Conference Transcript - TNYA 2026-06-04

Xander Gwana, Analyst — Investment Banking, Jeffries Healthcare

My name is Xander Gwana from the Jefferies Healthcare Investment Banking Team, and it's my pleasure to introduce Faraz Ali from Tenaya Therapeutics.

Faraz Ali, Board Member

Thanks, and thanks to the Jefferies team for inviting us and giving us this opportunity to tell you a little bit more about Tenaya Therapeutics. We're a publicly traded company. These are forward-looking statements. Our purpose is to transform and extend the lives of patients through the discovery, development, and delivery of potentially curative therapies that target the underlying causes of heart disease. There are a couple things that make Tenaya unique. One, the unique focus on heart disease. Two, we go after both rare and prevalent forms of heart disease. And three, that we actually are modality agnostic. And so when we pursue gene therapy, small molecules, cardiac regeneration, gene editing, we truly follow the science, and those are some of the things that set us apart. We have three exciting clinical stage programs, and in the time I've been allocated today, I won't be able to do justice to all of them. But most importantly, we have near-term catalysts in the form of readouts from our two gene therapy programs and including the potential for regulatory alignment and pivotal studies. So an exciting time for the company. And in fact, that is the immediate opportunity for the company right now. The two gene therapy programs are TN201 and TN41, and those are moving relentlessly towards pivotal studies. Both are attractive because they address large opportunities. You can see 120,000 patients and 75,000 patients in the U.S. alone. Both have already generated meaningful clinical data, and I want to share some of that with you today. And we have several planned data readouts. We just completed two in the last three or four weeks, and we have another two coming up in the second half of the year. We've already shown increases in protein and improvement in disease markers and significant disease modification. I'll share some of that data with you today. And exciting, we have committed to providing an update in the second half of the year on where we land with regulatory alignment on these studies with the FDA and other agencies with the potential for these studies to go into pivotal stage. The next opportunity after these gene therapies, I do want to touch on that briefly because we really won't have time to discuss it later with the time allocated today, and that is TN301. This is a small molecule going after a range of very attractive indications. It represents a true pipeline in a pill potential. We've already demonstrated with our preclinical data, and it's been verified by others, the broad clinical utility in a range of indications as diverse as HEF-PEF, PHF-PEF, PAH, dilated cardiomyopathy, and most recently, we also shared compelling data in DMD and DMD cardiomyopathy. Now, how is it possible that one molecule can do so many things? And it's because it's got a unique mechanism of action that we and others have verified repeatedly in different in vitro and in vivo models. Decreases in inflammation, oxidative stress, fibrosis, improvements in protein quality control, autophagy. And so that's part of why we have such high conviction in this molecule and the horizon of opportunities this opens up after the gene therapies. We've already completed a first in human healthy volunteer study for this, and there were no adverse events. Whatever we saw were mild and consistent, what was seen in the placebo arm, and we are advancing this towards phase two proof-of-efficacy, proof-of-concept studies, doing some enabling work to get there and to start those studies, ideally in 2027 to establish proof-of-activity. Now, the rest of my comments will be focused on the gene therapy programs, But we've already discussed the first horizons of opportunity, 21201, TN41 gene therapy, next TN301 small molecule. And then after that, there's a whole deep and diverse pipeline, the engine of the innovation engine that may provide the next set of value inflection points as they move into the clinic. Exciting time for the company also in that we announced a collaboration with El Nilem, an early multiple undisclosed targets, 10 million up front. more than a billion dollars in milestone payments to go after genetic targets with a range of modalities that, of course, they're well known for siRNA, but there are other modalities included in there, and that will come into focus over time as well. So a lot going on for tonight therapeutics. Okay, with that, I'm going to transition to the two-gene therapy programs for which we've released exciting clinical data even in the last couple of weeks. First up, TN201, which is going after my BP3-associated HCM. This is a bad disease. Genetic, progressive, severe. It affects adults, adolescents, children, even infants. There's more than 120,000 patients in the U.S. alone. It is the leading genetic cause of hypertrophic cardiomyopathy. It accounts for about 20% of all HCM. You know, the hallmark of the disease is large hearts and thickened ventricles that gets in the way of the proper functioning of the heart, eventually, in the most severe cases, leading to arrhythmia and heart failure and need for transplantation. We are conducting a study called the BiPeak1 study. It's a phase 1b, 2, open-label, multi-center dose escalation study. We've already completed the sentinel phase of dosing in cohort 1, sentinel phase of dosing in cohort 2, and we're now in the expansion phase where we're actively screening and dosing patients in the high-dose cohort. The doses here, I'd like to point out, are relatively low in the gene therapy space, 3E13 vector genomes per kilogram for one, and 6E13 vector genomes per kilogram for the higher-dose cohort, both of them well below the levels that have been associated with toxicity and bad outcomes in other gene therapy studies. There are diverse endpoints here, and you're going to see some of the data we showed today. This is a very data-rich study, giving us a variety of ways of seeing the effect of TN2-1, including circulating biomarkers, hypertrophy, feel, and function. And that's exactly the data that I'll share today. Big picture, we just did a, just two days ago, we did a data release. Actually, sorry, it was just yesterday morning. I'm losing track of time. Just yesterday morning, we had another update on this program with data from both Cohort 1 and Cohort 2, multiple parameters of the disease are clearly improving. We're seeing durability of the effect even at Dose Cohort 1 out to two years, and we're seeing exciting acceleration of that benefit and deepening of that benefit with Cohort 2, and we'll talk more about that. Biopsies show that the product is clearly reaching the heart and expressing there, so it's getting to the right spot and doing the right thing. And importantly, safety, well-tolerated at both doses. In fact, the safety profile is even better at the second dose than the first dose because of some adjustments we made. So we'll talk about that. Global impression first, you know, before we throw numbers at you. This is just showing cohort one and cohort two and showing at the most recent visit using color scheme of how we look at biomarkers, hypertrophy, feel, and function against multiple parameters. and you'll see a lot of green on that slide, and that's particularly the deep green showing improvement and generally improvement that is meaningful. Light green means stability, and brown is things that have declined. And what should be apparent is that there's a lot of green in the slide at both those cohorts. We're quite pleased with what we're seeing in both those cohorts, but a little bit more green on the second-dose cohort, and that's partly because in the second-dose cohort we're beginning to see improvements also in functional endpoints and field endpoints, Kansas City cardiomyopathy questionnaire, peak VO2 circumsummonate walk test. So exciting, and we'll walk you through that as well. We'll start with hypertrophy. What you're seeing here is left ventricular mass index, one of the classic hallmarks of the disease, is that it is very elevated in these patients. And in fact, if I was able to show you the baseline characteristics, these patients have some of the largest hearts studied in HCM to date, this partly comes part and parcel with a genetic defect, very large hearts, very thickened ventricles, and they have failed every standard of care medication. They are not washing out on their meds. They've already had, in many cases, open heart surgery to have myectomies, and despite that, the size of the heart and the thickness of ventricles remain large. After a single dose of TN201 at the most recent visit, what you can see In cohort one, reductions of 8% to 10%, with the deepest response being 18%, and you can see up to 21% in cohort two. There are multiple patients with 10% or more, four out of six at 10% or more, reductions in LVMI, which is considered significant in this disease. And again, reminding you that this is on top of standard of care. We're showing you LVMI over here, but we actually demonstrated this in multiple parameters. And what we're showing on the next slide has changes in LVMI, changes in left ventricular posterior wall thickness in the middle, LVPWT, and interventricular septum thickness. And in all three measures in blue, what you see with TN2O1 is a reduction, both in relative reduction as well as the absolute reduction, is actually compares very favorably to what has been seen with the cardamycin inhibitors like Mavicampton and Afikampton that has been in the news and in investor minds for quite prominently. We are seeing a 12% reduction in one, 9%, and 9% in the other two. And in pink, you can see how that compares to what has been demonstrated at the latest time point based on publicly available information. So we're quite pleased. It's early days. This is early data. We're talking about six patients. But we're headed in the right spot, that after a single dose, we're seeing a degree of cardiac remodeling that has not yet been achieved after chronic dosing with approved therapeutics. What does that translate to? How do patients feel? Is it enough to reduce the thickness? Well, actually, they feel better. So the symptom burden has been reduced in all patients. In the case of New York class, you see these patients who are all at either New York class 2 or 3, and all but one patient transitioned to New York heart class 1, which means they don't feel the effect of their heart disease on their daily living. So 83% achieved that class 1. For the first time, we also shared data from KCCQ, the Kansas City Cardiomyopathy Questionnaire, a gold standard that has been used as an approvable endpoint in the approval of those myosin inhibitors I mentioned earlier. And what you can see is we saw one out of three of the patients had a benefit in cohort one that was above MCID or minimally clinically important difference. But all three patients in cohort two had a meaningful change. And in fact, the cohort two average change from baseline was plus 36 points. against this questionnaire, and all cohort two patient scores would be considered in the good to excellent range, which is 75 to 100 points in the scale. So this is a meaningful, on two different measures, we're confirming that the patients actually feel better. And guess what? They're actually able to do more. So this is now, we're talking about functional impact and functional capacity. Functional improvements observed in at least one of these measures in the majority of the cohort two patients. So we're clearly seeing that dose effect more in cohort two versus cohort one. And you can see over here for patient four and seven, the improvements of plus 50 and plus 255 on six minute walk test. Those are significantly above the plus 15 to 30 that is considered minimally clinically important difference. And in cardiopulmonary exercise capacity. Many people know this as peak VO2 testing. We only have data from the very first patient in cohort two, but we thought to share it, it's exciting to see that it was a difference of plus 2.4 or 15 percent, also meaningfully above plus one, which would be considered the MCID for peak VO2 in this condition. So we're excited to see early hints of functional capacity improvements in cohort two, and we look forward to following these patients and generating more, which will come in the second half of this year. Importantly, safety has been very clean. The majority of the adverse events seen were mild, transient, and irreversible with no clinical sequelae. You can see that actually in cohort two, this is the new information, cohort one data had already been reported, that there were only instances of grade one. So this is asymptomatic, generally liver enzyme elevations, some complement activation, but not clinically meaningful, nothing that put the patients, nothing that the patients felt or put them in any danger. So we're quite pleased that there was no clinical TMA, no need for complement inhibitors, no signs of cardiotexicity. So we're quite pleased that at this stage, we're getting great results at both dose cohorts, getting better results at the high dose cohort, and that's coming with a safety profile that's quite acceptable. Now, all the data presented is from adults, but there's this intriguing opportunity in children. This disease does affect, it's one of the leading causes of morbidity and mortality among young children with HCM, this mutation is. And you can see that it affects everything from adolescents, peds, and infants. In fact, we've been so excited about this opportunity that several years ago, we launched something called the My Climb Natural History Study to characterize these patients a little bit better. I'll show you that in the next slide. There are now more than 220 patients or kids that have been enrolled in this study across 29 sites in four countries. So we've been thinking about this for a while, that this may serve as a run-in to a potential pivotal study focused on pediatric patients and provide a synthetic control arm for a study like that, which we will inform, We'll tell people more about where we land on that later in 2026. But we do have some important markers on that regards. We did recently receive prime designation from the EMA. It's exciting and recognized the potential for TN21 to do something that standard of care cannot. And this allows us to engage more frequently with them about opportunities to accelerate this program in Europe. And importantly, the U.S. FDA recently accepted us into something called RDEP, Rare Disease Evidence Principles. This is focused on biallelic, meaning the severe pediatric patients, less than 1,000 of them in the U.S. alone. The FDA recognizes the severe unmet need in these kids, which I'll highlight in a second, and may enable creative thinking about ways to accelerate TN201 towards approvals in this very, very severe population with a lot of unmet need. That unmet need is captured on the next slide. 3,000 patients diagnosed and currently under the age of 18 with this mutation. They almost all have the non-obstructive 90-plus percent non-obstructive form of ACM, So they don't benefit from a septal, like a myectomy, a septal reduction, because they don't have obstruction. And more than a third are going to experience life-threatening ventricular arrhythmias. When you take that population and you split them by genotype, you can see that the homozygous infants, which are captured in red in the Kaplan-Meier curve, they almost universally die within the first days, weeks, and months of life. There's very few examples of patients living past the first year of life. Then there's what we call the compound heterozygates. So you have two mutations on two different alleles, but they're not homozygates. And 64% will experience heart failure-related hospitalizations before the age of 10. About a third will either require a transplant or die. And then there's the heterozygates. You have one mutation on one allele, and the other is normal. And even in that population, you can see that the medium age of diagnosis was 6.5 years. So we've gone from adults to children, and even within children, we're able to really characterize what's happening to these patients. And this is exactly why the FDA created the opportunity through RDP to engage with us more deeply about how do we design a study that is appropriate for this very heterogeneous presentation, even within an ultra-severe and rapidly progressive population of children. So we're excited about where we are in our understanding of the disease, in our understanding of what TN-201 can do for adults, and the possible opportunity provided by this regulatory pathway to accelerate TN-201 in children. So more to come in the second half of the year. Now, in the remaining time I have, I'll turn my attention to TN-401, which is for PKP-2-associated ARVC, or Arrhythmogenic Right Ventricular Cardiomyopathy. This is another very important and very severe genetic disease, severe progressive. This is going after the leading genetic cause of arrhythmogenic cardiomyopathy. It is the leading genetic cause accounting for 40% of all cases, and that translates to more than 70,000 patients in the USA alone. Again, it's an orphan condition, but it's on the larger side in terms of unmet patient need and opportunity. The hallmark of the disease is not enlargement of hearts and thickening of ventricles as much as it is arrhythmia, electrical instability. These patients experience profound arrhythmia, and unfortunately, in fact, greater than 15% of heart-related deaths in patients, less than 35, are due to this condition. for many families. The unfortunate reality is the first time they realize they have this disease is when they've had an unexpected sudden cardiac arrest event. And if you don't get to them in time, that translates to sudden cardiac death. So you die before you know that you had the disease. So it's a terrible disease with a lot of unmet need. Very similar design as we showed to you for TN201, so I won't cover this in detail. Other than to say, it's another data-rich study, Also, cohort one, cohort two, we're done with the sentinel dosing period. The DSMB has cleared us for the optional dose expansion, which we are indeed doing right now. And the doses that we selected are the same, using the same caps at AV9 and using the same doses, which are 3E13 and 6E13 vector genomes per kilogram. So both, again, below that level that has been associated with toxicity in other studies. And again, a very similar story. All patients that we've treated to date have had meaningful changes in their disease trajectory. They all achieved consistent and meaningful reductions in arrhythmia burden that were sustained up to one year in the first dose cohort. And we saw hints of a dose effect in the second dose cohort, very similar to what we described in TN2O1. Also clear that TN4O1 is reaching the heart and expressing in the right cells of the heart. And as is the case for TN2O1, it has been well tolerated at both doses. with the second dose cohort potentially looking even a little bit better than the first dose cohort because of immune suppression optimization. Just to provide you a little bit of a backdrop on this condition, the PVCs and NSVTs, it's a lot of acronyms, PVCs, premature ventricular contractions, NSVTs, non-sustained ventricular tachycardia. These are key indicators of electrical instability and risk of life-threatening events. What you see is a spectrum of electrical instability in the top half of the page going from PVCs and NSVTs to the left all the way to ventricular fibrillations and sudden cardiac arrest on the right. Those events on the right are more rare and more severe, but the volume and the intensity and the frequency of PVCs and NSVTs on the left are the key predictors of those rare, severe, life-threatening events on the right. They're the hallmarks of the disease. Higher PVC counts, for example, has been associated with worse long-term outcomes and higher five-year risk of life-threatening ventricular arrhythmias. And in fact, they're used as an indication for these patients to get ICDs. 100% of the patients we've dosed have ICDs because of the risk of sudden cardiac arrest and death. So what's the goal of gene therapy? The goal of gene therapy, quite simply, is to express some of the missing protein as a result of this mutation, and with that, lower the PVC and the NSVT count, and by doing so, lower the risk of life-threatening ventricular arrhythmia events. And we're excited to say that that's exactly what we are achieving. In cohort one and cohort two, we reported this at the American Society of Genes and Cell Therapy just a few weeks ago. all patients had meaningful reductions in the count of both PVCs and NSVT burdens, which we'll cover in the next slide, post-TN-201 dosing. Over here, we're showing you PVCs. Cohort 1 average reduction was 60%. You can see a range here of anywhere from 31% to 43%. Cohort 2 average was a little bit higher at 67% reduction. I really want to point out the average human being doesn't have anything that approximates this. At best, you might have a few hundred PVCs per day. Most have very, very little. You have to be above 500 to even be considered for this study. We're talking about patients who have thousands a day. And in core two, I'll point out patient five and six, 7,000 a day, 8,000 a day. These are patients running a much higher risk of a life-threatening event. And in that population, they are all on standard of care medications. Almost all of them have had ventricular, they've had ablation, a VT ablation, which is a surgical procedure to try to burn the parts of the heart where their arrhythmia seems to be coming from. And despite that standard of care, they had this hibernative disease. And a single dose of 401, at both doses, 3E13 and 6E13, resulted in a dramatic reduction in PVC count. The product is working. It's doing what it was set out to do. So we're quite excited about that. We saw a similar pattern in NSVTs. Those are less frequent. But among the two patients who had the highest burden of NSVTs, which is patient 2 and patient 5 on this slide, they both came down dramatically. The others were down at levels that would be associated with noise and be considered stable. So the consistency of the effect and the durability of the effect for some patients out to one year is exciting to us. There are other parameters we measured as well, ECGs, T-wave inversions, QR restorations, echo parameters, and those are either for these patients either in the normal range or remain stable. So, safety. Both patients, as was the case for T and 201, both doses were tolerated equally well. Actually, we have an even, as was the case for 201, even lower burden of overall AEs. In fact, there was only one grade E. Most of the E's we saw in both those cohorts were mild and transient and easily addressable. There was one instance of grade 3 in the same patient, or two instances of grade 3 in the same patient in cohort 2, and that was actually due to a medication error. Every patient gets a prophylactic immune suppression regimen of prednisone and sirolimus, and in these patients, accidentally in the pharmacy, they were reversed, and so they were getting the wrong dose of both prednisone and sirolimus, and that resulted in the liver enzyme elevation and the thrombocytopenia, but that was resolved once the error was corrected. No clinical thrombotic microangiopathy or TMA, no sustained VTVF or ICDs, no cardiotoxicity, and it's based on the safety profile that we're allowed to expand to get out of the central dosing period, and we're actively dosing patients in parallel now at the high dose. So one last thing on this program. This is an interesting area where there's never been a product approved specifically for ARVC and specifically for certainly this mutation. That means there's less known about what could be approvable endpoints and a design of a pivotal study. Recognizing that a few years ago, we launched something called RIDGE, which is the largest natural history study in the world for PKP-2-associated ARVC. More than 185 patients are being prospectively followed at 21 sites in six countries, representing more than 2,500 patient years of follow-up. This is larger than any natural history study of its kind in the world, either academic or industry. We do have some peers in the space who are also operating with gene therapy programs. And nobody has something like this. What is the significance of this? It allows us to characterize the disease better than anybody has ever been able to, and therefore allows us to think carefully about what could be approvable endpoints and how would you, you know, for surrogates for accelerated approval and harder endpoints for full approval, and how could you make the connection between surrogates and hard long-term endpoints. It's also an excellent way for us to engage with the community. In fact, 100% of the patients we've dosed to date all came from patients who were in this study. We're operating in six countries. This provides a bolus of patients that could be relevant as we transition to pivotal studies. So overall, we're quite pleased with this investment. It is really another source of competitive advantage for us in this program. We have a small molecule, and we don't have time to talk about it, but as I already laid out for you earlier, that this is the next horizon of our future growth. If I had to say anything in the short time I have here, we have a lot of conviction that has been supported by others about its mechanism. We understand exactly where this operates. HDAC-6 specific inhibition is very different from pan-HDAC inhibition, and this is a highly, highly specific HDLT6 inhibitor, more than 3,500 folds selected for HDLT6 versus others. That means we can hit the target harder and we can avoid safety events. We have generated mountains of preclinical data that are quite compelling in a range of indications. I'm showing HEFPEF here, a very large attractive indication, more than three million patients in the U.S. alone, standard of care are SGLT2 inhibitors, and what we've demonstrated is that we can head-to-head comparisons as good as an STLT2 inhibitor and on the right we're showing additive benefit on top of the STLT2 inhibitor and that's because of an orthogonal mechanism of action. That's quite relevant as we go into potential proof of activity and proof of concept studies in the future and we'll be providing more updates on that. We did the exact same thing in DMD and showed compared to an existing approved product that we get were as good or better against both improvements in skeletal muscle and in a relevant MDX mouse model and in cells derived from the hearts of human DMD patients, we were able to show benefit in the heart cells compared to the available product. So we're quite excited about the broad clinical utility of TN301 in a range of indications and we look forward to providing updates to investors about what we plan to do with this molecule, HFBF, DMD, or something else, and what will be the design of the studies to prove the clinical utility of this molecule. A very different profile compared to gene therapies, but also equally exciting. In the remaining time we have, I won't talk about the alnihilam collaboration. I think I'll just focus on our milestones. We have achieved everything we set out to do in the first half of the year. We have enrolled patients, and we've now provided a data readout for both the MyPeaks1 study for 201 and the Bridge1 study for 401. I presented some of those data today. What we can look forward to in the second half this year is more data from both of those studies, so more durability from the first dose cohort and then more complete picture from the second dose cohort, but we're off to the races and very pleased with where we are today. And last but not least, and most importantly, it is in the second half of this year that we have committed to providing an update of where we stand with our regulatory discussions both with the FDA as well as the MEA. And with that, I'm right at time. Thank you for your time and attention.