Tenaya Therapeutics, Inc. ($TNYA)

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

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 of 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 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 3 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 2 gene therapy programs and including the potential for regulatory alignment on pivotal studies. So an exciting time for the company. And in fact, that is the immediate opportunity for the company right now. The 2 gene therapy programs are TN-201 and TN-401, 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'm going to share some of that with you today. And we have several planned data readouts. We just completed 2 in the last 3 or 4 weeks, and we have another 2 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 TN-301. 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 HFpEF, PH-HFpEF, 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 with what was seen in the placebo arm. And we are advancing this towards Phase II 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 horizon of opportunity TN-201, TN-401 gene therapy, next TN-301 small molecule. And then after that, there is 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 and that we announced a collaboration with Alnylam, and early multiple undisclosed targets, $10 million upfront, more than $1 billion 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 Tenaya Therapeutics. Okay. With that, I'm going to transition to the 2 gene therapy programs for which we've excited -- we released exciting clinical data even in the last couple of weeks. First up, TN-201, which is going after MYBPC3-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. It's 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 MyPEAK-1 study. It's a Phase Ib/II open-label multicenter 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 1 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 TN-201, including circulating biomarkers, hypertrophy, feel and function, and that's exactly the data that I'll share today. Big picture, we just did just 2 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 2 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 before we throw numbers at you. This is just showing Cohort 1 and Cohort 2 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 feel endpoints, Kansas City cardiomyopathy questionnaire, peak [ KCCQ ] 7-minute 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 -- they're 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 TN-201 at the most recent visit, what you can see in Cohort 1 reductions of 8% to 10% with the deepest response being 18%, and you can see up to 21% in Cohort 2, there is multiple patients with 10% or more, 4 out of 6 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've actually -- we're showing you LVMI over here, but we actually demonstrated this in multiple parameters. And what we're showing on the next slide is changes in LVMI, changes in left ventricular posterior wall thickness in the middle, LVPWT and intraventricular septum thickness. And in all 3 measures in blue, what you see with TN-201 is a reduction both in the relative reduction as well as the absolute reduction. This actually compares very favorably to what has been seen with the cardiac myosin inhibitors like mavacamten and aficamten 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 2. 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 with -- it's early days. This is early data. We're talking about 6 patients, but we are 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 were all at either New York Class II or III and all but 1 patient transitioned to New York Heart Class I, which means they don't feel the effect of their heart disease on their daily living. So 83% achieved that Class I. 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 1 out of 3 of the patients had a benefit in Cohort 1 that was above MCID or minimally clinically important difference. But all 3 patients in Cohort 2 had a meaningful change. And in fact, the Cohort 2 average change from baseline was plus 36 points against this questionnaire. And all Cohort 2 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 2 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 2 patients. So we're clearly seeing that dose effect more in Cohort 2 versus Cohort 1. And you can see over here, for patient 4 and 7, the improvements of plus 50 and plus 255 on 6-minute walk test, those are significantly above the plus 15 to 30 that is considered minimally clinically important difference, and the cardiopulmonary exercise capacity. Many people know this as peak VO2 testing. We only have data from the very first patient in Cohort 2, but we thought to share it. It's exciting to see that it was a difference of plus 2.4 or 15%, also meaningfully above plus 1, which would be considered the MCID for peak VO2 in this condition. So we're excited to see early hints of functional capacity improvement in Cohort 2, 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 reversible with no clinical sequelae. You can see that actually in Cohort 2, this is the new information Cohort 1 data had already been reported that there were only instances of Grade 1. 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 cardiotoxicity. 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 MyClimb 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 the study across 29 sites in 4 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 regard. We did recently receive PRIME designation from the EMA. It's exciting and recognizes the potential for TN-201 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 peds, 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 TN-201 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 nonobstructive 90-plus percent of nonobstructive form of HCM. So they don't benefit from septal -- like a myectomy septal reduction because they don't have obstruction. And more than 1/3 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 and 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 heterozygous. So you have 2 mutations on 2 different alleles, but they're not homozygous and 64% will experience heart failure-related hospitalizations before the age of 10. About 1/3 will either require a transplant or die. And then there's the heterozygous, you have one mutation and then the other is on one allele and the other is not -- is normal. And even in that population, you can see that the median age of diagnosis is 6.5 years. So we've gone from adults to children and even within children, we're able to really characterize what's happening in these patients. And this is exactly why the FDA created the opportunity through RDEP 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 PKP2-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 U.S.A. alone. Again, that is -- 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. It very similar design as we showed to you for TN-201, so I won't cover this in detail other than to say it's another data-rich study, also Cohort 1, Cohort 2, we were done with the sentinel dosing period. The DSMB has cleared us for the optional dose expansion, which we're indeed doing right now. And the doses that we selected are the same, using the same capsid AAV9 and using the same doses, which is 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 [ rizumab ] burden that were sustained up to 1 year in the first dose cohort, and we saw a hint of a dose effect in the second dose cohort, very similar to what we described in TN-201. Also clear that TN-401 is reaching the heart and expressing in the right cells of the heart. And as is the case for TN-201, 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,' a lot of acronyms, PVCs, premature ventricular contractions, NSVTs, nonsustained ventricular tachycardia, what you -- these are key indicators of electrical instability and risk of life-threatening events. What you see is a spectrum of electrical instability on the top half of the page, going from PVCs and NSVTs to the left all the way to ventricular fibrillation and sudden cardiac arrest in 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 5-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 1 and Cohort 2, we reported this at the American Society of Gene and Cell Therapy just a few weeks ago. All patients had meaningful reductions in the count of both PVCs and NSVTs burdens, which I'll cover on 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 Cohort 2, I'll point out patient 5 and 6, 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 of VT ablation, which is a surgical procedure to try to burn the parts of the heart where the arrhythmia seems to be coming from. And despite that standard of care, they had this high burden of the 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 2 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, some patients out to 1 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 TN-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 1 grade -- most of the AEs 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 instance of Grade 3 in the same patient in Cohort 2, and that was actually due to a medication error. Every patient gets a prophylactic immunosuppression 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 VT/VF or ICDs, no cardiotoxicity. And it's based on the safety profile that we are allowed to expand to get out of the sentinel 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 are the -- what could be approvable endpoint 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 PKP2-associated ARVC more than 185 patients are being prospectively followed and at 21 sites in more than -- in 6 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 -- for surrogates for accelerated approval at 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 or operating in 6 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 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. HDAC6 specific inhibition is very different from pan-HDAC inhibition, and this is a highly, highly specific HDAC6 inhibitor, more than 3,500 fold selective for HDAC6 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 HFpEF here, a very large attractive indication, more than 3 million patients in the U.S. alone. Standard of care are SGLT-2 inhibitors. And what we've demonstrated is that we can -- head-to-head comparisons as good as an SGLT-2 inhibitor. And on the right, we're showing additive benefit on top of the SGLT-2 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 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 TN-301 in a range of indications, and we look forward to providing updates to investors about what we plan to do with this molecule, PH-HFpEF, DMD or something else and what will be the design of those 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 Alnylam 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 MyPEAK-1 study and for 201 and the RIDGE-1 study for 401. I presented some of those data today. What we can look forward to in the second half of 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 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 on where we stand with the regulatory discussions, both with the FDA as well as the EMA. And with that, I'm right at time. Thank you for your time