five to 10 patients' worth of data at the one to two-year mark, have been able to convince the FDA to allow them to go into pivotal studies.
It's an exciting time where, you know, the past, the conversation was about safety, and today it's about early accelerated approvals and the potential for an accelerated approval based on a surrogate marker, which is, we think, a direct read-through to our two gene therapy programs and creates some exciting opportunities for the data that we're gonna generate over the next 12 months. Time doesn't allow us to go into the very deep and diverse pipeline and, and the sort of differentiated capabilities that we have, but, you know, these are just some markers of the success we've had preclinically. We have nine, a uniquely deep and diverse pipeline of cardiovascular gene therapy targets, including gene therapy, gene editing, gene silencing. We've been screening capsids and promoters.
We have screened at this point more than a billion variants in our own libraries and have some best-in-class capsids for delivery to the heart, as well as promoters for expression of the heart. We internalized manufacturing and produced all the material we need for these studies that I'm gonna talk about today in our own facility with our own process at the 1,000-liter scale, significantly de-risking the execution on these programs and moving them through the current studies and into pivotal studies. With that, I'm gonna transition to talking about the first gene therapy program. This is TN-201, addressing MYBPC3-associated HCM. What is this disease? Hypertrophic cardiomyopathy involves a thickening. It's a severe disease, 600,000 patients in the U.S. alone, thickening of the ventricles causing severe symptoms in patients. MYBPC3 is the leading genetic cause of this disease.
It accounts for about 19% of all patients, which translates to about 120,000 patients in the U.S. alone. What this time curve shows is that the age of diagnosis predicts the severity. The patients who are diagnosed before the age of 40, by the age of 50, 50% of them have the likelihood of a very serious adverse event. Those in the small, darker box in the bottom left, those are kids who are diagnosed within the first months and years of life who have very, very severe outcomes. It is a bad disease, and we are trying to address the underlying genetic cause. We understand the genetics of this disease very well.
It is, of all the mutations that have been identified, all of them involve haploinsufficiency, meaning as a result of mutation, you're not producing the protein, and as a result of that missing protein, you have all the downstream symptoms. The therapeutic hypothesis here is quite simple. This is a lock-and-key gene therapy. We're providing a full-length copy of the gene that's mutated and producing the wild-type protein, and by doing so, by restoring the protein levels, addressing the underlying cause, and preventing downward symptoms from there. Very, very clean approach, that has the potential, after a single dose, to not only halt but reverse the progress of the disease. That is what we've proved in our preclinical models. This is a high-bar model, and we say that in that these are mice who have zero mutation, so a mutation, and as a result, zero protein.
We have to restore the protein completely in these animals, and we're demonstrating that we're able to do so. After a single dose of AAV gene therapy with TN-201, we're able to reduce the heart mass, we're able to improve heart function, and we are able to improve survival. I'm not showing the data here, but we're able to restore 100% of the wild-type protein after a single dose of administration. Interestingly and importantly, we start to see effects at doses as low as 1E13, and we see a near maximal effect at 3E13. We chose the 3E13 dose to take into our clinical studies. What we're able to show here is that we're not only stabilizing this severe disease, but we're reversing it. That's what we hope to demonstrate in humans as well. Which brings us to our clinical study.
It's called the MyPEAK-1, phase 1b/2 clinical study. It is an open-label, multi-center, dose escalation and expansion study. We've already completed dosing in the first dose cohort, and we announced that we've already initiated, after DSMB clearance, and announced that we have initiated dosing in the high-dose cohort. In fact, we've already dosed two out of three of the patients in the high-dose cohort. We are well along our way on dosing and meeting the objectives that we have for this year. We have the ability to dose up to 24 patients in this study. That was done deliberately so that we have the opportunity to convert this into a phase I/II/III if the data support it, and we get to that kind of alignment with the FDA.
Importantly, we've produced, as I mentioned earlier, all the manufacturing material we need to make that transition if we go into the optional dose expansion of this study. Very exciting time for this program. Also, this is a data-rich study. For each patient, we're capturing a lot of endpoints, of course, safety, but also biopsy data, and then a range of echo parameters, functional changes, as well as quality of life. These are endpoints in this study that could, again, the intention from the beginning was to design a study that would allow us to get approval with a full clinical benefit endpoint or with a surrogate marker from protein biopsies. We have everything that we need in this study to go after endpoints that we know from prior experience of others have been validated as approvable endpoints.
This starts to describe the first three patients that were dosed. This is data that we released in December. The next couple of slides will cover the data that we released in December of last year. These are the first three patients that were dosed, and the big picture that we want to communicate is that these are very young and severe patients compared to the average HCM patient. Patient One, I'll call attention to her. She, at the age of 27, has already had an ICD implanted, has already failed all approved pharmacological therapies available to her, and has had an open heart surgery to remove excess tissue, and she still has severe progressive disease. That is because the underlying genetic defect has not been addressed.
She still has an enlarged heart, as measured by LVMI, still has high cardiac troponin I, and still has New York Heart Class, or functional limitations as defined by her New York Heart Class status. That is true for patient two and three as well. This is just showing the severity of the unmet need. By the way, these patients are all non-obstructive patients, which means they are not candidates for the approved CMI or Cardiac Myosin Inhibitor, Camzyos, from BMS. That product has not yet been approved in non-obstructive patients, and it is still to be seen whether the non-obstructive patients will benefit from this approach. A lot of unmet need here, and there is a reason why these patients showed up at the door of our sites to participate in this study. TN-201 was generally very well tolerated.
We're quite pleased with the safety profile, and the reported AEs were consistent with other gene therapies and the known effects of immune suppression. Everything was transient and addressable with immune suppression. There was no thrombotic microangiopathy. There was no cardiotoxicity, no arrhythmia. In fact, we removed the requirement to have an ICD in this study. No participants discontinued the study. I already mentioned that the DSMB cleared us to progress to the higher dose. Quite excited with the early safety profile with this program. Again, we're operating at doses that are significantly lower at 3E13 vector genomes per kilogram, significantly lower than the high doses that have been associated with some safety events in other AAV gene therapy programs. The next couple of slides I'm gonna cover will involve the biopsy data from these first couple of patients.
We are very, the very first slide is about transduction, and that's simply a fancy way of saying how much of the gene of interest, the virus is delivering the gene of interest to the relevant organ, which in this case is the heart, and that's measured by something called vector copy number. We have very consistent and high vector copy number in the first two patients, as shown here at 2.1. The green line, the green dotted line there at the bottom, that is the vector copy number that was associated with maximal efficacy in our preclinical data. We are well above the level that was associated with maximal clinical benefit in our preclinical studies.
More importantly, is the comparison against the purple lines, the dark and light purple lines, our data, comparable data with another AAV9 gene therapy program, and that's Rocket Pharmaceuticals' work in Danon disease, which has made tremendous progress. This is data from the New England Journal paper, from their clinical study published in November of 2024. Importantly, the light purple line, which is their 6.7E13 dose, which is the dose that has been taken into our pivotal study, we are achieving the same results as they are at less than half the dose. That's important. We're achieving the same result of a product that has demonstrated clinical benefit, but at half the dose. Very, very strong measures of cardiac transduction with TN-201. Importantly, we're seeing the same phenomena in RNA expression, right?
Once the gene is delivered, now it needs to start expressing, and the first way you can express it is with RNA. Patient one, we have their data at eight weeks and at 52 weeks. What you can see here, point number one is that they increased, that RNA expression went from zero to 1.7E5, and then from there continued to increase in expression out to 52 weeks. We do not even know whether we have yet achieved peak expression. We are quite excited to see that data. Also excited to see that, again, that purple bar, that band includes the Rocket data in Danon disease as well as 4DMT's data in Fabry cardiomyopathy. Two clinical stage programs that did have clinical benefit. In both cases, again, at less than half the dose, we are getting to the same amount of RNA expression as the Rocket study.
We're quite excited. Now, we keep on making comparisons with Rocket, and I do have to, full disclosure, just because we have the same biopsy data doesn't mean we'll enjoy the same clinical benefit, but it's still a good objective early marker of the robust transduction and expression of the gene of interest compared to another clinical stage program. Protein is what people are very interested in, is that RNA turning into protein. Before we go to protein, we need to make a few points. There is a tremendous amount of heterogeneity in the expression of this protein, both in humans, healthy humans, as well as in the disease population. On the right, you can see healthy humans. That's just you and I, all of us sitting in this room here.
If we went and took biopsies of your heart, which we're not proposing, but if we did, we would find a wide range in the levels of MYBPC3 in our hearts. Everything from, you know, around, if you take 100% as average, everything from 78%-109%. Now move to the left and in the orange, these were biopsies analyzed from patients with very, very severe disease. So severe that they had to have open heart surgeries to debulk their heart with a myectomy. That's how we even had these samples to analyze. This is not our data from our study. This is data by others. You can see a very wide range here of about 30%, everything from 47%-79%.
Somewhere out there in the world, there's a healthy human being with MYBPC3 levels at about 78% of average, and there's a patient who required open heart surgery at 79%. What does this tell us? We don't think that there's a single magical number that you have to be at to be healthy. We believe that each patient has their own sensitivity to the loss of this protein, and the primary objective with TN-201 AAV gene therapy is to add more protein back above your own baseline, above each patient's baseline. We're not trying to get everybody to 100%. We're just trying to get protein above their own baseline. Now, why do we believe that that is, that thesis should hold out is, again, the comparison with Lexeo and Rocket.
Both of those companies in their express protein expression are showing that with single-digit percentage of wild-type expression, they're seeing dramatic impact when measured at the one and two-year mark. That seems to suggest that a small amount of protein can go a long way, and we think that our, the picture we're painting here also suggests that. With that backdrop, we're very thrilled with where we are at this early time point. We only can evaluate the protein expression for patient one at both the eight-week and the 52-week mark. You can see that the patient started, we don't know what their baseline level was. We didn't take baseline biopsies in these first two patients, so it does limit our interpretation. We know that at eight-week, we have a very, very good mass spec assay that can measure protein quite accurately.
We know that they were at 56% of wild-type levels at the eight-week mark and that their protein expression grew by 3% to the 52-week mark. We do not yet have comparable data for week, for patient two at this early time point, but we are excited to see that increase in expression of protein at the same time as the increase in expression on RNA that I showed two slides earlier. It is exciting to speculate what they may have been at, at the week zero of baseline mark, but we do not have that data. We need to generate more data. For patient three going forward, we will have baseline biopsy data, and that will help make the protein more interpretable. We are quite excited about where we are at this early time point with just the first patient at the one-year mark.
With all those caveats, it is also very early to be speaking about clinical benefit, but if we did not show anything, we know that the, people would assume it was all bad. So it was important for us to get some green on the board. We did not put numbers here because we are saving it for a presentation. Actually, we have been accepted for a late breaker presentation at ACC in a few weeks, and so some of these greens will be converted into numbers. Again, dark green means improved and improved significantly and with significant separation from what we would consider noise for that particular measure. Light greens means stable, which, given how severely progressive this disease is, is a win. Green or white means mixed or we do not have the data yet.
We're quite pleased at this early time point that both patients experienced one full improvement in New York Heart Class. That's what the dark green represents. In particular, in patient two, you see several things all trending in the right direction and a meaningful improvement in hypertrophy, meaning improvement in their cardiac troponin I circulating biomarker and a meaningful improvement in diastolic dysfunction. That is for the first two patients at our first dose cohort at these early time points. We're quite excited by where we are, and certainly this has excited the physician community and the patient community as well. Obviously, we need more data here, and that's the, you know, that, and I'll talk about our upcoming milestones in a subsequent slide. Importantly, right now we're focused on the adults in the study.
Both the obstructive, currently our study is open for both the obstructive and the non-obstructive form of disease, patients with or without ICDs, and then New York Heart Class two or three. Quite a large population is now open to us to dose in this study. What we're really excited about is also the potential, once we've generated some more data in adults, to go to the children. There are, we estimate, about 3,000 kids in the United States alone who have very, very severe forms of cardiomyopathy. Some of them are presenting in the first days, weeks, and months of life. These patients, some of them are dying in the first year of life. They're getting ICDs, they're getting heart transplants, they're getting myectomies at very young ages. There is nothing available to help them other than a heart transplant.
Certainly, there's no evidence yet for cardiomyosin inhibitors in this very young and severe population. We truly do believe that a lock and key gene therapy that is adding back the missing protein is the only solution that's gonna really work for these patients. We are motivated, so motivated that we established a MyCLIMB natural history study to begin to characterize these patients around the world. At this point, we have more than 220 patients enrolled across 29 sites in several countries. Again, speaking to the unmet need, but also importantly, this study can provide a run-in for future pivotal phase I, II, III study in pediatrics and provide the synthetic control arm we're gonna need to make the case for an approval. Very excited about that potential future direction for this program. Okay.
With that, in the remaining time, I'm gonna turn my attention to the second gene therapy program, which is TN-401 for PKP2-associated ARVC. That's a lot of acronyms, so let me explain that. ARVC stands for Arrhythmogenic Right Ventricular Cardiomyopathy. I'll just call it arrhythmogenic cardiomyopathy for short, is another form of severe cardiomyopathy. Over here, in addition to the heart thickening, the primary dysfunction that you see in these patients is arrhythmia. One somewhat morbid statistic here is that for about a quarter of the patients, the first presentation is sudden cardiac death. By the time you find out you have this disease, you've died. It is a very, very severe disease that affects people without any warning. There are more than 70,000 patients by our estimate in the U.S. alone. Like the prior program, these are large orphan indications.
These are not, this is not gene therapy for ultra orphans, but for significantly large orphan populations. Another severe progressive genetic heart disease that does not have good options. There are no therapies approved that address the disease at all, nothing that addresses the underlying genetic cause. Most patients simply have an ICD that, all it does is prevent sudden cardiac arrest and death, which is important, but it does nothing to halt the underlying progressive heart disease that is causing their hearts to fail. This is also the genetics over here, very well understood. The genetic, the primary gene associated here is PKP2. That is the leading genetic cause of this condition. We know that that affects the functioning of the desmosome, which is the structure that holds the cardiomyocytes of the heart together.
As a result of the mutations, they're missing sufficient levels of the PKP2 protein that helps hold these cells together. The hypothesis again is another lock and key gene therapy. By adding a full-length copy of the healthy human gene, we're producing the missing protein, and by restoring protein levels, we hope to address and halt the progressive nature of this disease and even reverse the symptoms. In this study, the preclinical data certainly supports that hypothesis. We've demonstrated that we can reverse the arrhythmia, that is the hallmark of this disease. We can prevent the RV enlargement that happens in this disease and improve the survival after a single dose of this gene therapy.
Similar to the prior one, we're using AAV9, and we've been able to demonstrate that we see effects at doses as low as 1E13 and a near maximal effect at a dose of 3E13. Again, significantly below the doses that have been used in other AAV gene therapies. We're quite excited to demonstrate how this will work in humans. There are other companies who are working on gene therapy for this disease, and Rocket Pharmaceuticals and Lexeo, who I've referred to earlier, are peers who we have a lot of respect for. What sets our program apart from the other two? We think the primary difference is the capsid. We selected the capsid first, and we selected AAV9.
Why did we select AAV9 for this program, as well as for the TN-201 program that I mentioned earlier, is essentially captured in the data on this slide. We have done relentless head-to-head comparisons for all of our programs of all capsids, promoters, and other regulatory elements. What we have shown time and time again is that AAV9 outperforms these other parental capsids like AAVrh10 and AAVrh74, which are being used in other clinical stage programs. They both, they all transduce the heart relatively similarly, which is the data on the far left, but the expression in the cardiomyocytes is fundamentally different. AAV9 outperforms or out-expresses the rh74 and rh10 in both mice as well as NHPs.
We expect to see this is data not only in our hands, but in the hands of others that demonstrated in their own, preclinical models, both in industry and academia. We think that this gives us first and best in class potential compared to the other two gene therapy programs. The design of this clinical study, so this study is actively enrolling. We've already dosed the first two out of three of our first dose cohort patients, and we're looking forward to presenting data on that in the second half of this year. Again, like TN-201, this is a data-rich study.
We are capturing a lot from each patient, and we believe that the data points we're capturing, including the biopsy data, the pharmacodynamic data, which is you can monitor the arrhythmia in these patients, along with these exploratory efficacy measures, they can support either a full approval or an accelerated approval based on a surrogate endpoint. Which brings us to our milestones. What are we trying to achieve this year and, into next? For TN-201, we're well along the way of meeting our first half milestones. We intend to present additional cohort one data. We have been, as I mentioned at the top, accepted for a late-breaking presentation at ACC. That's where we'll present additional data. We're also on track for completing cohort two high-dose enrollment. We've already dosed two out of three of those patients. The third patient is scheduled. No news is good news.
If we have not said anything on the safety front, so far, so good at the high dose. In the second half of this year, we will present yet more data from cohort one and initial data from the high-dose cohort two population. In TN-401, we are also on track to meeting these objectives. The ex-U.S. expansion is going well. We already have clearance to dose in the U.K. and are activating sites over there. We have already dosed the first two out of three patients in the low-dose cohort one, and the third is scheduled. Very much on track to meeting our first half objectives, which sets us up for the second half, where we will present initial data from that first dose cohort in the second half of this year. Importantly, our cash balance as mentioned over here is $80 million as of September 30, 2024.
We will obviously update that cash balance when, in our Q4 earnings release. Importantly, as of yesterday, we did successfully raise $52.5 million in a follow-on financing. It was hard in this operating environment. We're very pleased to have brought in that additional capital. That, plus the existing cash balance, plus some other things that have gone our way, we did receive a grant from CIRM that offset some of our clinical spend on the TN-401 program. Altogether, that will update our guidance from second half of 2025 into something into the second half of 2026. What is the use of proceeds? What are we trying to get to with this financing? Very, very important milestones.
The goal is not only to get to the data that I'm showing here in the second half of 2025, but importantly, by the first half of 2026, for TN-201, we'll have for cohort one, patients at or near the two-year mark, and for cohort two, patients at the one-year mark. That quantum of clinical data, if it's good, which we knock on wood, hopefully it will be, will be enough, we think, to approach the FDA about turning this into a pivotal study or initiating a pivotal study. That's based on the precedent set by our colleagues at Rocket and Lexeo and their respective genetic cardiomyopathy programs. For TN-401, which is just one step behind, we'll have full dose cohort data for cohort one at the one-year mark and early high-dose cohort two data.
Exciting data points ahead over the next 12- 15 months, clear use of proceeds. If those cards all flip in our favor, would fundamentally transform the profile of this company 'cause we would be on the cusp of potentially two pivotal studies, not to mention everything else going on in the pipeline and portfolio and with some exciting potential BD opportunities 'cause there's a lot of interest in both of these programs as well as the other preclinical assets. With that, I will pause here to see if there's any questions. I've left a few minutes at the very end for that.
Okay, great. Thank you so much for that update. You have a lot of exciting things going on. To kind of kick off questions here, let's start with the TN-201 asset. It's currently in a Phase 1b/2 , the MyPEAK-1 trial. How should investors think about the additional low, low-dose cohort one data and what should we expect from the cardiac expression, the biomarker echo, functional data, and all the later time points?
Yeah, great. Thanks. I would describe the data presentation we're gonna do at ACC as additive to what we've already presented. We'll have, for patient two, they were not quite at the one-year mark, so now they'll be at the one-year mark with some additional data there, both biopsy, as well as some functional data. Patient three will not quite be at the one-year mark, but we'll have additional data on both of those patients, safety biopsy, as well as some efficacy and circulating biomarker data.
For the high dose, one thing that we, I did not point out in the prior slide, but we totally, we completely believe that with high dose, it is possible to have both higher vector copy number, and that is demonstrated by the Rocket data. They saw a big jump, as they went from low to high dose, and therefore we expect that to also show up in the RNA, and we expected that to show up in protein. Our expectation is that with high dose, consistent with other gene therapies, we will see an improvement in all three of these parameters, which we hope, suspect, will lead to even more robust clinical responses.
Great. Just one last question, as we are running out of time here. A quick question on the TN-401 program. What would good first data look like? Do you currently have a targeted threshold for the PKP2 expression?
You know, too early to talk about the expression there. I think our other colleagues in the other two programs will be generating that kind of data first, and then we are rooting for their success 'cause if they do well, we think we can do better based on what I mentioned about the capsids. What we're looking for early on is actually, I think what would be really exciting, this is the preclinical data, and you can see what a normal sinus rhythm looks like and what a patient with this mutation mimics in the animal model. It can be very, very deranged sinus rhythm. You can see non-sustained ventricular tachycardias. These, they have thousands of premature, premature ventricular contractions.
You see a lot, and those are all hallmarks, hallmarks of what eventually becomes life-threatening ventricular tachycardias, that can cause sudden cardiac arrest. We think that that might be one of the, just like it is in the preclinical models, one of the earliest PD markers of the effect of the expression of the gene of interest, before you get to some improvement in other things that we're measuring. As I mentioned, the frequency of ICD shocks and problems and the remodeling of the heart, as well as the patient-reported outcomes, 'cause these patients have very, very poor quality of life. The first thing we're looking for is that resolution of the arrhythmia signals, that we can measure with the Holter monitor, as well as by the ICDs.
Okay, great. With that, we are slightly over time. Thank you so much.
Thank you.
Everyone enjoy the rest of the conference.