Tenaya Therapeutics Inc Aktie

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

Thank you for standing by, and welcome to the MyPEAK-1 interim data call. [Operator Instructions]

I'd now like to turn the call over to Michelle Corral, Vice President of Corporate Communications and Investor Relations. You may begin.

Thank you, Rob. Hey, everyone, and thank you for joining us today. I'm Michelle Corral, as he said, Vice President of Corporate Communications and Investor Relations at Tenaya. Today, we are excited to share interim data from both cohorts of our MyPEAK-1 Phase Ib/II clinical trial of TN-201 gene therapy for potential treatment of MYBPC3-associated hypertrophic cardiomyopathy or HCM.

While the data we are discussing today will be described in full verbally, please note that during the course of today's call, we will be making references to slides. A PDF file of the slides accompanying this webcast is available on the Tenaya website in the IR section under Events and Presentations.

Before we dive in, let me remind you that the information discussed during this call will include forward-looking statements, which represent the company's views as of today, June 3, 2026. These statements involve certain assumptions, and we caution investors not to place undue reliance on this information. Please refer to today's press release as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements.

On the call with me are Faraz Ali, Tenaya's Chief Executive Officer; Dr. Kathy Ivey, our Senior Vice President of Research; and Dr. Whit Tingley, Tenaya's Chief Medical Officer.

With that business out of the way, let me turn the call over to Faraz Ali for opening remarks. Faraz?

Thank you, Michelle. Good morning, everyone, and thank you for joining us today. We're incredibly excited to share today's TN-201 update in MYBPC3-associated hypertrophic cardiomyopathy. As you know, a genetic heart disease driven by insufficient MyBP-C protein.

On Slide 4, we remind you of the scale of MYBPC3 mutations within the broader context of HCM as well as some of the defining characteristics and the toll of this disease on patients' lives. MYBPC3-associated HCM is a chronic progressive condition, affecting an estimated 120,000 adults, teens, children and even infants in the U.S. alone. And for those with mutation, we know disease progression is more rapid, and that their risk of serious cardiac events is far greater than those with other forms of HCM. The prognosis for those diagnosed at younger ages is even more grim, as we will cover in more detail later.

Turning to Slide 5. In MYBPC3-associated HCM, the mutated gene involves a deficit in a key sarcomeric protein needed to regulate the heart's contraction. Without that protein, the heart contracts at excess force. And over time, the walls of the left ventricle thicken or hypertrophy, reducing the ability for the heart to fill with sufficient oxygenated blood to meet the body's demand. The result of this progressive condition is heart failure and other comorbidities.

We believe TN-201 has the potential to fundamentally change the trajectory for these patients by delivering a fully functional MYBPC3 gene to the heart muscle cells, increasing MyBP-C protein levels and potentially halting or even reversing the course of genetic ACM with a single treatment. Importantly, TN-201 is targeting the underlying cause of the disease. And therefore, its impact is not dependent on phenotype. While great inroads have been made in the availability of myosin inhibitors for obstructive disease, 70% of the patients with the MYBPC3 mutation have the nonobstructive form of the disease.

Today's update represents a significant milestone for our program, one that we believe highlights the growing strength and consistency of treatment data for TN-201. Since we last shared data at the American Heart Association meeting in November 2025, we have meaningfully extended follow-up across both those cohorts, with some patients now reaching up to 2 years of observation at the 3E13 vector genome per kilogram dose, and up to 1 year for those who received TN-201 at the 6E13 factor genome per kilogram dose.

On Slide 6, we summarize the key findings for the compelling data set we are sharing today, which show consistent improvements in cardiac structure, including reversals in multiple measures of hypertrophy sustained over extended follow-up, reductions in symptom burden for all patients and emerging improvements in functional capacity, particularly among those at the higher dose level.

From biopsies, we continue to generate evidence that TN-201 is reaching the heart and robustly transducing and expressing in cardiomyocytes. We are also pleased with the continued tolerability profile across both those levels as we expand enrollment and gain additional experience with the therapy. Together, these findings support our expectations that TN-201 can drive a meaningful and durable impact on disease burden, which is especially encouraging given the limitations of today's standard of care.

Now with that, let me turn the call over to Whit Tingley, who will walk you through these compelling data in greater detail. Whit?

Thank you, Faraz. I will begin with a reminder of the trial design on Slide 8. MyPEAK-1 is intended to characterize the safety of 2 different doses, 3E13 and 6E13 vector genomes per kilogram of body weight. In addition to dose finding, the trial collects heart biopsy data to give us a sense of pharmacodynamics and includes several exploratory endpoints measuring changes in key parameters. The ultimate goal of treatment is to see multiple parameters of disease, biomarkers, echo measures, symptom burden, all improving with directional consistency within each patient and across all patients.

We have completed enrollment of both initial dose cohorts, and we are currently enrolling patients in our 6E13 vector genome per kilogram expansion cohort. The data presented today includes safety, biopsy and clinical results from 6 of the 7 patients enrolled. Slide 9 shows the baseline characteristics for the patients in MyPEAK-1 who have more severe disease than the average HCM patient, consistent with their genetic mutations. All patients enrolled to date have nonobstructive hypertrophic cardiomyopathy. s4 of the 7 have previously undergone myectomy. Their ages at the time of enrollment range from 27 to 63. They all have marked hypertrophy with LVAS well above typical HCM patients. And they all have symptoms of heart failure that impact the activities of daily living as measured by the New York Heart Association classification. The majority of MyPEAK-1 patients entered the study with elevated cardiac biomarkers.

On Slide 10, we show cardiac troponin eye levels at baseline and most recent visit. Troponin is a marker of injury to the heart cells. We follow it closely in HCM as it is a known prognosticator for increased risk of adverse cardiac events. In the chart, you can see troponin levels declined or remained essentially stable in all but 1 patient. Patient 7 in the high-dose cohort had a large and rapid drop. NT-proBNP is a circulating biomarker that indicates strain of the heart muscle and is known to be sensitive to diverse factors, including immunosuppression. NT-proBNP has declined from baseline in 3 patients.

On Slide 11, we turn to a critical assessment in hypertrophic cardiomyopathy, cardiac hypertrophy. All patients treated with TN-201 show improvements in hypertrophy. That means the defining characteristic of this condition, LV mass and thickened walls have been reduced. On the graph, we show the decrease in left ventricular mass index, a measure of the proportion of the LV size normalized to the total body surface area. Elevated LVMI is a strong independent predictor of cardiovascular events like heart failure and sudden cardiac death.

All patients entered MyPEAK-1 with severe hypertrophy, making these reductions in LVMI all the more important. For the first 2 patients dosed, improvements have been maintained through year 2. 4 of 6 patients have 10% or larger reductions in LVMI. But we're not seeing a decrease in a single measure, we see corresponding improvements in wall thickness as well. For example, the thickness of the intraventricular septum or IVS, decreased in 5 of the 6 patients. Other echocardiographic measures of cardiac structure and function remained stable. Taken together, these positive changes in hypertrophy suggest that favorable cardiac remodeling is taking place consistently and persistently over time.

For context, on Slide 12, we have mapped the average reductions in LVMI, posterior wall thickness, LVPWT and IVS thickness for our MyPEAK-1 patients in comparison to reported average changes for the cardiac myosin inhibitors pulled from available published data. With the caveat that cross-trial comparisons are always limited by differences between the trials and therefore, can risk overinterpretation, we do see that the decreases in hypertrophy after TN-201 compare favorably to the results reported for the cardiac myosin inhibitors.

We are certainly excited by these data, particularly the durability of changes in Cohort 1 and the pace and depth of changes emerging in Cohort 2. We certainly also want to know that patients feel better, and we are encouraged by the early changes in symptom burden.

On Slide 13, we're measuring how patients are feeling using 2 measures: New York Heart Association Class, a physician assessment of how disease affects daily living and the Kansas City Cardiomyopathy Questionnaire, a well-validated measure used to assess health status, symptom burden and quality of life among cardiomyopathy patients, including HCM. Most importantly, I'm happy to share that all patients in MyPEAK-1 are feeling better and experiencing fewer symptoms by at least one of these measures. Starting on the left, all but one patient is now New York Heart Association Class I, meaning that although they started the trial with heart failure symptoms affecting daily activities, they now have no limitations on daily activity.

On the right hand of this slide, we're sharing more encouraging new data. 2/3 or 4 out of 6 MyPEAK-1 patients report meaningful improvements in their clinical summary score. KCCQ clinical summary score uses a 100-point scale from very poor to poor, fair, good and excellent, with approximately 25 points between categories. A 5-point difference is considered the minimum change in score that is clinically meaningful. Patients in MyPEAK-1 started the study with scores as low as 22 points in the very poor category at baseline. 4 have had meaningful improvements and their scores now range from 78 to 100 points, meaning their symptoms and quality of life are now in the good to excellent category. I'd like to underscore the consistency among Cohort 2, whose average change from baseline was an impressive increase of 36 points. This exceeds the typical change seen in the placebo arms of blinded HCM studies.

Now let's turn to Slide 14, where we share results from 2 tests used to evaluate exercise capacity, 6-minute walk distance and cardiopulmonary exercise testing or Cohort 2. A majority of patients receiving the high dose of TN-201 showed improvement in at least one measure of exercise capacity. As to Cohort 1, not shown, there are several factors that may be confounding their functional performance. Given that we're seeing improvements in other parameters for patients in that cohort. And founders include comorbidities and unrelated medical events during the study.

Of note, Cohort 1 patients received more immunosuppression for a longer duration than Cohort 2, which can impact exercise capacity. We are actively enrolling new patients at the 6E13 dose level to further understand the positive observations we have seen so far, and we plan another data readout later this year. Now I'd like to ask Kathy Ivy to speak about TN-201's pharmacodynamics. Kathy?

Thank you, Wit. I'm glad to share details of the data we have obtained from heart biopsies. Turning to Slide 16. In MyPEAK-1, cardiac biopsies were collected from patients 1 and 2 at 8 weeks post dose and again at 52 weeks. All other patients were biopsied prior to dosing and are intended to be biopsied 2 additional times with the latest being at 52 weeks. The biopsy collection and analysis process was described in more detail in our RIDGE-1 data release webinar on May 15. But in brief, during each biopsy procedure, 6 to 8 small snips of tissue about 1 millimeter in size are collected from the septum using a catheter. Each of these valuable tissue samples is preserved and allocated to a specific quantitative analysis of DNA, RNA or protein.

The graph at the top of Slide 16 shows the number of TN-201 transcripts per microgram of RNA from the 6 patients at their earliest and most recent biopsies. Importantly, the RT-qPCR assay used is designed to specifically detect TN-201 and not detect mRNA from the endogenous MBPC3 gene. Therefore, these results provide clear evidence that TN-201 gene therapy is reaching the heart, entering the cardiomyocytes and producing messenger RNA, which ultimately provides instructions needed for the heart muscle to produce MyBP-C protein.

Notably, the average TN-201 mRNA levels in Cohort 2 at the most recent visit were about 2x higher than that of Cohort 1, reaching up to 3.2 E6 in patient 7. And those higher mRNA levels in Cohort 2 were achieved at an earlier time point. DNA transduction levels not shown here were also higher in the second cohort, confirming the expected dose response. The lower graph shows the ratio of MyBP-C to myosin heavy chain peptides as determined by liquid chromatography mass spectrometry.

Normalization to myosin heavy chain, which is a protein restricted to cardiac muscle cells, helps to account for differences in the cellular composition among biopsy samples. We also analyze multiple samples for protein where possible and consider the average value to help account for variability. As intended, TN-201-derived MyBP-C protein is indistinguishable from endogenous C protein. Acknowledging that the variance between and among samples, patients and clinical sites complicates interpretation, we nevertheless detect an average overall increase in total MyBP-C protein in both cohorts over time. And consistent with the mRNA results, the protein increase in Cohort 2 is comparable to Cohort 1 even at an earlier post-dose time point.

Together with the latest clinical data, the totality of the DNA, RNA and protein data from biopsy samples support that TN-201 is reaching and having effects in the heart. I'll now invite Whit back to review results of safety and tolerability.

Thank you, Kathy, for that clear explanation of our biopsy results. Before handing the call back to Faraz for closing remarks and then Q&A, I'd like to cover 2 slides on TN-201's safety, starting on Slide 18. Safety is our primary objective, and I'm very pleased to report that there are no new safety events since our last data presentation in November 2025. TN-201 has been generally well tolerated at both doses and the few adverse events related to treatment have primarily been wild, manageable or reversible.

The most common AEs associated with treatment have involved safety laboratory values such as elevated liver enzymes, low platelet count or elevation in complement factors. Platelet and complement changes all self resolved without need for treatment. As for the elevated liver enzymes, these were asymptomatic and responded well to steroid treatment. Patients in MyPEAK-1 received sirolimus and prednisone prophylactically before TN-201.

As shown in Slide 19, we refined our dosing and monitoring regimen during Cohort 1 to reduce the overall need for immunosuppression. As a result, we've been able to taper immunosuppression faster in Cohort 2 than Cohort 1 despite the higher dose of TN-2001. This limits side effects and is clearly better for patients for us.

Thank you, Wit. Turning to Slide 21. As we continue to build the data set, what stands out to us is the consistency of effect we are seeing across multiple measures of disease from cardiac biomarkers to cardiac structure to how patients feel and function in their daily lives. This is especially true for patients who received the higher dose of 6E13 vector genome per kilogram.

We believe this growing body of evidence reinforces the core promise of TN-201, namely that our onetime gene therapy has the potential to modify the underlying biology of disease rather than simply manage symptoms. As we look ahead, we have every reason to believe that TN-201 could have a positive impact on any patient with a MYBPC3 mutation causing HCM. Today, we are treating adults with either phenotype.

MyPEAK-1 has thus far enrolled only nonobstructive patients as we would expect, given that this phenotype is much more common among the MYBPC3 variants and the lack of available nonobstructive treatment options.

Turning to Slide 22. We also have long maintained that the significant unmet need in severe and rapidly progressive pediatric patients demands an answer and presents an important opportunity to fast track our late-stage development. It is with this sense of urgency that we initiated the MyClimb natural history study even before we started dosing adults with TN-201 in the MyPEAK-1 interventional study. MyClimb has thus far enrolled more than 220 patients at 29 sites in 4 countries. That includes retrospective patients who have already unfortunately passed due to their disease as well as prospective patients who could be eligible for future pediatric studies.

Now that we are generating increasingly positive efficacy and safety data with TN-201 in adults, we're excited to engage on next steps in that direction and to explore multiple possible pathways ahead to pivotal studies in adults or severe pediatrics. And on the topic of pivotal paths, one of our key goals as a company this year is to engage with regulatory agencies on our growing body of evidence and to pursue alignment on a path forward.

We are indeed engaged in such discussions and which are, by their very nature, iterative, and we expect to provide an update by year-end. However, in the meantime, we have 2 encouraging new items related to this to share on Slide 23. First, the European Medicines Agencies, or EMA, has granted TN-201 PRIME designation. PRIME designation is intended to offer early and proactive support to sponsors in order to accelerate the review and progress of promising new medicines.

We have long considered the EU as a near-at-hand extension of our U.S. development program and utilize the MyClimb study as a means of establishing relationship with KOLs and leading cardiomyopathy treatment centers, which, given the nature of medicine there tend to be more consolidated versus the mix of centers of excellence and community docs we have in the U.S.A.

Exciting, TM-201 has also been accepted into the FDA's new RDEP process for the indication of severe biolelic pediatric patients. RDEP stands for Rare Disease Evidence principles and is part of the agency's effort to provide sponsors with additional guidance on the development of genetic medicines for ultra-rare and severe genetic diseases, typically affecting fewer than 1,000 patients in the U.S. The process enables early and ongoing collaboration with the agency to align our regulatory strategy, trial design and approaches to generating convincing approvable evidence from multiple sources.

Turning to Slide 24. As a reminder of the opportunity in severe pediatric patients, we offer a snapshot of how we are thinking about the treatment of children with MYBPC3 mutations. We estimate that there are approximately 3,000 diagnosed patients under the age of 18 in the U.S.A. alone at any given time. We know that younger age of diagnosis leads to worse outcomes, a faster pace of disease progression and higher risk of heart failure, arrhythmias, symptom burden and hospitalizations, transplant or death.

And what we've learned from MyClimb is that there is an opportunity for further refinement within that population. Outcomes differ even within the severe population based on genotypes. For example, 85% of severe pediatric patients who are homozygous die or required transplant before the age of 1 and 64% of compound heterozygous children experienced heart failure-related hospitalizations before age 10, and 27% required transplant or died. These data from the MyClimb Natural History study offer the tantalizing possibility of being able to show movement on hard clinical endpoints sooner versus a natural history, and then expand to additional populations among additional patients under the age of 18.

As a reminder, there are no approved condition-specific treatments for these very severe pediatric patients, leaving a clear and urgent need.

That sense of urgency among families was illustrated by the results of a survey of patients of young children with severe cardiomyopathy that confirms high interest in gene therapy. The survey was conducted in collaboration with the Children's Cardiomyopathy Foundation and the DTC Clinic, a center of excellence taking care of such patients. We shared these results via poster at the recent ASGCT conference, and it is available on our website.

As a reminder, in addition to being admitted into the RDEB process for biallelic patients, we have received rare pediatric disease designation, which offers another incentive for pursuing the subgroup as a potential first path to approval in the form of a priority review voucher. So in addition to continuing to enroll adults in the 6E13 vector genome per kilogram cohort -- expansion cohort and engaged with the regulators on the data being generated from MyPEAK-1, we are actively exploring the advancement of TN-201 in a severe pediatric population as a key component of our pivotal trial planning and strategy for achieving a potential approval for TN-201.

While these are still early data from a small number of patients, we believe the breadth, depth and consistency of the signals we are seeing provide increasing confidence in the potential of TN-201, and support our ongoing development strategy.

Turning to Slide 25. As we look ahead, we remain focused on: continuing enrollment in the higher dose expansion cohort, generating additional follow-up to further characterize durability and dose response and engaging with regulators on the path forward for this very promising program.

Finally, on behalf of the entire Tenaya team, I'd like to express our gratitude to the MyPEAK-1 and MyClimb investigators and their clinical site teams. As always, a special note of gratitude to the patients and their families and caregivers. These individuals are at the heart of Tenaya's purpose. And without their willingness to believe in our mission and join us in our efforts, these data would not be possible.

With that, we have concluded our prepared comments. Operator, let's now open the lines for Q&A.

[Operator Instructions] Your first question today comes from the line of Mike Ulz from Morgan Stanley.

Maybe just one on protein expression. Just for the 2 patients in Cohort 2 that didn't experience an increase. Just curious if there's anything unique about those patients or any interpretation as to why that might be?

Mike, thanks for the question. And for that, I'll first turn it over to Kathy Ivy.

Yes. So I don't think anything about the baseline protein expression was particularly remarkable, although it's perhaps notable that patient 4 had the highest baseline protein that we detected in any of our patients at baseline. But yes, I think the evidence that we see from clinical improvement suggests that our detection of protein may just be a limiting factor here, and we think there really are underlying increases in protein over time.

Yes, I agree. Thanks for the question. I mean, overall, the RNA data and the totality of the data, including the transduction data that we don't -- we haven't shown here, just support that overall, we're getting higher transduction and RNA expression at the higher dose. And so the -- we do believe that, obviously, we're adding protein to these patients' hearts and the clinical results seem to bear that out.

Your next question comes from the line of Thibaut Pardo from LifeSci Capital.

So when you look patient by patient, how should we reconcile improvements in hypertrophy measures with some mixed changes in feel and function measures beyond the immunosuppression in Cohort 1, how that could affect, for example, the 6-minute walk, particularly patient 6 and how we saw increases in -- or decrease in hypertrophy, but the 6-minute walk did not improve.

Yes, it's a great question, Thibaut. Good to hear from you. For that, I'll turn it over to Whit.

Yes. As we noted, the changes in exercise capacity depend on multiple factors and can be confounded by underlying comorbidities or adverse events unrelated to the trial that can occur during the course of the trial or even right before an exercise assessment. Overall, though, we are very pleased, as you know, to see improvements in multiple parameters and consistent improvements within patients and across groups.

Yes. Thank you, Whit. And just to add to that, Thibaut, I think, I mean, our results in some ways are -- you can also make a comparison with what has been demonstrated with myosin inhibitor they've shown clear functional improvement. That's why they've been approved, but the level of hypertrophies are not quite as profound on average as what we're being able to demonstrate early on.

So it's an imperfect relationship. It's an important overall relationship, but an imperfect relationship at any individual patient level between the level of hypertrophy reduction you might see and the level of improvement in some functional measure like 6-minute walk test or PCO2. That's been seen in other studies, and we're seeing it here, too. So ultimately, the totality of the evidence does suggest that we are getting patients or moving them in the right direction by modifying the underlying disease.

Your next question comes from the line of Whitney Ijem from Canaccord Genuity.

On the update. In particular, congrats, I guess, on the progress on the pediatric side. And just wondering if we can get any more color there in terms of the discussions with regulators and maybe what feels like pushback or you kind of talked about the iteration. What needs to be iterated?

It feels, in particular, on the back of some of the natural history data you presented that there could -- should be a faster kind of more straightforward path. So are we thinking about that correctly? Or what's been the pushback? Why haven't you treated any pediatric patients as yet? And what do you need to do to get there going forward?

Whitney, thanks for the question. Let me first -- I'll turn it over to Whit again, and then I'll add some comments on top of that. Whit?

Yes. We're having productive discussions. I wouldn't say pushback. I would say we are aligning on a path forward that will -- for pediatric development that will be tailor-made for TN-201 therapy. So that process can take a little while.

Yes, I agree. It's not pushback at all Whitney. In fact, I would say quite the opposite. The inclusion of TN-201 in this new program, RDEP, that was introduced by this FDA is actually -- we take it as a positive sign that they understand the severity of this rare disease population and very severe population and want to work with us actually. And as we pointed out, there's heterogeneity within this group. as we show in the MyClimb data, some patients you could have a hard endpoint like survival.

Others who are on BADDS might have different endpoints and some... yet other patients present in a structure that's more consistent with the adults. So I think there's nuances here in this population, and we're very pleased with the engagement that we're having. And so the devil is always in the details. And so it's iterative not because of pushback, but because actually, in many ways, this is the first time that to our knowledge, somebody is trying to align on something with this kind of rapidly progressive early severity, including kids who are dying in some cases, as early as the first few days, weeks and months of life.

We haven't dosed any patients in a pediatric study yet because we haven't initiated one. We would initiate a pediatric study only under the side of full alignment on the design of pivotal studies to support that population. And so we would only either amend the current study or launch a new study with that under our belt. So just please rest assured, we -- the iteration is a good thing.

Your next question comes from the line of Mani Foroohar from Leerink Partners.

I know it's been touched on a little bit, but I wanted to circle back first on the data. So with 3 -- it looks like 3 or 3 patients in Cohort 1 increase in protein, robust results, bouncing around by time points as you expect versus Cohort 2, though again, obviously not a perfect metric. But the Cohort 2 patients to my eye did better on some functional endpoints. Can you just sort of a little bit test on how to interpret this? And then I have kind of a follow-up on broader strategy.

Yes, sure. Thank you, Benny. Good to hear from you, and thanks for the question. Let me turn it over to Wit to sort of share his impressions of the differences between Cohort 2 and Cohort 1.

Yes, we are seeing early signs that patients may be responding more strongly and more quickly to the higher dose. We can see that in how they're reporting their symptoms. We can see that in hypertrophy measures. And as you're noting, we're seeing encouraging signs for functional assessment. As it's still early, there's still more functional assessments we need to get from the high dose. We need longer follow-up, and we are dosing additional patients in that high dose cohort to fully understand it. But the overall trend appears to be better efficacy at the higher dose. And as we mentioned, is very well tolerated. So very encouraging overall. The RNA results are also encouraging for that cohort, the protein, clearly, more data will help.

Yes. The only thing I'd add to that is that while on the functional side, we didn't yet quite see those same improvements for Cohort 1, but the reductions in hypertrophy in a patient population that has some of the most hypertrophy hearts studied when we compare to other peer programs, that is meaningful as in many cases, as we've shared in the past, reductions in hypertrophy below certain levels are predictive of better long-term outcomes for these patients, including survival benefits. So we are very pleased with the improvements we're seeing in Cohort 1 and even more pleased with what we're seeing in Cohort 2. It sounded like you had a follow-up question, Mani.

I do. I have a separate question. Obviously, the meaningful differences between nHCM and oHCM, obstructive non-obstructive. As we think about your continued engagement with the FDA, what are the range of sort of strategies you could pursue in terms of separate studies, multiple cohorts or a stratified approach with a single study. These are clearly very different patient populations in terms of temp of response and underlying clinical course. Just walk us through what the possible outcomes and development strategies might be to serve patients with different needs of underlying clinical courses.

Yes, great question. And again, I'll first turn to Whit to see if he'd like to comment on that. On Slide 22, we lay out the different populations that I think you're referring to, Mani, non-obstructive and obstructive adults and then the adolescents in infants. So Whit, anything you'd like to add about our development strategies in the different groups and different studies or one study with different subtypes or subgroups?

Yes, there are different possibilities. As you know, we are necessarily going to have to follow the path that CMI follows. We have -- as you suggest, we have discussions ongoing with regulators, but still in the discussion phase. So it would be premature to hint to any potential direction.

Yes. But needless to say, I mean, Whit would agree. And I think the -- there are different populations as you pointed out, Mani. And the endpoints that might be most relevant are going to be different. For example, you can't measure peak 02 and 6-minute walk test in a homozygous infant. That's obvious, right? So what we're going to study in these different populations may be different. And then there's a little bit of logistics of how do you -- what's the best way to incorporate these different groups, whether can some groups be addressed by amending my MyPEAK-1 or other groups require just an entirely separate study because the sites and the endpoints are just completely different.

So I think more to come on this front, Mani, as the -- as the year progresses. And as we provide updates on our -- where we have aligned with the FDA on endpoints and design of pivotal studies and with specific populations, we continue to see that severity of the and the unmet need in the pediatrics as something we've been talking about, frankly, consistently for probably the last 5 years since we first launched the MyClimb natural history study. So more to come on that front.

Your next question comes from the line of Yasmeen Rahimi from Piper Sandler.

To these great data, really profound changes in feel and function of the patients. I mean putting that slide that you have 13 into perspective, right, you're getting normalization of patients feeling and functioning good. Question for you. Just one minor is you see patient #6 really changing KCCQ Class 1 normalization. Maybe why have -- but then the 6-minute walk test regresses. Like what is the disconnect in that patient where everything is tracking well, but then the 6-minute walk test for some reason goes down instead of going up, even though everything else is really astonishing.

And then second question is, given the KCCQ data in the NYHA class responses could we -- is it fair to think about in the future when you think about a pivotal study, and we have seen pivotal studies, right, in non-obstructive with the CMIs that sponsors have peak KCCQ as a key regulatory endpoint. Would love to get your thoughts on the data that you just reported on Slide #13, if that's the way we should be thinking about primary endpoint selections for the pivotal programs and the robustness of the effectiveness that you're seeing? Sorry for these long-winded questions.

Yes, it's always good to hear from you. Thank you for the question. Again, I'll turn it over to Whit to take the first response.

Yes, very good questions. Certainly, to your second question, Kansas City Cardiomyopathy Questionnaire is established as a potential pivotal endpoint, New York Heart Association class as well. And so these are certainly on the table as options for pivotal studies. And then in terms of parsing out a patient, patient that's improving in multiple domains that the 6-minute walk test is encouraging that particular day. I would encourage you to sort of think about integrating the preponderance of the data.

Again, as a patient is reporting their symptoms, it's not limited to one activity or one particular day. So when I say they're feeling better and their physician has interviewed them and found they're less limited on daily activities, that carries a lot of weight -- and individual exercise capacity measurements can be confounded.

We've seen from the CMI data, some published data will show the individual changes in PCO2, for example, and there's a huge range up and down amongst each individual patient. And that's not a drug effect or lack thereof, that's the variability of where people are at on that particular day of the test.

Yes. thank you. I agree. As we said earlier, I think there's any given patient will have some variability. We know some of these patients or our team does intimately know aware of other comorbidities they may have that may impact individual results. So we look at the totality of data, and we're pleased with what we're seeing, Yasmeen.

And then Again, yes, KCCQ is an important endpoint, 6-minute walk test, AT-02. But I will go back to in the pediatric population, that will not be as relevant, particularly as you're talking about very severe young patients. So we always said that MyPEAK-1 -- when we set out to do MyPEAK-1, we always said it was going to be a data-rich study and that we were looking at a lot of things. And I think you're seeing the fruit of that bear out, being able to now describe improvements in circulating biomarkers and multiple, in many cases, multiple forms of hypertrophy and now multiple ways of capturing both field and function.

This is exactly what it's set out to do, and this will help us inform both dose selection as well as design of future pivotal studies in different subpopulations. And so we're exactly where we wanted to be. with the data sets that are maturing. Still early days, and we look forward to providing more updates in the second half of the year.

And that concludes our question-and-answer session. I will now turn the call back over to Faraz for closing remarks.

Yes. Thank you. Thank you all for joining us on the call today. Exciting results on top of the exciting results we delivered for TN-401 just a few weeks ago. So a great first half of the year for Tenaya and an even more exciting second half of the year to come. We look forward to meeting some of you over the coming days, weeks and months and diving deeper into the data and answering your questions and to providing additional important clinical and regulatory updates on the TN-201 program and the 401 program in the second half of the year. With that, have a good day.

This concludes today's conference call. You may now disconnect.

Hello, and thank you for standing by. At this time, I would like to welcome everyone to the Tenaya Therapeutics RIDGE-1 Data Presentation Conference Call. [Operator Instructions] I would now like to turn the call over to Michelle Corral, Vice President of Corporate Communications and Investor Relations. Michelle, please go ahead.

Thank you, Tiffany. Hi, everyone, and thank you for joining us today. As you know, I'm Michelle Corral, Head of Investor Relations Corporate Communications here at Tenaya, and we are excited to share data today from our RIDGE-1 Phase Ib/II clinical trial of TN-401 therapy for the potential treatment of PKP-2 associated arrhythmogenic right ventricular cardiomyopathy or ARVC. The data were presented earlier today as a late-breaker oral presentation at the American Society of Gene and Cell Therapy.

While the data we are discussing today will be described to full verbally, please note that during the course of today's call we will be making references to this slide. A PDF file in the slides accompanying this webcast are available on the Tenaya website in the IR section under Events and Presentation.

Before we got in, let me remind you that the information discussed during this call will include forward-looking statements, which refers as the company's view as of today, May 15, 2026. These statements involve certain assumptions, and we caution investors that place undue reliance on the information. Please refer to today's press release as well as our filings with the SEC for information concerning risk factors -- actual results to differ materially from those expressed or imposed by these.

Turning to Slide 3. On the call with me today are Faraz Ali, Tenaya's Chief Executive Officer; Kathy Ivey, our Senior Vice President of Research; and Dr. Whit Tingley, Tenaya's Chief Medical Officer. We are also very pleased to be joined by Dr. John Giudicessi as the Mayo Clinic expert and -- a clinical investigator for RIDGE-1.

I would also like to note that [indiscernible] do not necessarily reflect the views company. Okay. With all that out of the way, let me turn the call over to Faraz for opening remarks. Faraz, go ahead.

Thank you, Michelle. Good morning, everyone, and thank you all for joining us today. As a reminder, Tenaya's mission is rooted in developing transformative therapies for patients with serious heart diseases including severe genetic cardiomyopathies where decades of research have clarified the understanding biology and underlying biology and yet patients continue to face limited -- significant disease burden. As we approach our 10-year anniversary since Tenaya's formation, our commitment to heart disease in the cardiology community is never wavered.

Across the board, we have invested in the deep understanding of these conditions and in the sciences area to bring new treatments and with that, you hope to patients. As you can see on Slide 4, in the near term, our focus is on the advancement of our gene therapy candidates, TN-201 and TN-401, which each represent significant patient populations with unmet need. As we look across our portfolio today, we believe we are reaching an important inflection point. The promising data we are sharing today from our TN-401 program builds meaningfully on the data we presented in December 2025 and are the first of several key data readouts anticipated throughout the year from both our TN-201 and TN-401 programs. And with each of these data cuts, we're gaining increasing clarity on the clinical potential of these programs and how they may support our path towards pivotal studies.

Turning to Slide 5. As you know, we've just come from the late breaker presentation of our RIDGE-1 Phase Ib/II clinical trial of TN-401 at the American Society for Gene and Cell Therapies Annual Meeting. We were very pleased to see our presentation garners such strong interest among an audience of leading cell and gene therapy researchers and clinicians. The enthusiasm was palpable and for good reason.

Today's interim data readout from RIDGE-1, which includes results from both cohorts with patient follow-up ranging from 20 to 52 weeks showed that all patients on study achieved consistent fee and sustained reductions in arrhythmia burden. Biopsy results show that TN-401 is reaching the cardiomyocyte and achieving its prime. And importantly, TN-401 gene therapy was well tolerated at both the 3E13 and the 6E13 vector genome per kilogram doses. We are very encouraged by these results.

Now before we dive into the data, I want to take a moment on Slide 6 to briefly ground us in the disease we're here to discuss, ARVC and why does work and these results matter. The most genetic driver of ARBC is mutations in the plakophilin-2 or PKP2 gene, which are estimated to account for roughly 40% of diagnosed cases. PKP2 associated RBC alone is believed to affect more than 70,000 individuals in the United States. Symptoms begin early in life and often include palpitations, lightheadedness, fainting and exercise intolerance. But for too many patients, sudden cardiac arrest and death may be the first manifestation of the disease.

What makes ARVC especially devastating is not just a severity, but its impact on otherwise young adults individuals and families. Despite the use of implantable cardioverter defibrillators or ICDs and strict lifestyle limitations. Patients often continue to suffer from recurrent arhythmias, painful ICD shock and a significant reduction in quality of life. The condition is progressive lifelong and places substantial emotional and physical burden not only on patients but also on their families and caregivers. Importantly, there are no approved disease-modifying therapies available today.

By targeting the underlying genetic cause of their condition, TN-401 gene therapy offers the potential to make a profound difference in the lives of patients and families suffering from PKP2-associated ARVC.

Therefore, should our data continue in line with these encouraging early results, we believe TN-401 has the potential to make a profound difference in the lives of patients and families suffering from PKP2-associated areas. Now starting with our own Dr. Whit Tingley, Tenaya's Chief Medical Officer. We will now turn to a more detailed look at the data and that will be followed with a Q&A discussion by Kathy Ivey and a Q&A with Dr. Giudicessi. Whit?

Thank you for us. Having touched on the disease and unmet need, I'd like to start with a discussion of how TN-401 in Adults with PKP2-associated ARVC the design and objectives of the RIDGE-1 trial and the newest interim clinical appeal.

As illustrated on Slide 8, PKP2 gene mutations describes the structural integrity of the heart. The PKP2 gene produces a key protein that provides critical support for the mechanical and electrical connections necessary for every heartbeat. Deficiency in PKP2 protein leads to degradation of a scaffolding structure called the DevZone, that helps the heart muscle hold tightly together and stabilizes the electrical channels or gas junctions that trigger each contraction.

TN-401 gene therapy is designed to deliver a full-length functional human PKP2 gene using a well-validated AV9 capsid and the cardiomyocyte specific promoter. Once delivered to cardiomyocytes, TN-401 produces TKP2 protein to increase levels of missing protein and thereby address the underlying cause of the disease. In preclinical studies, TN-401 halted the disease which maintains normal electrical stability, prevented structural damage in both the left and right ventricle and prevented premature death.

On Slide 9, we have an overview of the RIDGE-1 trial, which is designed to characterize the safety of 2 different doses, 3E13 and 6E13 vector genomes per kilogram body weight. In addition to dose finding, RIDGE-1 is looking at pharmacodynamics and includes several exploratory endpoints measuring changes in key clinical parameters. We've now completed enrollment of both dose cohorts, and we're currently enrolling patients in the 6E13 vector gene per kilogram expansion cohort. The data presented today includes safety biopsy and clinical results from the 6 patients enrolled in Cohort 1. Two additional patients have now been dosed in the expansion cohort and will be included in future data reader.

Slide 10 shows the baseline characteristics of screening. A couple of things to point out here. First, all 6 patients also participated in our RIDGE Natural SIRI study. Second, they have signs of severe disease. Most were diagnosed at a young age, many have undergone VT ablation procedures and all have required implants for cardioverter-defibrillators.

Despite a robust standard of care therapy, all remain at risk for life-threatening arrhythmias and continue to have electrical instability manifest by high numbers of premature ventricular contractions or PVC every day. TN-401 successfully improved electrical stability in preclinical models. So let discuss the results to date in the patients in RIDGE-1.

Let's begin with PVCs on Slide 12. These are single normal extra heartbeats that originate in the ventricles and alter the heart usual rhythm while the vast majority of PVCs are harmless. They are a clear sign of electrical instability and occasionally, a PVC at the exact wrong time and place and trigger a life-threatening arhythmia. Thus, high rates of PVCs indicate risk of sudden cardiac death. Because PVC rates could be highly variable, we measure them using a wearable continuous ECG monitor over 7 days and then take an average number per day.

All patients treated with TN-401 to date have experienced meaningful reductions in the rates of daily PVCs from screening to their most recent assessment. We previously disclosed drops in PVCs in the first 2 patients occurring 6 in a month after dosing. And these patients continue to have lower rates at 1 year. At this most recent data cut the average drop across all 3 cohort 1 patients was 60%. Part 2 has an average reduction of 67%, including patient 5 and 6 who had strikingly high rates at screening.

Two more things to point out. the reductions in Cohort 1 out to 1 year past sitting suggest a durable effect. Second, PVC counts in Cohort 2 are dropping before 6 months sooner than we thought in cohort 1. This may indicate faster onset of action at the higher dose. However, we will continue dosing more patients to cover. As we monitor PVCs, we also get at on nonsustained ventricular tachyarrhythmias or NSVT. These are rapid runs of the normal heart rhythms coming from the ventricle lasting up to 30 seconds that are severe and higher risk than PVC.

On Slide 13, we see that among those patients in RIDGE-1 who are experiencing high rates of nonsustained ventricular tachycardias, these were dramatically declined process. Patient 2 went from an average of 78 per day to 0 and patient 5 went from 43 to 4 per day. Drops like these persistent that reflect substantial improvement in electrical stability. The other patients in RIDGE-1 had low nonsustained detect counts at screening and their accounts remained low and stable [indiscernible].

Other measures of clinical response, including QRS duration, key wave inversions, echo parameters and New York Heart Association class were in the normal range or remained stable. Why do these results matter. Electrical and stability is the hallmark of CK2 associated ARPC, sudden cardiac arrest due to ventricular arrhythmia is the most feared consequence of the disease.

Slide 14 depicts the continuum of ventricular arrhythmias based on frequency and severity. On the left, PVCs and nonsustained Vtach are frequent and may or may not even be noticed by the patient. At the other end of the spectrum is the most severe arrhythmic event, ventricular fibrillation, which causes sudden cardiac arrest and thankfully, is far less frequent than the other ventricular arrhythmia. PVCs and nonsustained Vtach offer direct measures of electrical stability and are among the key risk predictors used by physicians in determining patients' risk for more severe ventricular arrhythmia events. PVCs and non-sustained Vtachs can be reliably quantified in a trial such as RIDGE-1, and our direct and early indicators of whether TN-401 is achieving disease-modifying effect as designed.

We are thrilled with these early consistent and persistent results that we have here today and look forward to presenting more clinical data with more patients and longer follow-up duration in the second half of this year. Next to speak about TN-401 pharmacodynamics, specifically delivery and expression in the heart itself. I introduce Dr. Kathy Ivey, our Senior Vice President of Research.

Thank you, Whit. I'm glad to be here to discuss the data we team from our biopsies. Slide 16 illustrates the purpose of the heart biopsies, which we take at 3 junctures, predose or baseline both doses, which was week 8 in the first 4 RIDGE-1 patients and week 22 for patient 5. And finally, again, at week 52. Patient 6 in post-dose biopsy analyses were not yet available as of our data cut. And we -- you'll note we vary the timing of post-dose biopsy in order to begin getting a sense of TN-401 genetics. Using a catheter, a small sniff of tissue about 1 millimeter in size is taken from the septum. 6 to 8 of these tissue samples are collected in the cath lab and received an initial visual inspection for quality and that each of these pressured tissue samples is preserved and earmarked for specific [indiscernible] of DNA, RNA or protein.

The measurements collected during the biopsy sample analysis allow us to affirm that our gene therapy is reaching heart entering cardiomyocytes and producing messenger RNA, which ultimately provides instructions needed for the cell to produce PKP2 protein. Results shared on Slide 17 provides clear evidence that TN-401 DNA is consistently reaching the heart with robust vector copy numbers per host genome ranging from 1.8 to 5 vector copies per cell.

On Slide 18, we see clear evidence of RNA expression, which is measured as transgene copies per microgram with RNA while the totality of our biopsy results are what fill the story, RNA levels may be the most reliable of the biopsy measures we collect. As a reminder, the PCR assay used to detect mRNA is only measuring mRNA produced by TN-401, which is specifically expressing cardiomyocytes of the selected promoter use and is able to do so with high sensitivity and specificity.

Here, we see robust levels of M&A expression ranging from 1T4 up to 2.95 RNA copy microgram of RNA -- for those samples in cohort where we have measurements across time, we can see that mRNA expression is sustained. As we look at protein [indiscernible] levels over time on Slide 19, these data show some encouraging apparent increases at different time lines, but the overall signal is confounded by the challenges of measuring PKP2 protein in disease heart.

As a reminder, the PKP2 protein produced by TN-401 is indistinguishable from PKP2 protein produced by the patients one working PKP2 gene. Despite the ups and downs of the bar chart view, it not make sense that protein levels would be lower after dosing than prior to treatment nor given the clear increases in DNA and RNA, coupled with the clinical results shared by Whit, you would believe that protein levels are staying flat.

So what is happening here and why are the results in sounding not just for us but also for others using different methods. We believe that key among the challenges and quantifying protein level changes due to the inherent variability in samples due to the nature of this disease. As illustrated on Slide 20, any given area of tissue may be made up of fully functioning cardiomyocyte, cardiomyocytes in decline, fatty or fibrotic tissue or a mix of some or all of the above. The original the right shows a section of cardiac disease from an ARVC donor heart with 2 incircled areas that at each represents a 1- to 2-millimeter biopsy. The area on the left in the dark blue circle contains a high proportion of cardiomyocyte than the area on the right in the red circle, which contains more value replacement. Because each collected biopsy sample is designated for a different measure, there will be variability from patient to patient asset to assay and time point to time point.

In an effort to minimize these variables, [indiscernible] has brought significant time and effort as well as our own and external expertise for us to develop an approach to measure PKP2 protein level in cardiac biopsy sample.

On Slide 21, we review our methodology. As you may recall, Tenaya had selected liquid chromatography, mass spectrometry or LCMS for this purpose. In the heart, PKP2 expression is high in cardiomyocyte that can be detected at lower levels in other cell types, including fat cells, which are known to infiltrate [indiscernible] card. Therefore, to get the most meaningful measure of our protein of interest, we normalize the LCMS measurement to a cardiomyocyte restricted proteins. In our case, [indiscernible], to provide a reliable and consistently quantified measure of PKP2 protein relative to the heart muscle content of the biopsy where it's needed to support the structural and electrical integrity of the heart.

Among our findings in the examination of PKP2 measurement method using [indiscernible] from donors without the need -- learned there's a wide range of normal PKP2 level I see nonetheless. This tells us that differences from person to person are to be expected and not interpreting comparisons across patients or between patients and healthy individual requires caution. The graphs on the right show PKP2 levels measured from the Phase 5 normal donor hearts but using 3 different methods: LCMS normalized to myosin or western blot with either a standard curve to calculate PKP2 level or normalized to ubiquitously expressed protein [indiscernible] normalized to myosin resulted in a twofold difference in PKP2 protein among these 5 hearts.

In contrast, without normalization to the myocyte-specific protein, Western Blot results showed up to sevenfold difference between the same 5 normal donor heart. The variability that occurs when credit myocyte composition is not taken into account may be further intensified in samples from disease heart due to their more varied composition. It quickly becomes [indiscernible] protein values are really not comparable across trials using different measurement method. Given the repricibility of the protein quantification available via mass back with normalization to myosin, we believe that this method is doing all we can to minimize the differences inherent in the composition of any given example. This is [indiscernible] biopsy data, and in particular, the evidence of TN-401-specific mRNA expression assures us that TN-401 is effectively delivering PKP2 to the heart muscle cells.

These results, coupled with the consistently decrease arrhythmia burden across all patients gives us confidence in TN-401 disease modifying activity. I'll now invite Whit to review results of safety and tolerability.

Thank you, Kathy, for that clear explanation of the biopsy data. The rigorous technical work of our translational medicine team under your leadership is clearly advancing our understanding both TN-401 pharmacodynamic activity and PKP2 associated ARBC biology at a molecular level. RIDGE-1's primary endpoint and purposes to assess the safety and tolerability of TN-401 at the 2 dose levels tested. We are very encouraged by the positive safety profile emerging as summarized on Slide 23. In short, it has been well tolerated to date. For both dose cohorts, the majority of TN-401-related events have been mild asymptomatic and easily manageable. These have primarily consisted of transient elevations of liver transaminases.

We previously reported mild grade 1 troponin elevations associated with TN-401 dosing, one of which we classified as an SAE because it was monitored in hospital. These elevations results spontaneously without treatment with no evidence of clinical myocarditis and no sequela. As of the current data cut, there are 2 new Grade 3 events, both associated with a medication error in one patient. One liver enzyme elevation attributed to TN-401 occurred in conjunction with an unintended interruption of steroid immunosuppression and one thrombocytopenia events not attributed to TN-401 was due to sirolimus overdosing with serum levels are exceeding the target range.

Importantly, there has been no evidence of cardiac inflammation by imaging or biopsy, no proarrhythmic events related to TN-401, no clinical TNA events and complement inhibitors have not been used. Following a review of all safety data for protocol, the RIDGE-1 Data Safety Monitoring Board endure continued dosing at either dose, and we are proceeding to enroll patients at the 6E13 expansion cohort. Safety is our priority. An immune suppression medications used for gene therapy administration can themselves a side effect. So our goal is to optimize the regimen to effectively control the immune reaction while minimizing the dose and duration of use.

Each patient is individually tapered off of immunosuppression as soon as they can tolerate. As seen on Slide 24, in RIDGE-1, we use prophylactic prednisone and sirolimus to manage the immune decline. Importantly, the duration and total dose of corticosteric has been comparable across both those dose cohorts, despite the increase in dose of TN-401. All 6 of these patients have successfully tapered off of their immunosuppression. All in all, we are thrilled by the data emerging from RIDGE-1. TN-401 has been well tolerated at both doses. Biopsy has demonstrated evidence of transduction and expression and most notably, the clinic data showed consistent evidence of reduced arrhythmia burden and improved electrical stability which would be expected to substantially reduce these patient's risk of sudden cardiac arrest.

Happily with us here today is Dr. John Giudicessi from the Mayo Clinic. Dr. Giudicessi is a renowned genetic cardiologist and specializes in the care of inherited cardiomyopathy including ARVC. He directs the Mayo Clinic's gene therapy program is one of the principal investigators for RIDGE-1 and just presented the data we've been discussing in today's late-breaker session at the American Society of Gene and Cell Therapy.

Before opening the line to your questions, we will ask John to share insights on the care of ARVC patients and his impression of the RIDGE-1 data.

John, thank you for joining us.

Thanks for having me, Whit. With pleasure.

John, could you tell us a bit about your background and experience in treating arrhythmogenic cardiomyopathies. How many of these patients are there at the Mayo Clinic? And of those, what percentage of the PKP2 mutate?

That's a great question. So I'm one of our now 3 genetic cardiologists in the broadcaster, and we just specialize in both clinical care and advancing research for patiently [indiscernible] disorders. Currently, we have about 1,600 patients with genotype positive arrythmogenic and dilated cardiomyopathy, of which 220 to 230 are PKP2 very positive. So this is a substantial subset of the patients with arrhythmogenic cardiomyopathy, that we treat [indiscernible].

Can you characterize how common genetic testing is?

In our practice, just by the nature of it being genetic cardiology is very common. And increasingly, it's playing a role in the diagnosis for specification and management, especially as there's more interest in these trials that are coming forward, we'll realize how much genetics play is in the role in the management of these patients.

Are there differences or distinctions between PKP2-driven ARVC and other forms of ARVC and arrhythmic cardiomyopathies in general.

There are. So PKP2 typically results in a right centric of predominant disease really characterized by a high prevalence of ventricular disease in comparison to other genes such as [indiscernible], which are much more less predominant. It's also helpful just to look at it from a mechanistic perspective. PKP2 is a disease of haploinsufficiency, which simply means these patients are missing a copy of PKP2, which makes a particular medical to a gene therapy approach such as team for our work.

How would you address the baseline characteristics of the patient that joined RIDGE-1 compared to PKP2 patients generally in your practice.

Yes. I think the most noticeable thing from a clinical standpoint is the age of onset or diagnosis of some of the patients in the RIDGE-1 trial. There are 3 patients who are diagnosed in the pediatric stage, that's generally a much higher risk substrate, have a much higher risk of progressing to transplant. So overall, you would expect that this patient population is going to have more severe or advanced disease and a typical PKP2 ARVC.

For these patients, what are the biggest challenges of this condition day-to-day and longer term? And what are they in terms of treatment goals and future therapy.

Yes. I think this is really -- you can divide it up into several categories. The first is obviously, the tachyarrhythmias, which we've talked about are a huge deal to the patients. They have ICDs in place. Those will often go off. And that has those psychosocial implications, but also physical implications. They lend themselves in the hospital, they're young patients where they spending time in the hospital, really disrupting their work in their lives. So that big consideration just from a clinical management perspective, it's just the burden of the revisions disease.

In addition, we know that exercise is a trigger for both ventricular arrythmias, but also advances the disease, and these patients are diagnosed or restricted from exercise. Often, they were athletes in their prior lives and this has profound implications on the [indiscernible] because they're restricted from those activities in the [indiscernible]. And that is a consistent thing in the patients in our practice that have enrolled in this site as they ask about when can I go back to exercise. It's really something that they're seeking, and they're seeking a disease-modifying therapy that just doesn't exist in what we have in our current toolbox.

Lastly, a genetic disease. And so these patients and their families, they're not the only one affected. Their children are affected. They're siblings are affected and are have far reaching impact and not just the patients but their entire family going forward. Many of these patients are really looking for something not just to help the children in the next generation.

As we look across the spectrum of ventricular arrhythmias, can you talk a little about how important PVCs and NSVT are in ARVC. Are they harbingers of more severe ventricular areas?

If you take a look at how we risk stratify [indiscernible], there are several why we use calculators, all of which incorporate PVC burden, which is the primary kind of outlook or outcome in this trial. They also incorporate nonsustained DT burden. They do predict life-threatening ventricular arrhythmia or sustained VT. And so they definitely play a huge role when we restressing patients and also when we're treating them. So in conventional care, we were using antiarrhythmic drugs or using catheter ablation, our biggest metric we're determining the success of those therapies is to take a look at the PVC burden, to take a look at the PVC burden because that gives us our best predictor of what these patients will have future then.

Would you consider a clinically meaningful reduction in..

I think anything that we're seeing in the 50%, 60%, 70% range is a substantial reduction we've got to realize that what we see trial for RIDGE-1 is on top of conventional medical therapy. So these are patients that at least in my practice, the ones that have enrolled have essentially exhausted what we have clinically available to them to see a 50% or 60% reduction is quite clinically significant and especially those nonsustained VT that was what was really impressive to me patients with the 70 and 40 [indiscernible] burden to see that sort of reduction really tells me that there's been some more electric stability to introduce my team forward.

Of course, the daily rates in PVC can be quite variable. How robust is the RIDGE-1 methodology to measure them and quantify and how convincing are the results to date to you?

Yes, I'm very pleased to see that it wasn't a spot check. A lot of [indiscernible] clinical practice, we don't leave a monitor on for 7 or 14 days. It's just a 24-hour spot check, and that can either give you some false hope right in all into a fulsome security or can make you more worried because the PVC rates do vary taking at over 7 days and then averaging as PVC burden, I think gives us a pretty good sense both these patients ventricular activity and often PVC burden.

You've been caring for these patients directly, what is your impression of the safety and tolerability of TN-401 state?

So far, I've had no concerns on the safety or the tolerability, the patient done very well receiving this therapy with those in my practice that have received it. They've all been very happy with the process. And I think at the end of the day, [indiscernible] from some slight liver elevations that we can treat very easily with increased steroid there really hasn't been any big safety concerns. And I think we're seeing more and more interest from the ARVC population about participating in these trials. And it's a good reason because they're seeing that there's a safety profile and with respect to that on the PVC burden on we're today is falling to generate increased interest.

One of the biggest limitations of current therapies for PKP2-related ARVC. And what motivated you to become involved in gene therapy research.

I think if you look at what's available toolbox right now, it's things like antiarrhythmic drugs, things like sotalol, flecanide, catheter ablation and clinical defibrillators. They're all bandaids. They not modify the disease function. They are not at all disease modifying. And so what we end up doing is just putting out fires and that's how we're managing these patients right now clinically as we're all sitting on edge waiting for something to happen and we're kind of power us to fight against the disease process.

This is where a therapy like TN-401 and the PKP2 gene in placement therapies really come in. Is this is the first as something that could be disease modifying. It's really needed in the space in the ventricular arhythmias in the disease process really cause a lot of angst patients, and they have something that we can actually fight against potentially would really be a big step for.

John, we're incredibly grateful to you, our long-standing commitment to advancing understanding and care of patients with inherited cardiomyopathies. And we're delighted as your insights as part of today's conversation.

Thank you.

Thank you, Whit. I'd like to close with acknowledgments on Slide 27 and also make a few comments about where we are going from here. Let me echo what gratitude for Dr. Giudicessi's expertise and leadership. In addition, we are grateful to all the other participating incubators and clinical site teams. We owe a debt of gratitude to the trial participants and their families and to the broader patient community, including the Fab Foundation.

We'd also like to recognize the important support provided by the California Institute for regenerative medicine, which is provided potential financial support for the TN-401 trial. Last but not least, I'd like to thank our own dedicated team at Tenaya, continue to work tirelessly to advance the promise of our plans towards patients.

On Slide 28, we'd also like to call attention the additional efforts related to our TN-401 program. A core foundation of our progress has been rich. The largest global natural history study ever conducted in PKP2 associated ARVC with more than 185 patients, over 2,500 patient years of follow-up and participation across 21 sites, which also reflects our organization's reach beyond the U.S. with sites in 6 countries. And of note, RIDGE1 also has multiple 9 sites open in both the U.S.A. and U.K.

You heard already the ways in which RIDGE has already contributed to trial enrollment, and we have every reason to believe it will continue to be a source of patients for the future studies. RIDGE has generated an unprecedented depth of insight into disease progression, clinical endpoints and patient experience. which in turn, directly inform the design of the RIDGE-1 clinical study, including eligibility criteria end points. Similarly, the RIDGE study also helps us in our engagement with global health regulators by offering perspective on the disease being generated for TN-401 and providing insights into pivotal trial design in support of future approvals.

And on that note, we were also pleased to share that based on the early data 401 has received prime designation from the European Medicines Agency or EMA. Prime designation is intended to offer early and proactive support to sponsors in order to accelerate the review and progress of promising new medicines. This new development is consistent with our publicly stated goal to seek regulatory alignment regarding pivotal studies and the path to approval for both TN-401 and TN-201 in 2026. Today's data set caths off a productive first half of the year for TN-401 program.

We received DSMB clearance with continued enrollment of patients in the 6E13 vector genome per kilogram expansion cohort and today, we have provided a meaningful data readout. As we look ahead, we plan to continue to enroll patients and expect to report additional clinical data in the back half of the year with longer-term follow-up data, particularly -- at later time points that will help confirm the durability of the promising clinical effects we are seeing as well as confirm the dose for future [indiscernible] studies.

We are actively engaging with regulators in the U.S.A. and abroad. We also plan to provide updates on the TN-201 program in the next month, including new meaningful data. We are looking forward to a productive 2026 as we drive each of these programs forward. Now with that, let's open the line to Q&A. Operator?

[Operator Instructions] Your first question comes from the line of Mani Foroohar with Leerink Partners.

A quick one here, sort of less on this data more looking forward, I'm sure we'll get a bunch of questions around nuancing the data later in this call. Obviously, the next event from a regulatory perspective for PKP2 is going to be the interaction that your counterparts that ROCCAT has for their potential pivotal study. How do you think about the sort of the goal posts around any kind of potential pivotal, what relation should you guys rocket anyone? Should you be studying a gene therapy in how do you about subdividing the population by severity, baseline characteristics, PVC versus NSVT, how should we prepare ourselves to divest that feedback in light of all the various PKP2 gene therapy developers.

Manny, good to hear from you, and thanks for the question. I'll take a first crack at this, but then turn it over to Dr. Whit Tingley and in the case strategy he has a point of view on this. There's 3 companies, all 3 of them are doing to PKP2 gene therapy. I won't use this call to compare our results and our trial design versus others. There are some key differences between the 3 programs. We see at some level, there's differences in dose. And clearly, there are some differences in the early clinical data. We're very pleased with the deep and consistent and sustained reductions in burden that we are seeing that I think compare quite favorably to the other programs.

I really can't comment and, as you know, Manny, in detail about regulatory engagement. We are engaged with agencies on both sides of the pond, as we just discussed receiving prime designation -- the details about which populations, what subsets. There is a lot of heterogeneity here. We think we've picked the right population to study. We think the results show that. And what are the specific endpoints that is the big unknown in that this is the first time. That's the beauty of this kind of innovation. This is the first time that the FDA and sponsors are engaging on the topic of what are end points that are appropriate for full approval, whether they are points that are appropriate for excellent approval. And so that is something that's a point of active discussion.

I don't know what our peers and other programs are discussing and how they're thinking about it. And we just know that as I just mentioned, with Ridge, we have a level of insight into the disease. We have retrospective of these patients, and we're following them prospectively. So I think we have a larger data set with which we can make some hopefully, good recommendations for the FDA, and we'll see. We'll be reporting out on or landed with some of the discussions in the second half of the year.

In the meantime, our focus will be enrolling patients and generating more data to help us with dose selection and to help us with the safety and efficacy data will help shape those discussions with the FDA. That's about as far as we can go today, I think. But I'd like to turn it over to Dr. Tingley. And Whit, do you have anything more to add to that?

I agree with what you've said or consistent reductions across all states in this trial, reductions in PVC suggest that we have as defined a population that can definitely run and raise the possibility that we could expand even to a broader population of PKP2 patients. And we are in conversation with regulators and look forward to sharing more about how we've aligned with them in the second half of the day.

Do you have anything about populations or subpopulations from your clinical experience?

I think as a clinician, we're all watching all 3 trials, right? We're seeing what it comes back and seeing what patients are responding, having meaningful reductions in PVCs, now [indiscernible] and other outcomes. I think it's still too early to call. clinically, I would guess that would be patients with more early-stage disease because there's less permits, but we'll see how that pans out. That's what we've tried to enroll from our side. We've been very selective in who we've offered enrollment to. They've generally been patients that have severe disease, but it's more electrical than structural. We'll see if that plays out in the date. But I think it's too early to call. But the nice thing about having 3 trial is there's going to be a lot more data to compare for as we go forward and hope we see these things in our pivotal players.

Your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

Thank you for the presentation and the consistency in the data. Thank you also for kind of highlighting the variability here in variability in protein levels in PKP2, but would love to understand in patients who have elevated PVC and SVT was correlated with event rates. If there's an opportunity to actually connect the dots maybe more between the changes in PVC to NSVT to maybe changes in protein level.

And then maybe secondly, I would love to understand maybe the lack of dose response on protein levels make sense. But maybe do you think we could have not picked it up just because patient 5 and patient 6 has such a high elated baseline. Would love to get some color around that and then...

Thanks for the question. And I'll then turn it over to others. I guess I would say that at this early stage with a small number of patients, not only from our data, but the data of other programs, I think it's still too early to try to draw a straight line between dose vector copy number, RNA protein and then link that to specific changes in measures of electrical in stability, including PVC and NSVT, and that's not only true for our program. I think that's been true for others as well as other gene therapies or other cardiomyopathies, including our own [indiscernible]. So I think we're not trying to draw to title line on all of that today. Maybe with more data sets, we'll be able to do so. I think what we're seeing in this program has been seen in other programs for genetic cardiomyopathies that a little protein can go a long way in terms of changing the clinical presentation of the disease.

We've certainly seen that in our other program as other peers. So right now, what we're very pleased is with the electric -- the changes in the electrical instability, which is clearly upside of noise that it's a clear effect, and it's a real effect. And I think we're seeing impressive changes in the electrical and stability at an earlier time point, patient 5 and 6, particularly high severe PVCs and those have changed dramatically and faster than what we saw in cohort 1 -- suggestive of a dose effect, but we're not calling it that yet. We just simply believe that we need to dose more patients before we can call it a dose effect if that's reproduced.

So right now, not trying to draw too close correlation between protein levels, specific protein levels and electrical instability. And I'll just remind you a point that Dr. Ivey made is that even as healthy patients, there is a tremendous amount of variability in the amount of [indiscernible] protein that and so I think it's hard to make direct relationships between protein level and disease severity and therefore, it will also be hard to make definitive comments about response to treatment and protein levels. So that's my quick reaction. Whit, I'd like to see...

I mean on the clinical side, we don't have any nonresponders. [indiscernible] and this challenge about the biopsy and the percent of cardiomyocytes versus fibrotic tissue or fat tissue, that applies to an individual patient, which means when -- if you take different biopsy from the same patient, you're going to get very variable results. So it really confounds the ability to correlate the clinical response with [indiscernible]. It also confound our ability to correlate potent with RNA because those have to come from different punches because the tissue is treated differently from the assay. So we're -- it's too early. We'll need kind of population level correlations rather than individual patient-level correlation. So it's a great question. We just don't have enough data to it.

I'll make a note that, again, not unique to us, another program that we're aware of they saw -- in fact, all 3 programs to our knowledge at this stage, have seen this phenomena of protein in some cases, after gene therapy have gone below the original baseline level for first went up and then went down. And these are 3 different sponsors using 3 different methods as we already covered in detail. So it seems like the phenomenon that we are seeing are similar to the others with some differences being in the wide swing in the going up or down, maybe more acerbated with other methods versus with ours, but that up-down phenomenon is something that all 3 brands have demonstrated to date.

So I'm sure and all of our peers are all going to be wrestling with that one, but we basically all need to dose more patients to generate more data. That is consistent point.

Dr. Giudicessi, is there anything you'd like to add to the sort of commentary about looking...

Well, it's everywhere say, as we look to the data that's publicly available, everyone is wrestling with the variability. That's clearly there in health and that's just a challenge and it's going to have to be overcome. That's why I think a focus on seeing like it's there, right? There's transduction. We're seeing DNA. We're seeing RNA. If there's protein and seeing that there's a clinical impact, I think, is going to be important obviously, we check perfect correlation, that would be fantastic. But we're stuck with what we've got. It's not oncology. We don't have access to tissue like we do for other diseases. And then that's, I think, part of this -- and my worry is, it's going to be patient-to-patient, sample-to-sample institution to institution because we all do then a little bit differently. And so that's all going to confound this result.

But I think this is just a learning opportunity so that everyone can figure out what is the best way to assess each pharmacodynamic outcomes. And that's something that us as investigators are starting to put our heads again against all 3 trials, try to figure out if we should get an answer from the field. And so it's given us some real opportunities, trying to figure out exactly what's going on and give all 3 companies a path forward.

Your next question comes from the line of Mike Ulz with Morgan Stanley.

Maybe just a follow-up on the PKP2 protein expression. Appreciating there's definitely variability there, and we've seen it with others in the space as well. But just curious what you make of the intrapatient sort of declines at week 52 versus baseline. I think there's 2 patients that kind of show that trend how does that influence your thinking on the durability here longer term?

I think, Mike, thanks for the question. I mean this is substantially similar to what we just covered the -- and the last one, their difference is we have spent some time investing to show that the differences in methods you contribute to differences in the kind of data you're going to generate. But as we said in the last response, all 3 companies are seeing the same [indiscernible]. And so -- is this something to be figured out over time. The bottom line is we see the totality of the information that we have, transduction, mRNA protein at different time points or different patients. And also not shown today but have surrender in the path the [indiscernible], the influence and the localization of PKP2 that we are able to demonstrate. We'll have more of that kind of data in the future. I think that vitality evidence tells us we are having a pharmacodynamic effect.

And then the durability is going to be for us, less about protein and so it's going to be about the durability of the clinical effect. Honestly, that's what we're going to pay more attention to. So that's, I think, the response today.

Yes, a good point that the clinical effect in durable, but also the RNA impression. If we look at Slide 18, the RNA expression is stable at high at the 52-week level. So that said, we can't make RNA without having the DNA there. And of course, that's RNA that's making proteins. So Yes, you can't have staple RNA without stable [indiscernible] sector.

Perfect. Thanks for sharing that Whit and in the first 2 patients that actually grew with time as the 52-week which is the [indiscernible] I remind you on our TN-201 program, we also saw. We saw that RNA levels increase over time. So there is that level of consistency and the fact that with the same method, we're seeing this slightly different presentation of protein will suggest that there's unique presentation of this disease with a very uneven fiber fatty replan across hearts and therefore, samples is what's contributing to the data confounding data for us and others. The clinical effect is clear. And that's what we, I guess, want to emphasize today.

Kathy, do you or you want to add?

Second, everything that you all said, I think this comes down to sampling limitations. We don't have those same sampling limitations in our preclinical studies. So sometimes the data comes out a little sharper and clearer but all signs seem to be pointing to a protein expression based on the transaction and RNA.

Your next question comes from the line of Thibaut Pardo-Garcia with LifeSci Capital.

Moving on from PKP2 protein expression, how should we interpret the a 60% mean PVC reduction in Cohort 1 versus 67 PVC reduction Cohort 2. Is there enough of a difference to begin thinking about 6E13 dose as a potential go forward? Or is it still too early given the limited sample side, different follow-ups.

Thanks, Thibaut. Thanks for the question. Look, we're pleased. First, we're pleased that in both those cohorts, we're seeing an average reduction that is consistent in the 60-plus percent range -- and so that is just an absolute good to start with. I think it is too early to declare that there is a dose effect. We're pleased that we're seeing this reduction in both. We are dosing more patients, as you know, expansion cohort at the 6E13 dose and we'll continue to generate data from there. And that will help us sort of confirm whether there is a dose effect right now, the best measure. I wouldn't say the difference between 64% and 67% is meaningful, but we are intrigued that in the patients with very, very high electrical instability and patients 5 and 6, but they saw this dramatic decrease and saw it happen faster than what we saw in the first dose cohort, a hint at a possible dose response.

But again, we just need to dose more patients. We're also -- frankly, we haven't talked about safety really pleased that at twice the dose, we are seeing a safety profile that's quite similar to what we saw at 3E13 and generally very well tolerated. And so that actually bodes well that whatever dose we select right now, we seem to have a profile of a drug that is well tolerated and compares quite favorably to some of the peers who had a higher level of drug-related assays. So the only assays we had were related to a medication error, as we described. So we're happy with what we're seeing with safety and clinical effect at both doses and time will tell whether there is a dose effect. Frankly, if we had to move forward with 3 in as a dose, we'd be pretty pleased with these results. In terms of putting 60% reduction in perspective on average for cover, I'd like to turn to you, Dr. Giudicessi you say like? How does that sound you?

I mean that's huge, right? And I'll just see anecdotally, that patient #5, that's my patient. And we have struggled to get that as arrhythmias under control. He's been on the kitchen sink, right? Everything could throw him ablations every so contract, you see that sort of reduction just on an anecdotal basis. It's just -- it's one of those things you look at and say, wow, we plan to actually have an answer for them that we have not had in the past. And so that's been incredible. I think for me, looking at the data, the thing you need to remember is that in that cohort 2 that PVC reduction is really driven by those 2 patients, right? And the patient was #4 as yes, there's been a reduction, but not nearly as significant. I'm really looking forward, as I said in my presentation, what I see is the next 7-day continuous ECG monitor to see if that's going to be terrible effect because if it is for those patients, I think those patient #5 and patient #6.

Those are truly where us as clinicians were scratching our heads and we don't have a lot of answers for those patients. Those are the patients that if we can't fix it, they go to transplant, right? That's our only way out of it, which is trading one disease for another. And so I think it's really promising to see that degree of PVC reduction that early. And if that hangs on at week 32 and week 52, as a clinician, all of a sudden, this becomes a very viable consideration in our toolbox in these patients.

Thank you. Good question. We have three more in line, I believe, so we'll try to get through them quickly before we lose time.

Your next question comes from the line of Whitney Ijem with Canaccord Genuity.

I have several, but I'll just pick one. I wanted to follow up on something. Well, I guess this is for Dr. Giudicessi. But you mentioned kind of prioritizing patients who had electrical issues, but less on the structural side. How are you assessing that structural involvement? And can -- I guess, is there -- is it a fat fraction -- or how are you thinking about that fibrofatty percentage, I guess, or severity in these patients?

No, it's a great question. So I think the thing that doesn't come through very clearly because a lot of centers are presenting at very late stage disease is that a lot of these patients will present with more electrical complications without any evidence of right ventricular dysfunction on echocardiogram recurring. In fact, I think our group was the first to describe it back in 2017 that they present like a disease called [indiscernible] ventricular tachycardia where they actually just have exercise-induced VT or very significant exercise in [indiscernible]. Those patients, we suspect, right, have a very low amount because you do a cardiac MRI, you can characterize the assets in the RV, and we don't see any, right? And there are RV size, there are already dimensions on RV function are perfectly normal. Those are the patients, if you ask me as a clinician, if I had a bet who would get them in for the box.

Those are the patients because it's stabilizing. Their arrhythmias they're not driven by SPAR. Their arrhythmias are probably driven by abnormal [indiscernible] handling and the evidence that's there is the efficacy of second in this disease that's really emerged over the last 5 years. And I think it drives some of the point that there may be 2 different arrythmia drivers in, both of which would be addressed by replacing that [indiscernible].

Your next question comes from Joe Pantginis with H.C. Wainwright.

This is Sara on for Joe. I had a question looking more at the safety profile you showed on Slide 24. Some variability in immunosuppression duration from 12.9% to 29.4 weeks on the corticosteroids I was just wondering if you could add some color on what's driving that. Is that mainly clinical factors, the immune response magnitude or is physician discretion? And as you're thinking of scaling to a pivotal trial, how do you anticipate standardizing the IS taper more rigidly?

Let me first turn it over to Dr. Tingley to just talk about our [indiscernible] across both programs. And then Dr. Giudicessi's practical experience administering and tapering.

Yes, it's an excellent question. I don't think our goals even in pivotal trials will be to standardize the taper. We really like the individualized to taper, but the goal is to get off as that quickly as possible, but some patients can tolerate that better than others. So for example, patients 5 here who had the longest duration, it was just at the tail and not all the safety labs were permed so out of an abundance of caution, the immunosuppression regimen was continued. Other patients successfully came completely off much sooner. But it's a tailored approach allows us to minimize the total immunosupression for each patient. John, you want to add?

Yes. I just -- practically, patient 5 is a patient that because of that steroid interruption, how that transaminitis that we had to do a prolonged steroid course. So we basically reset a steroid to treat that issue, which was due to a pharmacy air, and it happens even in 2026, despite all the safeguards. And so that patient, I think, is an outlier, right? Usually, we can move patients 4 also as a patient with Mayo Clinic. We move that patient very quickly. Us as clinicians, as we get more experience with these therapies, we know what tapers work, and we know how to dose these drugs much better than what we did when we started. And I think leaving it open to clinicians kind of comfort is a good thing because everybody -- there's different ways that's going to cap right? And I think for me, my goal going forward with these patients is I want them off as soon as possible. It's soon as safe, and that's what we're moving to do.

But there are going to be those patients because everybody right our genetic makeup, our biology is a little bit different. -- there are going to be things as the AAV gene therapies come along that are going to predict either genetically or environmentally, those that are going to have these responses from a liver enzyme perspective or whatever. And we're going to have to have longer dosing. And so -- we just need to kind of roll with that, get more data. But I like the flexible dosing. I think standardized, you can't do it because every patient is a little bit different -- that's just the way in the world.

I'll make one last comment here. We recently also had a presentation at the European study. heart failure conference, where we also presented data that looks like this. So I'm not going to throw up that information that will be available, I think, on slide soon. but we saw a set experience here. We're really pleased to see that the learnings that we've applied from after the first dose to the second dose, we've seen in both programs on average are shortening the duration on steroids. And that has been replicated in both the TN-401 program and on the TN-201 program. So I think we're I think this is a great example. During the sentinel period of gene therapy, this is exactly why you do it. learn, you apply and then you can go into the expansion cohort with confidence that you figured it out and how to manage these things, both on the prophylactic and then the tapering as well as how you monitor the patients during tapering.

So we've put a tremendous amount of effort on into this with our sites and just safety and we're very pleased that with we have an immunosuppression regimen that seems to work, but things look even better in Cohort 2 than they did in Cohort 1 at twice the dose. Next question?

Your final question comes from the line of [indiscernible] with Jarden.

I wanted to follow up a little bit on the trajectory of the PEC improvements. I know you mentioned cohort 2 may be showing effects a bit faster. For the Cohort 1 patients with the 52 follow-up, is there additional color that you can provide regarding the trajectory of the reduction over time? Was the improvement gradual or linear? Or did some patients show an initial rapid decline followed by a plateau or take longer. For example, I think patient 3 and the prior data cut had not yet shown improvement and now has -- so additional color that would be helpful to understand expectations for Cohort 2 as well?

Yes, sure. We do. No, that's absolutely right. So our last data released, the first 2 patients had drops in PVC, but that was after the 6-month time point. The third patient was before the 6-month time point, week 20 and haven't yet seen a drop. Now if we do see a drop on that patient and the drop for the first [indiscernible] have been maintained with a 52-week time point. And as we pointed out now in Cohort 2, we are seeing drops at that earlier time point of 20 weeks. So we're happy to see sustained again persistent reductions in the first cohort and now early reductions in the higher dose cohort. So it couldn't be more...

And I would only add to that, [indiscernible], that the -- what we really are excited about is the consistency. All 6 patients seeing these effects at web time point, the durability that we're seeing with the first 2 patients at 1 year, given that the wide heterogeneity that you're not going to see in the natural history, that wouldn't have happened by chance. And so we know it's not a spot effect at any time point, but it's also not a side effect when we're seeing it durable over a 1-year period now and just also love the consistency between PVCs and SVT data with patient 2 and 5 seeing the ones who had the highest number having the most dramatic decline, and that is just on what we're seeing in PVC.

As we know, in other programs, we haven't necessarily seen that kind of consistency where both PVC and NSVTs are going down. So it's one going up and the other going down. So overall, we couldn't be more pleased with this, the data. And then we'll see with time, whether the speed and the kinetics. We've always said that it will be the kinetics of the response, the magnitude of the response and the [indiscernible] of the response that will help us select the dose to go into pivotal studies, balanced with safety. Safety so far, so good. and then the data so far, so good. So more patients dosing, more data. We'll be reporting more in the second half of the year, all these patients in Cohort 2 should be at the 1-year time point by the time we view the next data release at or near the 1-year time point.

Operator, any more questions in queue?

That concludes our question-and-answer session. I'll turn the call back over to Faraz Ali for closing remarks.

Yes. No, that's -- we had an excellent day for the team forward program. We're importantly an excellent day for PKP2 associated MC community. Thank you again to everybody contributed to this. Thank you, particularly, Dr. Giudicessi for both your presentation at ASEC today and for spending so much time with us invaluable expert Q&A. So with that, these slides will go up into the public -- already in the public domain. And we look forward to our next data release that will be in the next few weeks for our commitment on TN-201 and looking forward to an exciting update on program as well. So thank you, everybody, for joining today.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

Thank you to the -- and welcome back to our next session of the Global Healthcare Conference here in sunny Miami. I guess I'm hosting everyone in more than one way in my adopted home. And with me I have Faraz Ali from Tenaya Therapeutics, who had -- you guys had some interesting data this morning that you put out already out. The press release is out so can have a chat about it.

Talk to me about what this data adds to the pool of evidence we have so far, and then we'll go to the strategic and scientific implications afterwards.

Yes. Great. So a lot going on at Tenaya. Just thanks, Leerink, for the opportunity to be here today. We have 3 clinical stage programs. So I know we'll spend a certain amount of time on the 2 gene therapy programs, which have been traditionally mostly in focus, TN-201 and 401. And indeed, that's -- our focus remains there and achieving milestones that we'll talk about later. And then 301, also clinical stage small molecule, highly specific HDAC6 inhibitor. And we completed a first healthy human volunteer study in the past, clean, good, nice data, no dose-limiting toxicities.

And then the question has always been what next? So limited resource in the last couple of years, we were focused on the gene therapy program, and that was the right thing to do. And now we're in a very good position that this year that we can generate data that might support pivotal studies and pursue regulatory alignment. But in parallel, we never sat still on this front. And so we continued to generate preclinical data on this program and mechanistic insights on this program. And so today, the data that was presented was at the muscular dystrophy or is being presented in a poster at the Muscular Dystrophy Association meeting. We've shown that this molecule also has a positive impact in DMD hearts and DMD skeletal muscle.

Why is this important? Is Tenaya going to become a DMD company? No. What we have done with this data set to put it in a broader perspective, is confirmed in yet another preclinical model, the potential for in vivo efficacy with HDAC-specific inhibition. We've demonstrated that by now in HFpEF. We've demonstrated this in genetic dilated cardiomyopathy. This is our own molecule in our own hands in peripheral arterial hypertension -- sorry, pulmonary arterial hypertension as well as now in DMD, skeletal muscle and cardiomyopathy.

This is verifying the broad clinical utility of TN-301 in a range of attractive indications and a true pipeline and a target or pipeline and a pill potential of this molecule. Now why is that the case? The other thing that we're verifying is this multimodal mechanism of action. Like how is it possible that one molecule against one target is having a benefit in many different things. One, we verified this from the outside. Other people have also demonstrated data in cardiac indications and cardiac adjacencies, including in some of the indications that we're interested in. So that verifies our data.

But also collectively, the field is beginning to understand with HDAC6 inhibition, you can get anti-inflammatory effects antifibrotic effects, improvement in protein quality control, improvement in metabolic dysregulation, just improvement in autophagy. It's that multimodal mechanism of action on very common pathways that seems to have an effect in multiple disease animal models. Now animals are great. We can all cure mice, right, including multiple mice.

One interesting thing that also happened in parallel over the last 2 years is the approval of a pan-HDAC inhibitor, givinostat brand named Duvyzat. So Italfarmaco, a company out of Italy, private company, so not a lot of people know about it, they quietly executed on a pan-HDAC inhibitor clinical study in DMD, showed statistically significant benefit versus placebo in decline of muscle function, got an approval in the U.S.A. and Europe and have a launch. And rapid uptake in hundreds of patients have been dosed, hundreds of millions have been generated in revenue. And this is -- and some people are using it on top of gene therapy.

Now why is that relevant? Our data shows that the benefits or suggests at least that the benefits that Duvyzat has demonstrated in DMD patients leading to an approval is due to HDAC6, not the other HDACs, right? And so we've shown that we have superiority with -- when we did a head-to-head comparison with HDAC6 and pan-HDAC inhibition, we are getting better results in both the skeletal muscle as well as in the cardiac engineered heart tissue. So that suggests that HDAC6 is the source of the efficacy, but without the liabilities associated with pan-HDAC.

So they have QT prolongation risk, we do not. They have thrombocytopenia in their clinical experience, we do not. And so overall, that gives us some clinical relevance and translatability of what we're showing in the mice because otherwise, who cares about like curing mice. It's that clinical relevance of HDAC6 specific inhibition that we're excited about. And again, this just is validating the target, validating the mechanism of action that we think also will derisk HFpEF and other attractive cardiac and cardiac indications, cardiac adjacencies because it's the same multimodal mechanism of action that's responsible for all this.

So that's why we're excited about this development today. We are moving this forward towards clinical development. We are not hurting our cash runway in the process of doing that, right? So we're doing enabling work that will support future proof of mechanism, proof-of-activity studies. And so it all fits within our current cash runway.

A little bit of CMC and formulation development, a little bit more toxicology, but we're building on the existing IND that we have open for the Phase I. And so we're excited about this. It's adding another leg to the Tenaya story. So TN-201 gene therapy, TN-401 gene therapy, now TN-301 small molecule and the exciting announcement of the collaboration with Alnylam.

Before we get to that clarification we will sort of the cross-franchise medicine crossover. Let's talk about this data in the context of the guidance you've given for cash runway, OpEx, et cetera. Just so we can think about what the incremental spend is, which clearly doesn't change the runway. But people think about how this fits into your existing infrastructure. That's a lot of programs to prosecute simultaneously with a relatively small absolute spend rate.

Yes. We've always been actually quite efficient, remarkably efficient. We do a lot with a little. But -- so the enabling work is not very capital intensive. That's first and foremost. That's why there's no impact on the cash runway. What would become capital intensive is once we start doing studies, right? And so we have to be clever about the selection of the specific indications and the design of those studies to be capital efficient there. Now initial studies would not be -- we're not looking at large outcome studies here quite at this stage, right? These are smaller proof-of-activity studies that would be the next logical step here in this program. That could be executed on by our company.

Now you did raise an important point, with so many potential indications in play, are we going to do this all alone? Are we going to do this as a partner? We think we'll continue to explore partnership opportunities. We do think that there are people who are quite interested, and we know this from direct engagement, quite interested in what we're doing. We also know that a lot of value and a lot of derisking will be achieved and a lot of value will be created by generating this -- the data in disease populations.

And then after that, clearly, we're never going to do HFpEF on our own, large indication, large outcome studies required. We will need a partner for that. However, the data we generate from proof-of-activity studies can actually, I think, result in a lot of people interested in the molecule, not only for HFpEF or DMD, but potentially many other indications.

So let's talk a little bit about how you think about what should be useful for what from a strategic perspective because there will be a universe of investors who will argue, shouldn't this be your primary in-house focus rather than a primary partnership. And that's not...

You mean 301...

Yes. It's just how you -- you talked about being nimble, rational, data-driven is actually how you've called it in previous calls. How do you think about that? When is it appropriate to pivot, tack, since we're in a port city? And when is it not?

Well, I mean, one thing -- so we're not pivoting. This is -- I just want to be clear here. This is not a -- it's important to say out loud. This is not because of any lack of conviction on our TN-201. TN201, TN-401 for which we raised money last year, we are very pleased with where we are, very pleased with where we're going, maintaining our guidance, data in the first and second half of the year of both programs and potential for regulatory alignment. Our conviction in those gene therapies have only gone up in terms of sort of the data set and what we think is possible there.

So this is not a oh s****, we might pivot here. This is not a pivot. This is an and, not an or. Now yes, choices have to be made in the future, what to do ourselves, what to partner, which one to prioritize. Today, for this year, we don't have to make those choices. Today, for this year, our capital substantially is going on 201 and 401 gene therapies, right? Then when we come in the second half of this year and on the other side of catalyst, as we think about the next round or the next raise, then it could be that at that point, we have to make some choices about what do we want to -- where do we want to allocate capital in the future prospectively.

But for now, 201, our conviction is high. And for now, we would like to -- we own it completely. We still don't have a partnership for that. And if today, somebody wanted to just take us off our hands for little dollars, we wouldn't do that because we just see too much value here right now. So we'll continue to own this and drive this forward. And either a very, very attractive deal will materialize that will take us off our hands or from which we can meaningfully still codevelop and collaborate or we will drive this.

We see a very capital-efficient way to get to clinical data in one or more indications through possibly multiple proof-of-activity studies. We'll give a little bit more updates as we get further into the year. And that could just transform the profile of the company. That could just completely transform the profile of the company that in addition to gene therapies, now we've got another entire value driver with multiple horizons of opportunity, and then those will be good problems to have.

Those are good problems to have.

Yes.

Let's -- I'm going to take a step back to the -- what we think of as sort of the base gene therapy business. Let's talk a little bit about where we are in HCM, having navigated a pretty deep engagement with the agency. We can touch base on the status of your conversation with the agency separately. What is the data pathway from here through the next 18 months in that indication? And what are some of the key events that unlock clinical value now that we're sort of -- now that we're back on the runway?

Yes. Yes. So look, I mean, we were very pleased with the data that we shared at the AHA meeting last year that was published at the same time in Circulation Research. And for those who are not familiar with it, just as a reminder, that included improvement at the very first dose, which is a relatively low dose, 3e13, the first 3 patients treated, all of them with sufficient follow-up dramatic reductions in circulating biomarkers like cardiac troponin I, dramatic reductions in measures of hypertrophy, including LVMI and posterior wall thickness and all patients at New York Heart Class I. This established a very good base from which we're operating.

Now we're dosing more -- we have completed dosing of the second dose cohort. And now we, in fact, had initiated dosing in the expansion cohort. So dosing more patients, mostly at the high-dose cohort. That data will mature. So over the course of this year, we're going to see a few things. We're going to see the Cohort 1 patients now approaching the 2-year mark. So do we see the persistency of that data? Do we see a deepening of the effect? That's Cohort 1.

And then Cohort 2 will come into focus. Do we see deeper effect, faster effects? What do we see with the higher-dose cohort. So that will help address multiple things. One is the product working at both doses? What's the right dose to take into pivotal studies? And what does the safety and efficacy profile look like at both doses. So that is all going to come out with the patients that we already have, plus the new patients we're dosing. But substantially, actually, most of the data from the patients already dosed will help drive this decision. Of course, we're going to be dosing more patients and we'll generate data for that in the second half of this year as well.

So very important derisking of the program, very important opportunities to generate yet more positive data and use that data to engage with the regulatory agencies about what's the right path forward here. What are approvable endpoints for full approval, what are the approvable endpoints for accelerated approval? What's the right population to advance this in? Is it adults? Is it severe pediatrics? So a lot will come out over the course of this year.

So let's talk a little bit about those conversations with the agency. I had this discussion with a few companies over the course of days, as you can imagine.

We love the FDA, yes.

I hear you. The agency has had some volatility and leadership. Talk to us about how much change, if any, you've seen, an evolution you've seen in terms of your counterparties for your particular filings or filings in terms of who you're working with at the FDA, infrastructure, resources, morale, how has that evolved?

I can't speak to anything about what's going on at the FDA. We just have our interactions with our own group, and I don't have any new data points to suggest that anything has changed with the specific groups that we're working with right now. We just have -- we hear the same rumors and reporting from everybody else, but I can't say anything specific about the specific teams that we're working with. Yes.

That makes sense. So hopping back into the pipeline. There's been a lot of discussion around...

But I will just say on the regulatory side, one thing that we like to remind people about, there has been this whiplash of like, wait, they said this, then they said this, they said this and then they said that, REGENXBIO, uniQure have probably been the 2 worst hit in terms of that regulatory uncertainty. But we do like to -- on the HCM program in particular, so the TN-201 program, over there, our best precedents are from Lexeo and Rocket, right, on their respective lead programs, Friedreich's ataxia and Danon disease.

And for both of those companies, they had an alignment with the FDA about protein expression and improvement in hypertrophy of greater than 10% as co-primary endpoints for accelerated approval. They had established that under the old FDA regime, and they reaffirmed it last year under the new FDA regime. So I think that's good that the current -- their teams, whoever their teams are, those teams under the current FDA reaffirmed what the previous team had said.

So that, I think, hopefully will reduce the likelihood of unpleasant surprises on the HCM side because they've already reaffirmed the guidance from the previous, and that's a good thing. So we have to prove that those could also be applicable to us, protein expression and improvements in hypertrophy as a base of accelerated approval. We have to prove that for ourselves, but we're glad to see that the guidance did not change for those 2 companies who are the best comps yet for us on that program.

I think that's useful to hop back on the pipeline exactly that topic. Obviously, Rocket is a comp for the lead program, also a competitor, teammate, depending how you want to think about it from PKP2, et cetera. How do you think about the universe of data you've seen across companies? And what should be the endpoints we consider as meaningful, maybe eventually registrational for PKP2, recognizing there was a debate around Lexeo's data around NSVT versus PVCs. Is that debate meaningful in your mind? Or is it sort of a Wall Street splitting hands on 2 things that are very closely related biologically?

Well, we're glad that Wall Street cares. We're glad that they're paying attention to these programs. We are super excited about our TN-201 program. And for a while, we had to like get interest going on TN-401 that we're past that. People are interested in TN-401 as well, and that has very much come into focus. So we're glad with the attention and partly perhaps the competitive dynamic has contributed to that.

Look, there is a continuum of things that contribute to the disease in these patients, right, on the electrical and stability side, PVCs, NSVTs, sustained ventricular tachycardias, ventricular fibrillations all the way to sudden cardiac arrest and death, right? The PVCs are more frequent, sudden cardiac arrest, thankfully, less frequent, but very severe. We have clear data that suggests that -- and the risk calculator that has been produced not by the companies, but by third-party academics who are experts in this field, that reductions in PVCs and NSVTs are both -- and then also T-wave inversions. They are part of a broad -- gender, a couple of different factors that contribute to risk calculations. Both PVCs and NSVTs are included there.

So we don't -- I do think it's trying to zoom in and saying this is it. This is the perfect endpoint. I think everybody is going to have to make their own case with their own review team. We like what we're seeing with our early data that we've seen improvement -- clinically meaningful improvement in both PVCs and the one patient who had high NSVTs came down to 0. We think our -- those data, while early, are differentiated. They are sort of more consistently robust. And we're not going to pick a winner here that it's PVCs or it's NSVTs. So that's -- I think it's splitting here. It is part of a common mechanism. These things both get -- if you look at antiarrhythmic medications like flecainide and amiodarone and others, they tend to benefit not just one, but both.

So it suggests that there's a connection between those 2. And so trying to say like, no, it's NSVTs. We say that it's PVCs, I don't want to get into those kind of arguments. I think we will make the argument with the FDA about what is the right endpoint for clinical development, right? That's -- even though those 2 may go in tandem, maybe one is up, one is down, but what's the right endpoint that you pick for clinical development? That is exactly the discussion we're having right now among ourselves. Those are the arguments we'll make with the FDA.

I would say that one thing that is underappreciated by the field is that we have the largest natural history data in the world -- data set in the world with a RIDGE study. So there's more than 185 patients from 21 sites in 6 countries that have been enrolled prospectively into that study, representing like more than 2,000 patient years of patient data. That gives us access to a very rich data set. That allows us to look at PVCs and NSVTs and what remain -- what's the level of variability with or without different doses of different medications. There's just a very rich data set that we think, in addition to our own clinical data, allows us to approach the agency, hopefully, with better arguments about why one endpoint versus another or a composite or whatever is the right way to go with this -- as you're coming up with endpoints for whether full approval or accelerated approval. So that will come into play as we have our negotiations with the regulatory agencies. I think that data set is -- in an indication with a lot of variability, having a larger data set matters.

I think in thinking about the sort of pathway towards an eventual pivotal, I'm be showing my colors here who trained me in this business. But I think of things a little bit like a matrix of who you are dosing and what you're trying to show. And we talked about what you're trying to show and the decisions people have to make around endpoint. As the question of who you are dosing, obviously, at the top of the funnel and this indication is vast, then you have incomplete penetrants, patients who are symptomatic or not, patients who have been instrumented or not at which point they are protected from immediate death, although shocks are extremely unpleasant and like quite distressing and like terrifying to some patients.

Where along that funnel from everyone with a genotype everyone with a phenotype all the way down to the universe of patients that are instrumented but are experiencing extreme nervousness and painful shocks, like where should we be dosing patients for potential gene therapy application for PKP2?

Yes. So look, I believe this is the case for every one of the companies. All of these patients are already on ICDs. So we're -- that's off the table. We're already enriching for patients with higher severity. At least we are, I can't speak for the others, but we're enriching -- you must have more than 500 PVCs a day to even enter into our study. Now that -- not everybody shares that. If you look at the Rocket, the first 3 patients they dosed, they have a patient below -- I think that's down to 100 or 200 PVCs a day. That patient wouldn't even have entered our study.

So we're enriching for a little bit more severity, right? Obviously, we're enriching for patients who don't have the neutralizing antibodies, et cetera, et cetera. All the patients are on background medications. And clearly, they've failed. At some level, virtually every patient we're treating, they're on standard of care background, whether it's flecainide or amiodarone or something like that, many of them have already had ablations. And so despite surgical intervention like ablations, despite medications, they still have these elevated PVCs and NSVTs and therefore, risk of severe ventricular arhythmic events, including shocks.

So I mean, I don't think there's any further enrichment that we're going to be doing now. Now having said that, connecting the dots with my previous comment, if we find through our data sets or engagement with the agency that enriching for a particular population for a particular endpoint would be advantageous for clinical development, Again, the natural history study puts us in a better position because we have 185 patients to draw from. So if there is a stratification to be done and say like, let's get patients with this threshold of PVCs or NSVTs or some other attribute, right, and that will likely result in a better clinical outcome or a better study for us, we have the data. We have the patients to draw from if there's further substratification to be done.

But right now, I wouldn't say that there's anything else that we have to do. The patients have the mutation, they have severe disease despite standard of care therapy, and we're demonstrating that we can make a dent in that electrical instability of a kind that wasn't being achieved with surgical interventions and standard of care medications. Remember, none of these patients are washing out. They're staying stable on their dose of their existing therapies. So anything that we are achieving any of the 3 companies, I believe, is on top of what they're already getting.

So -- and I think we're coming down to the end of time, but I don't want to like leave this unspoken. We've talked about the dynamic on patient selection, endpoint selection. What is the pool of data we're going to be seeing in this indication from you over the next 18 months? And how will you be strategically digesting and responding to whatever we get from Rocket's engagement around pivotal trial, the design with the FDA?

So the data we'll be generating is -- so the early data release that we did, it was the first 3 patients at early time point. The first 2 patients were at 6 months. The third patient was not at 6 months. So first things first. First half of this year, we're going to get all 3 patients in the first dose cohort close to 1-year time point or at the 1-year time point plus early data from Cohort 2. Second half of the year, we'll have further data from Cohort 1 and Cohort 2, all at the 1-year time point. So meaningful full cohort data sets. So that's what we've committed. That is consistent with our guidance.

How are we responding to others? Well, we didn't have a chance to talk about like Lexeo's update in January. There's a lot of noise there in the protein as well as in NSVTs and the PVCs, right? So that says something about the disease, says something about the therapy, says something about their protein measurement methods. Rocket, whenever they release data that will provide to get more information, I'm sure the data release, we did inform them as well.

So I think this is an exciting and dynamic time for the companies and for patients where there's 3 companies advancing 3 programs, and it's too early to declare winners and losers yet. But I think this will be a year where there will start to be some separation on the basis of safety and/or protein consistency and/or markers of electrical instability and/or announcement of alignment of pivotal studies. So we're watching them. They're watching us and you're watching all of us.

Can you talk about the Alnylam partnership, the near-term milestones [indiscernible] and earn additional capital from that partnership this year?

Yes. Great. So first, we're super excited about that. World leader in RNA siRNA therapeutics, perfect marriage. They've got an established cardiovascular franchise now, including a TTR. And then we've got these differentiated capabilities. They like what we have. We like what they have. So it's a perfect marriage that way.

And then in terms of the actual capital, so we get the $10 million upfront, we get research reimbursement for 2 years and then about $1 billion and change, $1.1 billion in biobucks. Are there -- so those biobucks include payment for different milestones as they're achieved on a per target basis. But we're not going to provide guidance at this time of what could be achieved in the coming, say, 12 to 18 months of our runway.

But yes, there are milestones that are tied to -- there are payments tied to more near-term milestones and, of course, higher payments for the longer-term milestones, but we're super excited about this collaboration. Deep validation of our research capabilities, true to our modality-agnostic approach to the cardiac disease, gene therapy, small molecule and now a partner with deep expertise in siRNA. So we're just continuing to execute on the original vision of the company and hedging our bets with a lot of different modalities. So we don't just -- we're not just a gene therapy company, which is how some have come to think of us over the last 2 years. We've got a lot more going on here. And I think if you look at a company like us, we have multiple horizons of opportunity.

Right now, we have a horizon of opportunity with gene therapy, 201 and/or 401. That's a this year thing. 301 is going to provide the next horizon of opportunity in the coming nearish future. And then right behind that now, then we'll have the opportunities with Alnylam and the pipeline there, not to mention our own homegrown pipeline product candidates. So there's a lot going on at the company. It's an exciting time for us and it's an exciting time for investors. And it seems like the market is reacting well to both the Alnylam announcement as well as the announcement that we're moving 301 forward, and that's a little bit of the flavor of the dialogue we've had with investors here today. People like what they're hearing. Sorry, I didn't -- I can't specifically answer your question, but I'm going to answer the question I wish you had asked, which is what is exciting me about where Tenaya is today, and all of this is exciting me. It's a great -- it's going to be a great year for us.

All right.

Thank you.

Hi, everyone, and thank you for joining us today. I'm Michelle Corral, Vice President of Corporate Communications and Investor Relations at Tenaya. Today, we are excited to present initial data from Cohort 1 of the RIDGE-1 Phase Ib/II clinical trial of TN-401 gene therapy for the potential treatment of PKP2-associated arrhythmogenic right ventricular cardiomyopathy or otherwise known as ARVC.

On the call with me are Faraz Ali, Tenaya's Chief Executive Officer; Dr. Kathy Ivey, our SVP of Research; and Dr. Whit Tingley, Tenaya's Chief Medical Officer.

While the data we are disclosing will be described in full verbally, please note that during the course of today's call, we will be making references to slides. A PDF file of these slides is available on the Tenaya website in the IR section under Events and Presentations.

As a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of today, December 11, 2025. These statements involve certain assumptions, and we caution investors not to place undue reliance on this information. Please refer to today's press release as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements.

In addition, I'd like to remind folks that we are unable to take questions on today's call due to the launch of a follow-on offering. That being said, we always welcome the opportunity to engage and look forward to our next opportunities to do so. Please reach out to me directly with any questions or to set up time with our team.

With that introduction complete, let me turn the call over to Faraz Ali for opening remarks. Faraz?

Thank you, Michelle, and thanks to everyone for joining us today. Tenaya has made significant progress in the past year across our 2 gene therapy programs. And while the focus of today's call is on the compelling early data generated from our TN-401 program, we also want to take a moment to share a positive update on TN-201, our gene therapy program for MYBPC3-associated hypertrophic cardiomyopathy or HCM. We are pleased to share that the procedural clinical hold that was placed on the MyPEAK-1 trial of TN-201 has been lifted by the FDA.

As you may recall, the hold was instituted following our proactive outreach to the agency to share clinical data from the TN-201 program and to discuss next steps for development. We amended the MyPEAK-1 protocol per FDA request to incorporate learnings related to patient monitoring and management of the immune suppression regimen.

We were completely aligned with the FDA's suggestions and after addressing all of their questions and concerns, the hold was lifted within about 5 short weeks after it was first put in place. We're now proceeding with the implementation of those changes to the MyPEAK-1 trial protocol. Where applicable, we are also proactively doing so in the RIDGE-1 protocol for this TN-401 study, although that was not formally requested by the FDA.

Now on to today's focus, which is TN-401. We are thrilled to be sharing the first look at results from Cohort 1 of the RIDGE-1 Phase Ib/II clinical trial of TN-401 for PKP2-associated ARVC, a genetic form of arrhythmogenic cardiomyopathy.

On Slide 3, we're jumping right into the results at a high level. First, TN-401 has been well tolerated at the 3e13 vector genome per kilogram dose. DSB clearance has been achieved to move to Cohort 2 and Cohort 2 has been fully dosed. We're waiting for DSMB clearance. Now from the available biopsies we have in hand to date, we see consistent evidence of TN-401 DNA reaching cardiomyocytes and consistent expression of RNA that's being transcribed. Importantly, as we look from baseline to week 8 biopsy data, PKP2 protein levels have increased significantly by a mean of 10% in 2 of 3 patients.

Finally, and very excitingly, we are seeing early evidence of clinical impact on electrical instability, a hallmark of the disease, with significant and clinically meaningful drops in PVC counts of 46% to 89%, along with positive changes in non-sustained ventricular arrhythmias or NSVTs. We are very encouraged by the emerging safety profile, biopsy and initial clinical results that we can share with you today.

Should our data continue in line with these encouraging early results, we believe TN-401 has the potential to make a profound difference in the lives of PKP2-associated ARVC patients. We look forward to following the patients from both dose cohorts. We look forward to dosing more patients following DSMB clearance, the move in the direction of the expansion cohort, and we look forward to exploring opportunities to transition to late-stage clinical development and pivotal studies potentially as early as

2026.

However, before we go deeper into the data, I'd like to provide some context on Slide 4 for the disease and our objectives with TN-401 gene therapy. ARVC is a rare progressive genetic familial disorder characterized by ventricular arrhythmias. During the course of the disease, cardiac muscle is replaced with fibrofatty tissue enlargement of the ventricle occurs. At the same time, the degradation of the tissue contributes to electrical instability, resulting in arrhythmias that endanger patients' lives and that may exacerbate the buildup of scar tissue.

Now PKP2 is the most common genetic mutation responsible for approximately 40% of cases. The PKP2 of ARVC is estimated to affect approximately 70,000 people in the U.S.A. alone. In PKP2-associated ARVC, the average age of symptom onset and diagnosis is a young 30 years of age. Symptoms may include syncope, palpitations and lightheadedness, but it's estimated that about 1/4 of people with ARVC present with sudden cardiac death, which speaks to the unmet need.

Quality of life may also be significantly impacted. Current treatments consist of beta blockers and antiarrhythmic drugs, both of which can cause side effects. A large portion of patients receive an ICD that can shock their heart back into normal rhythm. While life-saving, the shocks themselves can be traumatic. And last but not least, patients are typically placed on exercise restrictions and warned to avoid any exertion that could trigger an event. All of these factors contribute to diminished quality of life.

On Slide 5, we offer a closer look at the key characteristics associated with PKP2 disease. ARVC is generally divided into 3 distinct phases of progression. The concealed stage is primarily asymptomatic. At this early phase of disease, it may be difficult to detect irregular rhythms or structural abnormalities. In the overt electrical stage, symptoms emerge and the risk of dangerous arrhythmias increase. Rhythm irregularities are apparent on ACG.

End-stage or structural dysfunction stage of disease is when changes to the heart, such as the distortion of the right ventricle are visible via imaging. Patients are at risk of sudden card arrest and death and heart failure symptoms may emerge. However, it's important to point out that dangerous arrhythmias, including sudden cardiac arrest or death, can occur at any stage, including during the concealed stage before patients are even aware that they are at risk.

Data from our RIDGE natural history study of PKP2-associated ARVC tells us that genotype matters, influencing disease course and disease burden. These findings are reaffirmed in the literature tell us that tell us that PKP2 patients are more likely to suffer consequences of electrical instability versus heart failure. In fact, among PKP2positive patients, electrical instability and its associated risks predominate. Specifically, our data tell us that greater than 80% carry a high PVC burden despite standard of care therapies and surgical interventions and nearly half have a history of ventricular tachycardia, whereas approximately 51% have apparent right ventricular dysfunction, but only 30% have left ventricular involvement or heart failure symptoms. We want to bear this background on disease burden in mind as it provides disease-specific insights for why we're excited by the results we are sharing at this early time point.

On Slide 6, we provide an overview of the RIDGE natural history study, which we just referred to on the prior slide. RIDGE is now the largest known natural history study for PKP2 disease with nearly 190 patients enrolled across 21 sites in 6 countries and with greater than 2,500 patient years of follow-up. We believe the insights provided by RIDGE offer us a unique competitive advantage, particularly as we head into later stages of development, providing context for how to interpret emerging results from our clinical trials, enabling us to make smarter choices about future enrollment and enables us to have smarter discussions with regulatory agencies about trial design and endpoints for either accelerated or full approval.

Underpinning the distinct experience of patients with PKP2 variants is the mutation itself. So on Slide 7, we start with a closer look of the important role of the PKP2 protein. Heart muscles, known as cardiomyocytes, must be connected to one another to remove and careful synchrony with every beat. The space where cardiomyocytes are linked is the intercalated discs made of different protein structures.

Among the protein structure that work in the discs are gap junctions, which provide pathways for electrical signaling and the desmosome, a collection of interdependent proteins that together provide the structural integrity by providing the Velcro holding cardiomyocytes together. In addition to its mechanical role, the desmosome supports electrical firing. Now PKP2 is a critical protein in the desmosome and serves as a linchpin for structural and electrical stability to coordinate heartbeats.

This background helps set up what we are trying to do in our TN-401 program on Slide 8. PKP2, as we described, is a critical protein in the desmosomes and the loss of the PKP2 protein as occurs in patients with PKP2 gene mutations results in profound disruption to the heart. TN-401 gene therapy is intended to address this underlying genetic problem. TN-401 delivers a full-length functional human PKP2 gene using a well-validated AAV9 capsid and a cardiac-specific promoter. Once delivered to cardiomyocytes, TN-401 produces PKP2 protein to restore missing protein that is caused by the mutation.

Importantly, the protein produced is indistinguishable from the wild-type protein that is already there. In our preclinical studies that have been published, TN-401 reversed electrophysiological problems such as PVCs and NSVTs. TN-401 halted the progression of adverse remodeling and heart failure and extended survival in the animal model. The goal for TN-401 is to achieve a similar treatment effect in humans. And based on the data we will present today, we are off to a good start.

With that, I'd like to ask Dr. Whit Tingley, our Chief Medical Officer, to tell us about the RIDGE-1 clinical trial and the first patients to receive TN-401 and the early and exciting data we've seen thus far. Whit?

Thank you, Faraz, and good evening, everyone, on the line. Our RIDGE-1 Phase Ib trial is designed to characterize the safety of TN-401 to identify a dose for future studies and to assess pharmacodynamic measures of efficacy. We have completed enrollment of both cohorts and look forward to reviving the emergency data at the DSMB and potentially opening a second expansion cohort. The preliminary data that we will review today focuses on safety, biopsy and clinical results from Cohort 1 at the 3e13 vector genome per kilogram dose.

Slide 11 shows the baseline characteristics of the 3 participants in Cohort 1. In the shaded column on the left, we've included data for the average PKP2 positive ARVC patient based on the participants in the RIDGE natural history study that Faraz just described. The 3 participants in Cohort 1 have high-risk features typical of PKP2-associated ARVC. In particular, all 3 have undergone ventricular tachycardia ablation procedures and implantation of cardiac defibrillators to prevent sudden cardiac arrest. Despite these procedures plus standard of care medications, they remain electrically unstable manifested by high PBC counts with persistent risk of life-threatening arrhythmias. Each of these 3 participants enrolled in Cohort 1 enrolled after participating in the RIDGE natural history study.

Slide 12 provides their relevant past medical histories. Among all 3, we see commonalities of their disease that appear to be in line with this genotype. Patient 1, diagnosed about 15 years ago, has struggled with recurrent serious ventricular arrhythmias over the last 2 years, requiring multiple ICD-mediated therapies, both antitachycardia pacing and electrical shock. Patient 2, diagnosed at the young age of 16 has been living with PKP2-associated ARVC for 20 years and required an ICD at age 20. In spite of a prior ventricular ablation and multiple antiarrhythmic agents, he experienced a cluster of ICD shocks and antitachycardia pacing.

Patient 3 also had a history of VT ablation and persistently high PVC counts. Elevated PVC counts are associated with greater risk of life-threatening ventricular arrhythmia. The medical history of these 3 patients is generally consistent with our findings from the RIDGE natural history study overall. Standard of care medications and procedures are not sufficient to control this disease. As a reminder, the primary purpose of the RIDGE-1 clinical trial is to establish the safety and tolerability of TN-401 gene therapy.

At Tenaya, we have taken a comprehensive approach to safety summarized on Slide 13. We know what to focus on from our prior experience, and we incorporate new learnings from the field. We are very thankful for the robust collaborations between sponsors, all working to optimize safety protocols for all of our patients. Safety is multifactorial, including selection of a proper capsid, design of the cassette, close attention to immunosuppression, selection of dose and safety monitoring.

Capsid selection. AAV9 has a large safety track record through its commercial use for spinal muscular atrophy and is also the best validated for cardiac gene therapy at low doses in the 3e13 vector genome per kilogram range.

Immunosuppression. We use common prophylactic immunosuppressive agents, prednisone and sirolimus, which has served us well across both of our gene therapies, TN-201 and TN-401. The timing of immunosuppression initiation and tapering regimen matter, and we have been able to refine these to reduce the total dose of prednisone as we shared last month at the American Heart Association. We have never needed to use a complement inhibitor.

Dose. We are encouraged by the signs of efficacy we are seeing in both programs at a doses of 3e13 vector genomes per kilogram and do not need to escalate into the E14 dose range where safety can be most problematic. And finally, monitoring. frequent monitoring of safety laboratories is the key to safely managing the immune system's response to AAV in the days to weeks after infusion.

Slide 14. For the data readout today, we are focusing on Cohort 1. These patients have had 20 to 40 weeks of follow-up. We are very encouraged by the positive safety profile emerging for TN-401. It has been well tolerated to date. For Cohort 1, the majority of related adverse events have been mild, asymptomatic and manageable. Transient mild elevations of transaminases have been easily managed. One mild grade 1 out of 5 troponin elevation is classified as an SAE only because it was monitored in the hospital. It resolved spontaneously without treatment and had no sequelae.

Importantly, there has been no evidence of cardiac inflammation by imaging and cardiac biopsy and no evidence of proarrhythmic effects. There have also been no clinical TMA events and complement inhibitors have not been used. All patients in Cohort 1 have tapered off immunosuppressives and remain on study. Cohort 2 patients dosed more recently are at various stages of the taper now.

I will now hand over to Dr. Kathy Ivey to go over the encouraging biopsy results from Cohort 1.

Thank you, Whit. I'm glad to be here today to share the data we've obtained from each of these precious biopsies.

Turning to Slide 16. In RIDGE -1, biopsies are taken at 3 junctures. These are pre-dose or baseline, week 8 and week 52. Using a catheter, a small snip of tissue of about the size of a peppercorn is taken from the cardiac spectrum. 6 to 8 of these tissue samples are collected in the cath lab and receive an initial visual infection for quality and then each of these precious tissue samples is preserved and earmarked for specific quantitative analysis of DNA, RNA or protein.

The measurements collected during these biopsy sample analysis allow us to affirm that our gene therapy is reaching the heart, entering the cardiomyocytes and producing messenger RNA, which ultimately provides instructions needed for the cells to produce more PKP2 protein.

Results on Slide 17 provide evidence that TN-401 DNA is consistently reaching cardiomyocytes and being robustly transcribed into PKP2 mRNA. The bar chart on the left side shows the effective transduction of TN-401, which is achieving robust vector copy numbers per host genome of 3.4 and 5 vector copies per cell for patients 1 and 2, respectively.

On the right-hand side of the slide, we see clear evidence of RNA expression, which is measured as transgene copies per microgram of RNA. As a reminder, the PCR assay used here detects only mRNA produced by TN-401 with high sensitivity and specificity. Preclinically, the TN-401 RNA levels continued to increase over the first year, and we look forward to results from future biopsies of these patients.

On Slide 18, we can see protein levels from biopsies taken pre-dose and at week 8. Since PKP2 protein from TN-401 is identical to the patient's endogenous PKP2 protein, total levels of PKP2 are reported. Following the TN-401 treatment, PKP2 protein in the heart increased by 11% and 9% in patients 1 and 2. All patients' baseline PKP2 protein levels were below normal, consistent with PKP2 haploinsufficiency. As with mRNA, we would expect protein levels to increase somewhat over time based on preclinical and clinical experience, and we are very pleased by the magnitude of increase we are seeing at this early time point.

Turning to Slide 19. We note that patient 3's protein change is within the noise of the assay based on the extent of TN-401 mRNA expression we detected in this patient at 8 weeks. We believe this protein result is simply attributable to the inherent variability between samples, and we look forward to the opportunity to analyze future biopsies from this individual.

On Slide 20, we outlined the challenges of accurately measuring and comparing PKP2 protein levels in patient biopsies and why our carefully developed method provides a reliable and consistently quantifiable result. As a result of fibro fatty replacement associated with disease, ARVC cardiac tissue is highly heterogeneous with variable cardiomyocyte content in different samples. Since PKP2 is expressed primarily in cardiomyocytes, overall PKP2 levels in individual biopsies will be inherently variable based on cardiomyocyte composition in any given biopsy.

The image on the left shows a section of cardiac tissues from an ARVC donor heart with 2 encircled areas that could each represent a 1- to 2-millimeter biopsy. The area on the left in the dark blue circle contains a higher proportion of cardiomyocytes than the area on the right in the red circle, which contains more fibrofatty replacement. A key step built into our protein analysis accounts for this difference in composition by normalizing PKP2 levels to levels of the cardiomyocyte restricted protein myosin heavy chain or MYH.

The graphs on the right show PKP2 levels measured from the same 5 normal donor hearts by using 3 different methods: Liquid Chromatography-Mass Spec or LC-MS with normalization to MYH or Western blot with a standard curve to calculate absolute PKP2 levels or normalized to the ubiquitously expressed protein GAPDH. Without normalization to the myocyte-specific protein, Western results show up to sevenfold difference between these 5 normal donor hearts.

In comparison, LC-MS normalized to MYH results in a twofold difference in PKP2 protein between these same 5 hearts. The variability that occurs when cardiomyocyte composition is not taken into account may be further intensified in samples from disease hearts due to their higher degree of heterogeneity. A KOL webinar we conducted in August 2025 with Dr. Mike Previs, an expert in cardiac protein quantification methods, provides a more fulsome explanation of our methodology and its merits and is available on our website.

On Slide 21, we have representative images of the changes we've observed in PKP2 protein levels following gene therapy treatment. Using multiplex immunofluorescence, we can visualize not only PKP2 protein, but also N-Cadherin and the gap junction protein Connexin-43, co-localized at intercolated disc. We know that in the setting of PKP2 haploinsufficiency, such as this patient's pre-dose biopsy, not only are PKP2 protein levels decreased, but as a result, desmosomes structures are degraded and there's a decrease in the levels of other intercalated disc proteins.

Patient 1's 8-week biopsy shows both an increase in PKP2 protein compared to baseline as well as more structured intercolated disc with a higher degree of Connexin-43 and N-Cadherin colocalization. Together, these data provide visual confirmation of what we are observing by LC-MS.

I'd like to invite Whit back to tell us about observed clinical changes at this point in the trial. Whit?

Thank you, Kathy. While today's readout was always intended as an early look to focus on safety and biopsy results, we are pleased to be able to share promising clinical data on arrhythmias as well. As mentioned in PKP2-associated ARVC, electrical instability is the hallmark of disease and sudden cardiac arrest due to ventricular arrhythmia is the most feared consequence.

Across the top of Slide 23, we show the continuum of ventricular arrhythmias based on frequency and severity. The most severe arrhythmic event, ventricular fibrillation and sudden cardiac arrests, are thankfully rare compared to other ventricular arrhythmias. At the other end, there are premature ventricular contraction, single abnormal beats and nonsustained ventricular tachycardia, runs of fast arrhythmias lasting up to 30 seconds. These can be symptomatic, they cause significant anxiety and they're frequent, hundreds to thousands of times per day in the case of premature ventricular contraction.

These are valuable indicators of electrical stability that can be monitored in real time and in our trial. PVCs and nonsustained V-tachs are also direct measures of disease severity and risk of life-threatening arrhythmias. High counts are associated with high risk. PVCs and NSVTs can directly trigger the more severe ventricular arrhythmias. The values, the numbers of PVCs and the presence of nonsustained V-tachs are used to calculate risk in ARVC patients and make decisions about implanting cardiac defibrillators. The goal of TN-401 is to stabilize the PVCs, reduce NSVT and prevent life-threatening ventricular arrhythmias.

Slide 24 shows initial PVC data from Cohort 1. Clinic meaningful reductions in PVCs were observed in the first 2 patients for whom we have the longest follow-up beyond 6 months, specifically reductions of 46% and 89% at their most recent visits. Patient 3 remains essentially unchanged at this early time point. Given the relatively early stage of this trial, we are excited by the emerging evidence of TN-401's potential to impact disease, promote electrical stability and reduce this critical risk factor for life-threatening ventricular arrhythmias.

Slide 25 shows nonsustained attack rates for Cohort 1. Patient 2 had a very high burden of NSVT at baseline, 78 per day. Importantly, we measure arrhythmias over the course of a full week and 78 was the average daily number. So this patient was experiencing a very large number of NSVT. It is great to see that fall to 0 at week 32. Patients 1 and 3 had lower burdens of NSVT at baseline, so we would not expect to see a large signal. Other measures of clinical response, including QRS duration, T-wave inversions, heart function and New York Heart Association class were in the normal range or remained stable.

In all, we are thrilled by the data emerging from the 3e13 dose of TN-401. To date, the safety profile looks promising and biopsy data has been robust, as Kathy described. Most importantly, the clinical data show meaningful evidence of reduced arrhythmia burden and improved electrical stability, which are expected to substantially reduce the risk of sudden cardiac arrest.

We are grateful to the trial participants and their families, to our investigators and the clinical site teams and to our own Tenaya team who have all been working tirelessly to advance these gene therapies for patients with severe genetic cardiomyopathy who need better options. I'd also like to recognize the important support provided by the California Institute of Regenerative Medicine, which has provided financial support for the TN-401 trial.

Faraz, your closing thoughts?

Thank you, Whit. Sorry, I was on mute. Thank you for that important update. Now we're aware that we're not the only company that is operating in this space and data has been presented by other gene therapy programs earlier this year.

To place the results that we've just shared with you into context, we believe that across those measures where data can be compared, such as safety, DNA transduction, mRNA expression and clinical measures of electrical stability such as PVCs and NSVTs that Whit just shared, our results look quite favorable as compared to our peers working on the other gene therapy programs. That is even more so the case, if you recall that we are operating at doses of only 3e13 vector genome per kilogram in this first dose cohort, which is less than half the dose of a peer program. And also important in that these data are at least are at less than 1 year of follow-up for all patients with the opportunity to improve as more patients are followed up longer.

We will now close with Slide 27 that captures our progress and our future milestones. It has truly been a remarkable year of execution and momentum for Tenaya. Approximately this time last year, we were presenting our very first look at safety and biopsy data for TN-201. And just last month, we provided an exciting update for that program at the Annual Meeting of the American Heart Association, showing early but significant and clinically meaningful improvements for all 3 patients in the first dose cohort. The data was also concurrently published in circulation research.

Today, with the presentation of these results for the TN-401 program, we now have shared evidence of disease modification in 2 programs and with internally consistent performance across multiple clinically significant parameters. This is the promise of genetic medicines such as TN-201 and TN-401. And we hope you'll agree that the data we shared for each of our gene therapy programs in the last month have been compelling. We're optimistic that they will continue to get even stronger over time.

Executing on aggressive milestones each year is in Tenaya's DNA. And as we end the year of 2025, this year is no exception. With the presentation of TN-401 Cohort 1 data, we will have accomplished everything we had set out to do this year and then some, including dosing patients and presenting data from our natural history studies and our clinical studies. We are looking forward to a similarly productive 2026 as we drive each of these programs forward. We plan to share new meaningful data for TN-201 and TN-401 at key junctures throughout the year, with the goal of engaging with regulators in the pursuit of alignment on endpoints and trial design for late-stage and potentially pivotal studies.

Thank you for joining us on the call, for your engagement and for your support.

Ladies and gentlemen, thank you for standing by. My name is Krista, and I'll be your conference operator today. At this time, I would like to welcome you to the Tenaya Therapeutics Interim Clinical Data for TN-201 Conference Call. [Operator Instructions]

I would now like to turn the conference over to Michelle Corral, Vice President of Corporate Communications and Investor Relations. Michelle, please go ahead.

Thank you, Krista, and good morning, everyone. As introduced, I'm Michelle Corral and your point of contact should you have any follow-up questions after the call or be interested in speaking further with the team.

It's been an eventful few days, and we are looking forward to reviewing the interim data from our MyPEAK-1 Phase Ib/IIa clinical trial of TN-201 for MYBPC3-associated HCM. These data were presented this weekend at the American Heart Association's scientific sessions during a late-breaker session devoted to the topic of advancements in HCM care.

Joining us on today's call are Faraz Ali, Tenaya's Chief Executive Officer; and Dr. Whit Tingley, Chief Medical Officer. While the data we are disclosing will be described in full verbally, please note that during the course of today's call, we will be making references to slides. A PDF file of these slides is available on the Tenaya website in the IR section under Events & Presentations.

Speaking up on Slide 2, you'll see a reminder, the information discussed during this call will include forward-looking statements, which represent the company's views as of today, November 11 -- November 10, 2025. These statements involve certain assumptions and we caution investors not to place undue reliance on this information.

Please refer to today's press release as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements.

And with that introduction complete, let me turn the call over to Faraz Ali for opening remarks. Faraz?

Thank you, Michelle, and thank you to everyone for joining us today. Tenaya has made significant progress over the last year across our 2 gene therapy programs, TN-201 and TN-401 and we are pleased to be sharing the first of 2 meaningful data readouts with you today.

After some brief stage-setting remarks and a regulatory update, Whit will be walking us through the status of the TN-201 gene therapy program for MYBPC3-associated hypertrophic cardiomyopathy and today's main event. A recap of the data presented this past weekend, the discussion of why we are excited about the continued strong emerging data package from the Phase Ib/IIa clinical trial.

On Slide 4, on Saturday, at the American Heart Association's 2025 Scientific Session, Dr. Milind Desai, a renowned cardiologist, Director of the HCM Center at the Cleveland Clinic and an investigator on the trial, presented interim data from the MyPEAK-1 clinical trial of TN-201 gene therapy.

This was a late-breaker presentation on the main stage at AHA during the session dedicated to advances in hypertrophic cardiomyopathy care and also in genetic medicine took a commended spotlight. Simultaneous with Dr. Desai's presentation was the publication of these promising data in cardiovascular research, which you can see on Slide 4.

Links to both the slides from AHA, which we are presenting to you today and the publication are also posted to the Tenaya website. Today's presentation will also include a few extra slides of data and content that we believe are important, but that could not quite fit to the 10 minutes available to Dr. Desai at the AHA presentation.

Moving on to Slide 5. The data presented from MyPEAK-1 included longer-term follow-up from Cohort 1 patients and the first look at results from Cohort 2. For those following along with the presentation accompanying this call on Slide 5, we're jumping right into the results at a high level.

First, all patients on study really have objectively severe disease and significant [indiscernible] levels that we will be putting into perspective over the course of this presentation. The unmet need is high.

Second, TN-201 has been well tolerated at both the 3E13 vector genome per kilogram and 6E13 vector genome per kilogram doses. Further, through our experience in dosing patients, we have optimized our prophylactic immunosuppressive regimens and monitoring such that we have reduced steroid use without increasing AEs or sacrificing safety.

Importantly, from the biopsies, MYBPC3 protein levels increased in all patients, including, we can say confidently exactly with the benefit of baseline biopsies. And they did so in a dose-responsive manner in fact, with twice -- 2x higher transduction and expression observed in the first evaluable Cohort 2 patients.

And importantly, the positive indicators of TN-201's activity from the biopsy that we reported earlier this year are deepening over time and we're seeing multiple measures of disease moving towards normalization, including circulating biomarkers and hypertrophy and measures of burden of disease on daily living.

We'll put the changes in hypertrophy findings into broader context towards the end of this presentation since it really defines this condition. We are very encouraged by the emerging safety profile and biopsy results that we can share with you today. And then on safety and biopsy, we're pleased by the early but meaningful signs of clinical activity observed.

Our next steps are to continue to follow the maturation of clinical data in these patients and to resume dosing once we have implemented certain changes to our protocol requested by the FDA.

With that, we are transitioning -- I'm being told that my audio is a little bit choppy. I will -- not sure why. I will try to make a modest adjustment here if that improves things and my team will tell me if it does.

On Slide 6, before we go deeper into these data, I'd like to briefly address a surprising but ultimately benign action taken by our reviewers at the FDA. In the course of proactive outreach to regulators to discuss data obtained to date, the FDA made a request for certain protocol amendments in order to minimize potential site-to-site variability.

Most of these changes are intended to standardize patient monitoring and individualized immune suppression that we have successfully put into practice. During this time, while we're making those protocol changes, the enrollment in MyPEAK-1 is on clinical hold.

We have submitted a revised -- we have already submitted a revised protocol to the agency in respect to their request. We agree with the recommended changes, which were consistent with our plans anyway as we look ahead to TN-201's future development.#

Importantly, there have been no recent safety events of concern related to TN-201. Prior to the FDA communication, the MyPEAK-1's independent DSMB endorsed growing patients in expansion cohorts at either dose level and continue the trial with no changes.

We are working very collaboratively with the agency to resolve this matter swiftly and currently do not anticipate this action will have any impact to our overall data development milestones and near-term data milestones and development time lines.

On Slide 7, given the lack of any recent treatment-related adverse events, the whole action was quite unexpected. But given the backdrop of certain safety events reported in the field, the FDA's caution is understandable.

As we've shared with many of you since the summer when other gene therapy sponsors reported deaths or other severe events that appear to be associated with their respective approaches to immune suppression and the underlying disease, we do not see any direct read-throughs from those situations to our program.

We believe gene therapy safety is multifactorial and we have taken a very comprehensive approach to safety summarized on Slide 7 that takes into consideration factors like capsid selection, cassette design, dose, immune suppression agents, all against the backdrop of the condition being treated.

Each of our trials include its own panel of independent experts in cardiology, hepatology, immunology and gene therapy. The DSMB reviews the safety data for each patient following dosing and looks per protocol at results from each cohort.

FDA is also kept informed periodically of any and all adverse events in our study, whether treatment-related or unrelated. As we prepared for IND, we even surveyed other sponsors to learn from their experiences and designed our immunosuppression and monitoring protocol accordingly.

Both -- as a reminder, for both TN-201 and TN-401, we utilized prophylactic sirolimus and prednisone that are administered in the weeks ahead of dosing and then continued thereafter and then tapered.

I thought to have the option of a C5 complement inhibitor that can be used reactively on demand if needed. But to date, we have not had a situation where that has been warranted. We keep patients in hospitals for close monitoring of any signs of unusual activity.

And as we've run along in the clinic, we've increased the frequency of lab assessments and patient monitoring to enable swift interventions and to inform individualized tapering. We have learned a lot so far and our learnings from patient monitoring and tapering are what we've been asked to protocolize by the agency, such that should we expand to new sites in the future, variabilities -- we minimize the variabilities and the potential for variabilities in how immunosuppression is administered, monitored and tapered from site to site.

With that under our belt, I'd like to ask Dr. Whit Tingley to tell us about the TN-201 development program and specifically the data presented this weekend from the MyPEAK-1 clinical trial at AHA.

Thank you, Faraz, and good morning to everyone on the line. Thank you for joining us. Those of you who have been following Tenaya will likely recognize Slide 9. But as a reminder, MYBPC3-associated HCM is the most common genetic form of hypertrophic cardiomyopathy associated with 57% of familial HCM cases and estimated to affect 120,000 adults, adolescents and children in the U.S. alone.

As you'll hear more today, this is a severe and progressive condition in which the heart walls become significantly thickened, impinging on the capacity of the ventricle to expand until it is too stiff to pump enough blood to meet the body's needs. The disease also causes fibrosis and leads to abnormal heart rhythms, heart failure, sudden cardiac arrest and in the worst cases, death.

In spite of innovations in the field, there is significant unmet need, particularly among patients with the nonobstructive form of hypertrophic cardiomyopathy. Nonobstructive disease accounts for 70% of all MYBPC3 cases. There are no approved therapies that address the underlying genetic cause of this condition.

Our lead gene therapy program, TN-201, is the first treatment being developed to address genetic mutations that cause this disease.

Slide 10 offers an illustration of its intended mechanism. Causal variants in the MYBPC3 gene failed to produce protein, resulting in low levels. MyBP-C protein is essential for regulating heart contraction.

It determines the force and speed of each contraction and relaxation based on the body's current needs, a little at rest, a lot during exertion. It does this by coordinating the thick and thin filaments of the sarcomeres in the muscle tissue. When there is not enough MyBP-C protein, sarcomeres produce too much force overall, ultimately leading to cardiomyopathy.

TN-201 directly addresses this phenomenon by delivering a full-length healthy and functioning copy of the gene to heart cells, which then produce MyBP-C protein. The overall vision and design of TN-201 is to increase MyBP-C protein levels, fix the cause of disease, halt progression and potentially reverse symptoms and do all this with a single dose of onetime IV treatment.

A brief overview of the MyPEAK-1 Phase Ib/II study is provided on Slide 11. This is multicenter open-label dose escalation trial designed to assess the safety and tolerability of TN-201. It is also designed to identify the optimal dose.

Finally, it collects numerous data points for an early look at TN-201's activity, though the study is not powered for efficacy. I'm happy to say we've completed the dosing of both cohorts 1 and 2.

Over the summer, the study's Independent Data Safety Monitoring Board reviewed all available safety and activity data across both of these cohorts and recommend the trial proceed per protocol with dosing of additional patients at either dose level in the expansion part of the protocol.

There have been no meaningful safety events since that DSMB review in the summer.

Now we'll turn to the new data presented Saturday at the American Heart Association meeting underway here in New Orleans. Slide 13 shows the baseline characteristics for the 6 patients from cohorts 1 and 2, consisting of 5 women and 1 man between the ages of 27 and 63.

All have objectively severe disease. All 6 have nonobstructive disease and are at high risk requiring implantation of a cardiac defibrillator device to prevent sudden death. 4 of the 6 have previously undergone myectomy and open heart surgery to directly treat extra heart muscle at the outflow tract. But despite this, they remain symptomatic. All were experienced symptoms of heart failure, interfering with daily living and meeting New York Heart Association Class II and III. Left ventricular mass index, a key measure of hypertrophy is higher in these study participants than in most HCM patients.

The data in this presentation includes over 1 year of follow-up for all Cohort 1 patients. Cohort 2, on the other hand, has a shorter follow-up of 26 weeks or less.

Unfortunately, patient 5 has decided to withdraw from the study for unclear reasons and stop participating in assessments at the study center. However, she did successfully complete the immunosuppression regimen and local safety laboratories have been very reassuring.

All other patients remain on study and compliant with the protocol. Patient 4's early post-dose biopsy was postponed for unrelated reasons, though it is not included in this presentation. Subsequent to this data cut, a seventh patient has been enrolled at the 6E13 vg per kilogram expansion cohort.

MyPEAK-1's primary objective is to establish the safety and tolerability of TN-201 at the 2 doses being tested.

On Slide 15, we detail the events observed on study across both cohorts. TN-201 was generally well tolerated at both the 3E13 and 6E13 doses. No dose-limiting toxicities were observed.

Nausea was the most common adverse event reported on study of the treatment-related adverse events, reversible and asymptomatic liver enzyme elevations, grades 1 through 3 were the most frequent, occurring in 4 patients.

One of these, a Grade 2 transamination elevation was classified as a serious adverse event because extra steroids were administered and monitored in the hospital setting for pragmatic reasons. The patient's enzyme elevation normalized rapidly following this treatment.

Within Cohort 2, 2 patients have experienced lab abnormalities of complement activation starting a week after dosing. One of these was deemed Grade 1, mild, but classified as an SAE because the protocol-defined hospitalization was extended for further monitoring.

All complement activation is resolved spontaneously without the need for any additional therapy or intervention. There were no signs of cardiotoxicities, including no declines in LV ejection fraction, no clinical myocarditis and no ventricular arrhythmias. All 6 patients have successfully tapered off immunosuppression.

Slide 16 summarizes our experience and progress optimizing the immunosuppressive regimen. The immunosuppression used in the first patient successfully controlled the immune response to TN-201. So we chose to make some changes in order to reduce the total amount of immunosuppression used.

Over the course of Cohort 1, we switched to starting sirolimus earlier, but at the same dose. We lowered the starting dose of prednisone and we increased the frequency of monitoring at the end of the taper.

These minor adjustments resulted in faster tapers and lower total cumulative doses of steroid. As a result, the total immunosuppression used in Cohort 2 was lower than Cohort 1, better tolerated with better control, all despite the doubling of the TN-201 dose.

Given the time constraints of the AHA presentation, TN-201 transduction of the heart data was not presented, but we have included it here for you today.

Slide 17 shows robust transduction of the heart with TN-201 DNA levels well above the threshold set by our preclinical models. The mean vector copy number is 2.1 early post-dose in Cohort 1 and this increased in a dose-dependent manner in the first patient at the 6E13 vg per kilogram dose as expected.

As was shared at ACC in March, mRNA levels are clearly detectable early post-dose and increase over the course of the year. I note that our assays used for both DNA and RNA are specific to TN-201.

They do not detect the patient's original DNA or RNA. And so the assays are 0 at baseline and everything we show here is derived from the gene therapy. The therapeutic protein, on the other hand, is indistinguishable from endogenous MYBPC3.

On Slide 18, we have the results of MyBP-C protein analysis. Protein levels increased above baseline in all patients over time and the higher dose of 6E13 resulted in the largest dose response, a 14% increase.

In Cohort 1, patient 3 is the first to have pre- and post-dose protein levels and the levels increased by 5% at 1 year. In Cohort 2, patient 6 MyBP-C level increased 14% from baseline within just 12 weeks, so more protein produced more quickly.

Patient 6 is the only Cohort 2 patient with post-dose protein available, patient 4's biopsy was delayed, as I mentioned. We look forward to seeing additional protein data from Cohort 2 in the near future and watching for the impact of these protein level changes across all patients.

Turning next to measures of TN-201 activity starting on Slide 19. We see some positive and promising early results on circulating biomarkers. All Cohort 1 patients had abnormal cardiac troponin levels at baseline.

These troponins improved by as much as 74% to normal or near normal levels by the most recent visits. As a reminder, troponin is a plasma marker of ongoing cardiac injury. Among HCM patients, elevated troponins predict worse outcomes such as ventricular arrhythmias, sudden cardiac death and progression to end-stage heart failure.

NT-proBNP, on the other hand, is a marker of heart muscle strain and it can be sensitive to steroids. So it does increase in some patients at early time points in the trial.

We are happy to see NT-proBNP levels improved at the latest time points, the most recent visits in most patients with at least 26 weeks of follow-up. AHA measurements of hypertrophy improved or remained stable in patients with at least 26 weeks of follow-up.

Most notably, as shown on Slide 20, the reductions in posterior wall thickness that were observed when we reported data at ACC have further improved with time and with more patients. All 3 Cohort 1 patients have seen meaningful reductions in posterior wall thickness, ranging from 21% to 39% at week 52.

Left ventricular posterior wall thickness is an established risk factor for reduced long-term survival after septal myectomy in HCM patients and these patients all fit that description.

We are all encouraged by the changes we're seeing in LV mass index with reductions in overall mass ranging from 12% to 22% for the Cohort 1 patients or 2 of the Cohort 1 patients at week 52.

New York Heart Association class improvements were measured briefly in the AHA presentation. On Slide 21, we share more data showing the consistent improvements over time. New York Heart Association is a well-established classification of the impact of heart failure on symptoms affecting activities of daily living.

At week 26 post-dose, NYHA had approved and improved in all patients. And by 1 year, all patients were Class I, the best class, indicating no limitations from symptoms. The first 2 Cohort 1 patients now out at 78 weeks, the change in New York Heart Association class has endured.

In summary, on Slide 22, TN-201 has been well tolerated at both doses. Our immunosuppressive regimen is working well and it is now working with lower overall amounts.

TN-201 is working as intended, delivering DNA to the heart and expressing mRNA and protein. Protein levels increased dramatically at the 6E13 dose in just 12 weeks.

We look forward to seeing Cohort 2 data mature with time to learn whether the higher protein levels accelerate and increase the response to TN-201. We anticipate sharing this data as early as the first half of next year.

Perhaps most exciting among those patients with at least 26 weeks of follow-up, multiple measures of disease are moving together toward normal at the 3E13 dose level. We see responses deepening over time, consistent with other cardiac gene therapies for other diseases.

We believe the improvements in troponin posterior wall thickness in New York Heart Association class may be clinically meaningful as these are all known risk factors for serious cardiovascular complications and reduced survival.

On Slide 23, before handing the line back to Faraz, I'd like to acknowledge all the contributors supporting this trial. First and foremost, the people with HCM who have participated in MyPEAK-1 and their families.

Their contributions and efforts are fundamental to our shared mission of creating a gene therapy to stop this genetic disease. As part of the session at AHA, the very first patient in the world to receive gene therapy treatment for MYBPC3-associated HCM shared her remarkable story of resilience in the face of severe disease, which took her mother, unfortunately, at a young age. In my book, she is a hero.

In addition, our mission would not be possible without the leadership of our investigators, the dedication of the site staff, oversight and guidance from our expert DSMB members and careful data analysis from our partners at the Previs lab at the University of Vermont, the Brigham and Women's Cardiovascular Imaging Core lab and of course, our tenacious Tenaya team. Faraz. Faraz?

Thank you, Whit, and thank you for your leadership as well and your contributions to bringing this all together, both internally and externally. I will now make some comments over a few slides to try to put our program and our data into strategic and kind of clinical perspective.

I'm going to now refer to Slide 25, where we're putting the disease epidemiology into perspective. This slide provides a reminder that the indications that we're pursuing, including MYBPC3-associated HCM that we're discussing today are important in part because they represent significantly larger indications versus those being pursued in other gene therapy clinical trials for genetic diseases, whether approved or in later stages of clinical development.

The epidemiology of MYBPC3-associated HCM has been very well established through independent studies. And all of that work leads us to believe that there are an estimated more than 120,000 patients with this mutation in the USA alone. This is at least one reason why we think there is strategic and overall interest in this program and why the data we are presenting today are important.

On Slide 26, we're now trying to put the disease severity into perspective. And we're doing so here by comparing the average LVMI, Left Ventricular Mass Index and the range of LVMI for the first 3 patients in Cohort 1 that have been dosed in our study and we're comparing that to other studies.

Those peer studies include contemporaneous cardiac gene therapy studies or cardiac myosin inhibitor studies in the obstructive or nonobstructive HCM population. And what these data help illustrate is that at least as measured by LVMI, Cohort 1 patients enrolled in the MyPEAK-1 study are significantly more affected and severely affected than those that have been studied by our peers and other studies.

In fact, comparing the results of hypertrophy using LV mass or LV posterior wall thickness would lead to similar comparative results.

As reminded us early in this presentation, these patients have continued to progress despite access to standard of care medications and despite successful myectomies that debulks the heart tissue and provided transient but important relief.

We think this analysis speaks to the relentlessly progressive nature of this genetic condition that we believe can only be fully addressed with a genetic intervention like TN-201 that is trying to address the underlying genetic cause of the disease in these patients.

Finally, on Slide 26, we're trying to put the early performance of 201 into perspective as measured by both the relative and absolute decrease in both LVMI and LV posterior wall thickness as compared to the same peers referred to on the prior slide.

On the left portion of the Slide 26, we're showing the improvements in LVMI shared at the AHA. For 2 of 3 patients in Cohort 1, the relative reductions in LVMI are in line with cardiac gene therapy peers and the average absolute reduction across all 3 patients in Cohort 1 is in line or even higher than what has been observed in studies of the cardiac myosin inhibitors, such as mavacamten or aficamten.

On the right portion of the slide, we're similarly showing that the improvements in LV posterior wall thickness, the relative reductions in hypertrophy. The relative reductions in hypertrophy here are better than all peers and the absolute reductions are significantly higher than virtually all peer comparisons.

Importantly, the reductions we're seeing in left ventricular posterior wall thickness are associated with improved long-term survival in HCM patients post myectomy as all 3 patients are now well below the threshold for left ventricular posterior wall thickness associated with higher mortality in patients post myectomy.

To be clear, our intention of presenting these data is not to take away from the clinical significance of the data from our peers. Quite the opposite, the data from these peers represent product candidates that have either already been approved in the case of mavacamten or are in late stages of clinical development and product candidates that represent meaningful improvements in the lives of those patients.

It is precisely for that reason that we feel our data, while early and only in 3 patients with at least 1 year of follow-up, represent a true signal of something quite meaningful.

In summary, today, we have had the opportunity to present clinical data from the first 3 patients in dose Cohort 1 of the MyPEAK-1 study of TN-201 for MYBPC3-associated HCM.

Against the backdrop of the uniquely high disease severity described on the prior slide and the comparisons we're making against our peers on this slide, we believe that the changes we're seeing in measures of hypertrophy are truly compelling.

We are excited by the data being generated by TN-201 in adults with objectively severe nonobstructive HCM. At 1 year or greater, we're seeing robust and durable DNA transduction and mRNA expression as well as protein level changes that track to the TN-201 mRNA expression.

Clinically, there's evidence of multiple parameters moving towards normalization across different domains with biomarker changes, reduction in hypertrophy and improvements in the burden of heart failure symptoms.

And with that, we're going to transition to Q&A. And operator, we're ready to open the call to questions.

[Operator Instructions] And your first question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on the really strong data, and thank you for the comparative slides that you put together, very helpful. Team, I guess, given Cohort 2 showed remarkable protein expression, help us understand with really almost tripling of the protein, how we should conceptualize sort of what the clinical cardiac biomarkers and data points are potentially going to look like when you report out early next year, maybe -- and obviously, it's very clear from Cohort 1, the longer we go, the greater the treatment response becomes.

So just help us conceptualize what expectations should be for Cohort 2. And then the next one is based on your prepared remarks, it seems like the procedural paperwork submitted to the FDA is already in process.

I just want to make sure that these commentaries that were made with -- in regards to immunosuppression protocol for 201 and therefore, there's no need for them to review the protocol for 401. Just a clarification. And then the third one is how soon can you engage with the agency on pivotal design and come back?

Maybe -- thank you, Yasmeen, for 3 very good and needy questions that I'm sure many people have an interest in. Maybe, Whit, I'll ask you to first address the question about the FDA's action on TN-201 and any read-through to 401?

Yes, we have very productive discussions with the FDA on 201. They have not expressed any concerns about 401. We are partnering with them to basically formalize what we've been doing by interacting with sites directly, formalize that in the protocol in terms of just precise monitoring of these patients.

And this will benefit the 401 protocol as well. So we will voluntarily update that protocol as soon as we have finalized the 201 protocol with the FDA. But again, FDA has not expressed any concern about TN-401.

Yes. And Yas, to add to that, really, most of the things that were -- there was no new information on either 201 or on 401 and we -- many of the changes, as I mentioned in my opening comments, we are aligned with that because those are things that we were thinking about doing anyway.

You're always thinking about ways to tweak your protocol as you think ahead to future development, which we are in both programs. And so some of the changes that we had already intended to put in motion or already had put in motion, we'll certainly do that once we have got the final alignment and final review with the agency. And all of that has been going very swiftly and rapidly. So we don't anticipate any knock-on effects on TN-401 where patients continue to get dosed.

To your first question, which is how do the changes in protein, how might that show itself in clinical data in Cohort 2. We are very pleased with the high both transduction and expression from the first evaluable patient. And you're asking whether that might translate to different kind of clinical benefit.

And I think the short answer is time will tell. We don't want to project too soon whether we will see a greater magnitude effect or a faster kinetics of effect from the Cohort 2 data. Frankly, Yas, we're just thrilled with what we're seeing from Cohort 1.

So -- and I would also say that based on our experience and the experience of peers, it's sometimes hard to draw a straight line between dose, vector copy number, mRNA expression, protein and clinical benefit. There's so much patient-to-patient variability.

And so we're pleased with what we're seeing from Cohort 1. We're optimistic for what we're going to see from Cohort 2, but don't want to speculate too soon with too early a time point and not enough patients about what the trajectory, magnitude and kinetics of Cohort 2 data may look like. Is there anything you'd like to add to that, Whit?

I agree.

And then, Yas, to your third question, which is about future plans, I think we stand by our -- what we have been saying all throughout this year and is captured in our public statement that in 2026, we aspire to have both the quantity of clinical data as well as the quality of clinical data that may allow us to engage with the regulators on this program for either future late-stage development in adults and/or in pediatric, severely affected pediatric patients on whom we've presented data quite extensively about the burden of severity in the pediatric population.

We believe we're still on track for that. In fact, this data presentation at AHA is a wonderful marker of progress of where we are. We will have full cohort sets for those Cohort 2 next year.

And at that point, if we're based on the experience of our peers, we may be in a position to engage with the regulators about what the design of future studies may look like, the use of surrogate markers, et cetera, et cetera. Too early to speculate now.

We don't believe that the regulatory action taken has any impact on that for those forward-looking plans because the data from the patients already dosed is what we think will be most relevant. And of course, we're going to resume dosing once we've implemented changes.

Clearly, we're thinking ahead to the future, Yas, because it was our -- it was our own proactive reach out to the FDA with our current data set that resulted in this request for protocol changes on -- before we dose additional patients and we're aligned with that and we're doing that. Hopefully, that answers all 3 of your questions. Thank you. Great questions.

Your next question comes from the line of Mike Ulz with Morgan Stanley.

Maybe just a follow-up on the clinical hold and it sounds like you should be able to make some quick progress there, but any thoughts on when that hold could potentially be lifted? Is it weeks? Or is it months?

And then secondly, just prior to the hold, were you able to dose any patients in the expansion cohort at the higher dose? Just trying to get a sense of when you might get a couple more patients at that higher dose, which looks very promising.

That's a great question. First, Whit, do you want to address just the question about the dosing of that additional patient in the expansion cohort?

Yes. We have dosed 7 patients to date. So we completed the planned Cohort 2 and have expanded that by 1 patient before the hold and we do have patients in the queue waiting. And we are optimistic about resolving this with the FDA quickly.

We appreciate and share their mission to optimize for safety. And we acknowledge they have moved very quickly. We've had more than one back and forth round with them and exceeding their usual time lines. So I can't say when this will be finalized.

We have submitted a revised protocol that we believe addresses all of their requests and they are actively reviewing now. So we are cautiously optimistic that this will be resolved very soon.

Mike, with comments. It has been very productive, very collaborative and very swift rounds of discussion, I think, in part because we're aligned with their thinking and in part because there is a shared understanding that the things that we're doing, while individually small, collectively, they will just add up to more consistency in the conduct of our studies and we're quite aligned with doing that.

So there's really no kind of pushback between us and the FDA on the things that they're interested in learning more about and implementing. And so we are hopeful, but we've never put a date on it, Mike.

Your next question comes from the line of Joseph Pantginis with H.C. Wainwright.

This is Sara on for Joe. Also regarding the clinical hold, just curious whether any of the patients that were dosed under your current or what will be the old immunosuppressive monitoring regimen, will any of those need to be in terms of future analysis, will they be treated any differently, put into a separate subgroup from patients maybe added after these changes are made? Or how should we think about those differences looking forward?

Yes, I'll just say quickly, the short answer is no. Good question, but the short answer is no, I wouldn't have any reason to believe that would be the case. But I'll let Whit respond and then I'll probably add to that. Go ahead, Whit.

Yes, you said exactly -- well, that's a great question, but a very clear answer, no. These modifications are not major at all. We are not changing the immunosuppression regimen of prednisone or sirolimus nor are we changing the doses.

It has been a good discussion sharing with the FDA all the progress we've made with the adjustments, the minor adjustments that I described during the presentation part of the call. My sense is that they also find that very reassuring.

And the protocol amendment is more about making sure that stays consistent across all sites and it's formalized in the protocol. As I said, we talk with sites regularly and we've been managing this with them and it will be good to have it all explicitly spelled out in the protocol.

There are other minor tweaks, but this does not affect the population that we're enrolling and it certainly doesn't -- won't affect the interpretation of the results.

Yes. I think the only thing I'll add to what Whit just said is, once, just -- this is a new review team for us. So they're becoming familiar with the program for the first time.

We -- they respect that we know our product and our study very well. And then we respect that they are seeing things across sponsors that maybe they want to harmonize, right? Not only site-to-site variabilities left at the site level in our study, but maybe there are things that they're seeing across programs that they just like to tighten up based on the information that they have.

So I think there's a lot of mutual respect. We know our product and its profile and they know what is going on across studies. So I think there's a lot of mutual respect here.

The other thing -- so no changes are being made, as Whit described. However, I'd also like to point out that even in situations where changes have been made, which is not the case for us, that doesn't seem to have changed the ability of that data to be pooled for future pivotal studies.

And I'm just referring to our cardiac gene therapy peers in this regards that even changes in manufacturing platform, changes in immune suppression regimen, changes in dose, that has not gotten in the way of data being pooled for the purposes of pivotal studies and looking at the totality of the evidence, which is very much on course for rare disease drug development and particularly for gene therapy drug development. So we do not have any concerns in that regard.

Your next question comes from the line of Cory Jubinville with LifeSci Capital.

Congrats on the data update. Can you just speak to the differences that we're seeing in left ventricular mass index versus LV posterior wall thickness? I know typically, LVMI is seen as what could be an approvable endpoint in these types of cardiac indications.

Posterior wall thickness demonstrated these really profound improvements, but this wasn't the case for all patients in LVMI. Intuitively, I anticipate that these 2 endpoints would be pretty lockstep with one another.

I guess are there any factors in your view that would drive a robust improvement in posterior wall thickness, but an increase in LVMI? And I guess, in your view, is one measurement more objective or cleaner to measure for lack of a better term?

Whit?

Yes. It's all objective that the wall thickness is cleaner than LVMI, a great word, a great question also. So the wall thickness is a one-dimensional measurement. You just put a ruler onto the image.

LV mass index has to be calculated from several measurements that are multiplied. And so small errors in each one of those can multiply out. And two, it is more sensitive to the physiologic what we say is the volume status of the patient, whether they're dehydrated or have extra fluid volume, extra blood volume, that just changes the shape of the ventricle and it's that volume or size of the ventricle is part of the equation for LV mass index.

So with small numbers like we're talking about now, we are really very focused on the wall thickness as we're showing terrific improvements and consistent across patients with a consistent time course. And as we get more data with more patients, we expect the LV mass to follow.

Yes. That's a great question, Cory. And the only thing I'd add to that is it is actually quite remarkable when you look at the patient that has not yet had an overall reduction in LVMI is patient 1. And you look at that LVMI and it's at 203.

And if you were to plot out all HCM patients, you'd see what an outlier that number is. It's incredible. It's maybe one of the largest ever seen. And so this is a patient who spoke eloquently at AHA, her mother died before the age of 40, runs in her family, had a myectomy, felt better, still had symptoms and really just felt like she needed more than what she had from the medications and from the myectomy.

And we're super pleased that in a patient that really would be described as refractory and as Dr. Desai said at AHA headed towards potentially heart transplant, a single dose of TN-201 is producing the protein and we're seeing a dramatic reduction in at least the left ventricular posterior wall thickness at this time.

And who knows what will happen over time with this patient. This is -- with the other 2 patients who are also objectively severe, we see that consistency of both LVMI and LV posterior wall thickness. And we'll see more with time, including from dose Cohort 2.

So we're not overreading too much into one data point from one patient. Overall, it seems like directionally, many things are moving in the right directions for Cohort 1 patients, the circulating biomarkers, measures of hypertrophy, New York Heart class and it's still at a relatively early time point with a small number of patients. Too early to say whether we will always have consistency between LVPWT and LVMI or other measures of hypertrophy over time. It's a good question.

Your next question comes from the line of Sami Corwin with William Blair.

Congrats on the data. Given the FDA's clinical hold is based on the protocol uniformity, I was curious what the protocol is for using the complement inhibitor given the laboratory signs of complement activation were seen in Cohort 2.

And then on Slide 29, you suggest that you could have multiple pivotal studies, including one in pediatrics. So I guess I was just curious if you plan on treating a pediatric patient in the MyPEAK-1 study prior to those discussions with FDA.

Whit, maybe you take the first one first and I might talk about the second one.

Yes, absolutely. So to be clear, we have not had any cases of clinical TMA, any organ involvement. We can detect innate immune response as expected to TN-201 and that does include complement activation.

As Faraz was saying, the FDA can't say, but we suspect and hope that they're integrating information across multiple AAV programs to improve safety for all participants across all studies.

And part of the discussion is how to best monitor the complement activation and be ready to use a complement inhibitor if it were to be needed. Again, we are very aligned with their thoughts on this and happy to implement the minor changes that they have proposed.

Yes. It's a good question, Sami. And in the past, this is something that may not have even been caught in early studies of gene therapy, including high-dose gene therapy, as patients were being discharged before the time we now know that the lab values are increasing.

And we're fortunate that maybe there were not more cases of full-blown TMA and aHUS, but that had clinical [indiscernible], but that was not the case for us. And everybody, I think, is more consistently and I think that's where the FDA is trying to get to, that everybody more consistently monitors the same things, whether it's the specific points in the complement cascade, platelets, whatever, they just want to make sure that everybody, I believe, is kind of consistently looking at the same things and then consistently responding in the same ways, right?

And so that -- we're 100% aligned with that and we're glad to be implementing the changes. And we believe that the changes that they're suggesting are with data from other programs that suggest that there may be a emerging kind of best-in-class approach to doing this in a more consistent and safe way across programs.

And frankly, that's a gift to us now before we go into pivotal studies. We've seen some products in the case of Sarepta in the commercial domain and then having to make changes in their immunosuppression regimen by the addition of sirolimus, which we already have.

In the case of Rocket, they had the unfortunate situation of adding something during the pivotal study to manage complement. And so I think that we are being handed a gift here with the opportunity to implement changes that the FDA thinks are the best for these patients and doing it now before we are in those late-stage clinical developments and before we are rapidly dosing many patients maybe in expansion cohorts. So that's another perspective on all this. It's quite positive.

And then the other thing regarding pivotal studies, adults and children, I think too early to say, Sami, about whether we would first have to dose a patient in children before going into pivotal studies.

Just a reminder, our current study is only focused on adults. It would require a change to the current study in order to start dosing children. So we're not open to do that.

And frankly, the endpoints are quite different and quite unique in some of the severe pediatric populations. And so it may not be as simple as just changing our current study to go to those, for example, very, very severe homozygous infants that die within the first days, weeks and months of life.

And so one thing it is in the public domain that we have actually opened ourselves to compassionate use approaches. So families or patients around the world through their physicians can approach us about a compassionate use for those very, very severe, very rapidly progressive patients who frankly, cannot wait until we are in a pivotal study in children.

So that is in the public domain. It's on our website. And it is possible that we end up dosing a patient through a compassionate use pathway before we've aligned with the FDA on a pivotal study. But that is one indication of intent.

We do believe with these data that we have in the adult there's justification, there's equipoise between efficacy and safety to give a shot to very young children who would otherwise die within the first days, weeks and months of life unless they get a heart transplant, which is quite complicated for such young patients. So hopefully, that answers your question, Sami.

Yes, very helpful.

Your next question comes from the line of Mani Foroohar with Leerink Partners.

I guess one key one for me. Just looking further out, there's been a lot of questions around the specific state of the programs now. More broadly, when you think about regulatory path, we've seen from a couple of other companies in the space, a mix of protein and LVMI, the co-primary endpoint.

Would you expect that to be similar for you guys? Or would you expect a different approach in terms of endpoints, co-primary analysis as opposed to some other arrangement of the endpoints? Like how do you think about potential regulatory path and endpoint construction here?

I mean, we're pleased, Mani -- I'll say good question. We're pleased that both of our cardiac gene therapy peers for whom we have a lot of respect, Rocket and Lexeo and their respective programs, Danon and Friedreich's ataxia, that both under the new administration, under new leadership at the FDA, both reaffirmed the alignment with the FDA that their co-primary endpoints of any level of expression of protein, not with any quantifiable threshold, any level of expression of protein, along with an improvement in LVMI reductions of greater than 10% are sufficient for -- or could set them up for potential accelerated approval based on surrogate markers.

We're glad to see that reaffirmation. There have been some surprises in the space recently. And so it's nice to know that this was relatively recent.

And in the case of Rocket, it was reconfirmed after a very unfortunate safety event in their study that no dramatic changes were proposed to their study to the best of my knowledge from the public statements we've made.

So it seems like there's some consistency here, Mani. And what we certainly hope is that what's sauce for the goose will be sauce for the gander and that will be also true for us. But look, each program needs to make the case for their own study, right? And so we have pointed out that the levels of hypertrophy we're seeing in these patients is uniquely high.

And if you look at the comparative data with Rocket and Lexeo, you can see that we're glad to see that our peers have gotten that alignment with those endpoints. We also are seeing changes in hypertrophy and a pattern that maybe some of it is similar to theirs and some of it is unique to us, including those changes in posterior wall thickness, which does have a mortality benefit that is predicted based on the data of others.

So I think too early to declare exactly what our future pivotal designs will look like. Will it be LVMI? Will it be LVMI or any other measure of hypertrophy associated with long-term benefit? We're hopeful that we are going to, in 2026, have the quantity and quality of data, Mani, that will allow us to have that discussion with the FDA.

And so we can continue to come back to that guidance over and over again that this is a 2026 problem for us, not problem, but opportunity and nothing about the regulatory action changes that. Is there anything, Whit, that you'd like to add to that to those points or to make different points, including for the pediatric population?

No, I agree.

Mani, does that answer your question?

Yes, it does.

Your next question comes from the line of Geulah Livshits with Chardan.

Congrats on the data again. Just to follow up on some of the previous questions on the left ventricular posterior wall thickness. And you mentioned these patients declining below that threshold that's associated with mortality.

Can you maybe elaborate a little bit on that from your discussions with investigators or clinicians, expand on maybe the relative importance of that and the degree of risk reduction that you might see with incremental improvements there? And also, what about any other hypertrophy metrics that you're collecting?

I think in the past, you may have reported data on septum thickness and things like that. So any other metrics that we can look forward to in future updates?

Great. And Whit, do you want to take a first crack at that question?

Yes, absolutely. So yes, there is data specifically for patients who have undergone septal myectomy as our Cohort 1 patients have, showing that that posterior wall thickness is predictive of survival.

And so we're very encouraged to see the reduction in posterior wall thickness consistently across all these patients, which could correlate with survival benefit in the future. We're cautiously optimistic about that.

The other measurements of the septum, as you noticed, has stabilized in these patients. It is interesting seeing the magnitude of improvement in the posterior wall being numerically greater than in the septum in these patients at this point.

But as I just mentioned, all of these patients have had open heart surgery on that septum. So it's possible that leftover scarring and so forth means it will take longer for us to see large reductions in the septal wall thickness.

That is something we'll have to monitor with time. And as discussed at the beginning of this call, the higher protein expression we've seen so far in the second cohort, that could lead to faster improvements and potentially larger improvements, although we don't know. We're very happy with what we're seeing with the 3E13 dose and look forward to sharing more data from the higher dose in the first half of next year.

Yes. And Geulah, the only thing I'll add to that is the specific paper that we referenced there will point out that the threshold is 1.3 centimeters or 13 millimeters for posterior wall thickness, but above that post-myectomy [indiscernible] thrombectomy, you still have that much or more than that is associated with higher mortality.

And of course, there is still elevated mortality in those patients, all patients because they have genetic disease and they have thickened hearts. But within that, there is an even higher risk of mortality if you have a posterior wall thickness of 1.3 millimeters or more -- centimeters or more.

And so in our first 3 patients dose in Cohort 1, patient 3 is objectively above that threshold and comes down below that threshold by 1-year mark. And then for patient 1, they were very close to that threshold and have come down to almost the normal range with dramatic reductions there.

So that's partly why we're -- and then patient -- 1 patient, patient 2 was below that threshold and yet further, but still hypertrophy and came down well within the normal range. So that's why we're pleased in focusing in on those measures of posterior wall thickness is partly because of that experience in the literature.

I would also say that with septum wall thickness, in addition to what Whit said, we've also analyzed septum wall thickness across all of these programs. And what we see consistently is septal wall thickness is something that everybody has seen varying degrees of changes and our changes are very much in line with others.

And the -- but the septal wall thickness is also more -- it seems to be more recalcitrant to major changes in the way that other walls of the heart are and that sometimes -- and I don't exactly know the full biology behind it. In our case, it could be because the patients had myectomies.

And so there may be some scarring in that, but that doesn't explain that for all the programs that are represented here. But it seems like a ventricular IBS or ventricular septum thickness is something that doesn't move quite as much as other hearts or other walls of the heart.

But the data, the pattern that we would be showing here would be very similar. The reduction seen with TN-201 are quite consistent with and in many cases, better than both on an absolute and a relative basis than in these other studies.

And we've also made these comparisons with things not represented here like ATTR cardiomyopathy and Fabry cardiomyopathy. So we now have quite a deep data set of understanding and this is partly what will go into our thinking as we thoughtfully approach the agency with our data in 2026 is what arguments we want to make about the best markers for potential further approval and with what logic.

And that logic may overlap with what some of our gene therapy peers have done, but there may be some differences that are based on the data that are available in other studies as well as in our study and in the HCM population.

And that concludes our question-and-answer session. I will now turn it back to Faraz Ali for closing comments.

Yes. Thanks for staying here. I know we've gone over and this is -- thanks for joining us today and all the great questions. We've had an outstanding year of performance. I'm now referring to Slide 29, the last slide in the deck.

We only have one more exciting milestone left to check here for 2025 and we're looking forward to doing that -- doing this again soon for the initial readout from our RIDGE-1 clinical trial for TN-401.

And as a reminder, those data will provide a first look at Cohort 1 safety and biopsy results. And so we have, of course, we've already been referencing several times on this call, exciting milestones ahead of us in the first half of 2026.

And as a reminder, these data milestones have not changed as a result of any recent regulatory interactions and they're not impacted by the hold that we mentioned because these are data from patients who have already been dosed. That's what we're looking forward to in the first half and of course, adding to that with the dosing of additional patients and that data set would be more likely to mature later in 2026.

We look forward to more data from the TN-201 program for Cohort 1 and maturation of clinical data from Cohort 2, including more biopsy data and changes in clinical parameters. We continue to believe that we have an exciting year ahead of us for both programs in 2026 and we welcome the follow-up questions.

I'm sure we didn't get to all of them today and we hope to connect with many of you over the coming days. Please reach out to Michelle, if you'd like to schedule some one-on-one time with our team to discuss these data and Tenaya's progress and our forward-looking plans. And with that, we will close. Thank you, everybody, for your time and attention, and thanks to the patients who have contributed to our results today.

Ladies and gentlemen, thank you for your participation. You may now disconnect.

Okay. Great. Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, one of the biotech analysts here. And it's my pleasure to introduce Faraz Ali, CEO of Tenaya Therapeutics. Before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative. And with that, Faraz, thanks for joining us today, and I'll -- maybe I'll hand it over to you, and you can give us some just introductory comments for people that may not be familiar...

Yes. Just overall, before we dive into the deeper questions, I just wanted to say that we've had a great start to the year and looking forward to closing strong. Everything that we set out do in our guidance, we've accomplished. So on our 201 lead gene therapy program for the leading genetic cause of HCM, we dosed -- successfully dosed the high-dose cohort, successfully got the DSMB clearance, which is important from a safety perspective. We've released data from our natural history study, which is the largest natural history study in the world for this disease for the children with this mutation, a very severe disease.

And then we're on track to deliver data in the second half of this year, and we had first narrowed our guidance to Q4, but we're happy to share today breaking news at Morgan Stanley Healthcare Conference that as of 2:00 p.m. Eastern today, we're able to share that we were accepted for a late-breaker clinical presentation in the main conference at the American Heart Association. Happens to be a joint session of the American Heart Association and the Hypertrophic Cardiomyopathy Society. So it's a big event for us in general this year and even bigger now that we'll be giving our data update in November now. So we're able to announce that.

That was not shared before. And then on 401 [indiscernible] hitting all of our milestones. We dosed the first dose cohort successfully. We got DSMB clearance. We've already started dosing in the high-dose cohort. So that's already announced. Also presented data from the largest natural history study in the world for that condition. 190 patients have been enrolled in that natural history study, and we're on track for delivering data in Q4. No big announcements there. But presumably, that data will be released around the same time as the AHA presentation for 201. So we have met all the objectives that we set out for this year so far, and we're closing in on the most important stuff, which is delivering data -- meaningful data updates in the second half in Q4.

Great. Thanks for that introduction. Also congratulations on the late-breaker at AHA, very exciting. And I thought maybe we can just start with a couple of big picture questions, gene therapy, FDA, sort of what's happening there and maybe just any thoughts you have there that you want to share.

Yes. I mean, first, I want to say, and I have a fellow -- I sit on the -- so I sit on the Board of Alliance for Regenerative Medicine. I have a fellow Board member in the audience here. And one thing I will speak both as a Tenaya CEO, but also as a Board member of the Alliance for Regenerative Medicine, which is the largest industry organization for the cell and gene therapy field, we should stop thinking about like the FDA as like individuals or like Democratic leadership or Republican leadership. From our vantage point, the FDA -- their commitment to rare diseases, their commitment to cell and gene therapy for rare diseases and cell and gene therapy in general, it's a bipartisan support that we see.

So when we have gone to Washington, D.C., when we've seen the roundtables that they've held, there is a consistent commitment for innovative medicines for rare diseases. They recently released some new sort of pathways for diseases that might be relevant to some of us in the field. So overall, I feel that the FDA, yes, there have been some comings and goings of some people. And -- but overall, I think that the environment is as positive as it's ever been, even though there have been changes in leadership over there. And then the other thing I would say about the FDA, the main thing that we all worry about is, are they going to keep to the alignments that they've already announced, right?

And that's really important to us because some of those alignments are with peer companies, Rocket, Lexeo, [ REGENX ], uniQure, where they've said, yes, you can pursue accelerated approval based on protein plus some other surrogate marker for an accelerated approval. And the big concern is, are they going to change their stance? Was that just a feature of Peter Marks and Nicole Verdun?

And from both private -- discussions with individuals plus their own public statements, we see no changes in the stance of the commitment to accelerated approval pathways based on surrogate markers, including protein. And so that's a positive. So overall, yes, a lot of drama maybe at the FDA, but the substance remains the same and it remains positive. And I will continue to say, I think it's as positive a time as it's ever been for cell and gene therapies for rare diseases.

Got it. That's good to hear. And I guess maybe another sort of topical question just in gene therapy space just has to do with the immunosuppressive regimens. And maybe you can share your thoughts on some of the changes that are being going on out there in sort of how that influences your program and what's your regimen look like?

I mean we all put patients first. And so their safety is paramount. We -- I think I'm not alone. I think we all -- all of us are thinking about that every day. It's terrible what happened. In the last couple of months, we had both a death in the Rocket's study for Danon disease as well as 3 deaths in the Sarepta's study or -- well, commercial products, so 2 DMD and 1 limb-girdle. So 4 in total deaths have happened in short order. And I think it's important to first understand what it was and what it wasn't. What it was is in the case of Rocket, they said, and the FDA agreed the death was attributed to the use of a -- an experimental use of a C3 inhibitor to blunt complement activation in those patients.

And they had not seen that before, the kind of capillary leak syndrome with their established regimen in prior patients. They only saw it here. They discontinued it. And no read-through to us. We're not using that C3 inhibitor or any other prophylactic complement inhibitor. And in the case of Sarepta, I think that was an instance where they may not have been doing enough on the immune suppression side. They were only giving corticosteroids. And in limb-girdle and in DMD, corticosteroids is like the foundational standard of care for these patients, and they all get it.

So effectively, Sarepta wasn't doing anything incremental for immune suppression, even though they're giving very high doses. And as they dose rapidly, as they became a commercial product, I think eventually they caught up. And so what did they have to do in that case in agreement with the FDA, add sirolimus. Well, guess what, that's what we're already [ using ]. So our immune suppression is prednisone, which is a corticosteroid and sirolimus. That's what we've had from the beginning. We have not had to make a change.

We talked to the DSMBs who are connected to some of these companies and said, anything you're hearing, should we be making any adjustments? And the answer was no. But you're -- I hate to put it in Goldilocks terms, but we are just right, not too much, not too little. And I would also say that it's -- we should get beyond talking about it's an AAV9 thing or it's a capsid thing because it wasn't capsid in either case. And it was immune suppression. And this speaks to the broader being vigilant about immune suppression, total dose, [ empty capsid ], monitoring, how you're monitoring them in the immediate post-dose period, how you're monitoring their steroid taper.

Many of us have like internalized that. We're just doing this day in, day out. And sometimes it takes a small slip up from somebody to bring this back into focus again. We feel very good where we are. And at the big picture total field level, we just have to always remind ourselves that at this point, between the 2 commercially approved AAV products that have the most patients, ELEVIDYS and Zolgensma, more than 5,000 patients have been dosed in more than 50 countries with AAV -- high-dose AAV gene therapy and the number of patients who have died and all AAV gene therapies is still less than 1%. It's a fraction of a percent.

So the benefit that have been seen by patients around the world with these severe diseases versus terrible, always terrible outcomes is it's still a minuscule fraction. And so we just needed to put that into perspective.

Yes. That makes sense. I wanted to talk about a webinar also that you recently hosted discussing sort of measuring protein expression, which is obviously important for gene therapies. But maybe talk about some of the challenges in doing that and some of your sort of solutions to that problem.

Yes. So I mean, why do we do that? I mean, one is I think there's some -- protein measurement is uniquely important and it's also uniquely challenging. And so -- and there are differences between how different companies are doing it. So we thought it was the right time to do it. Why is it uniquely important? Well, first, it's our first indicator of efficacy. The very first thing we get is like protein, whether protein or RNA expression. So the biopsy data is really important. And so we take that seriously as a leading indicator of downstream efficacy. It's also uniquely important because we just talked about earlier, the FDA has said that protein can be an important surrogate marker for accelerated approval.

So being able to measure that and being able to measure that consistently and accurately is super important. And so for those reasons, very important to make sure that we get this right. And then I'll also say it's somewhat challenging because most people [indiscernible] gene therapy that the patients are homozygous, they inherited a defect from both parents. They're not producing any of their protein. And so they're starting from 0. Well, in those situations, it's actually quite -- it's quite a bit easier to both measure and to visualize even the extra protein that's being produced from the vector.

But in both of our programs, and we had to learn this with the first program. In both programs, we had to figure out -- the patients -- the average patient is heterozygous, and they're producing an abundant amount of naturally occurring protein, 30%, 40%, even 50%. So how do you measure your -- the effect of your product against that backdrop? So we had to think about that, and that's why it was uniquely sort of challenging for us. So one of the things we did is we paired up with -- this is going back to now several years ago, paired up with Mike Previs, who is one of our guests on that as a world expert in measuring MYBPC3 protein.

It was his papers that drew us to like, okay, this is the way to do it. We paired up with him. We successfully deployed those methods. We compared our methods like mass spec, which we believe is highly sensitive and the best way to do this with other methods like Western blot. And it was clear that you get much more interpretable and consistent information with mass spec compared -- and not just mass spec, but mass spec and normalizing to like another protein myosin that's in the cardiomyocyte versus from Western blot, normalizing to something like GAPDH. So we had that insight going into the MYBPC3, the 201 study. We deployed them. We like the data we're getting there.

We'll present more of that at the AHA. And then we applied that to PKP2 as well. Those methods work very well for us. And so -- and they are now also working very well for us on the PKP2 side. Two of the other companies working in PKP2 gene therapy, Rocket and Lexeo, they're using Western blot. They are using their own methods. And that might make -- so there will be differences in the way the data is presented, and there will be -- it will make it harder for investors to compare head-to-head. It will be more like apples and oranges. Everybody will be able to say we're producing some protein, right?

That's no surprise. But we will we be able to say, can we compare their data set to their data set? Could we compare their normal average or lower or upper bound to our normals, right? Maybe not because we have differences in methods, even though we're all dealing with the exact same population. So for those reasons, we wanted to put out there our methods and why we believe in our methods and other challenges that we had to solve along the way, how do you deal with a [ pinch ] with fibro-fatty replacement in it and things like that. So that was the motivation behind that.

Makes sense, and that was very helpful. Maybe we can switch to 201 HCM program. You shared some early Cohort 1 data. I think 2 updates there from the MyPEAK study. So maybe just talk about that data and what you've learned.

Yes. I mean, so we've done -- we're very happy with where we are in that program. I already mentioned the operational progress we've made. We presented initial data on that program back in December of last year, just a webinar for investors. A few short months later at the American College of Cardiology, we had a presentation by Milind Desai, who is the lead investigator on this program at the Cleveland Clinic, meaningful additional information versus December. What we were able to show at that time is that all 3 patients, we -- the first 2 out of 3 patients, sorry, that we had evaluated, we had evidence of protein increases from 8 weeks to a later time point.

We had a robust RNA expression that was in line with some of our peers, including Rocket. Even at half the dose, we had robust transduction. We had -- so overall, we're happy with the biopsy data, RNA protein and transduction. We're happy with the safety data. And so that the safety profile was well tolerable. Any events we saw were consistent with other gene therapies and the effects of immune suppression. Everybody continued, no proarrhythmic effects of the gene therapy, no cardiotoxicities. So we're quite pleased with the safety profile. And then we saw on the clinical efficacy side, all 3 patients -- so 2 out of 3 patients had normalized their cardiac troponin I, which is an important blood-based biomarker of cardiac stress and injury.

And so normalization is good. Then we had -- for all 3 patients, they had improvements in one or more measure of hypertrophy, like meaningful improvements. And then all 3 patients had gone from New York Heart Class II or III to New York Heart Class I. So even at this early time point, even at this first dose, we were already beginning to see signs of benefit. And so we're quite pleased with that. And then, of course, we're looking forward to presenting additional data at AHA later this year.

And that was going to be my next question. Just when you present at AHA, just what additional data should we be looking for from Cohort 1 as well as how...

Yes. So on Cohort 1, we're going to have -- by that point, all 3 patients in Cohort 1 are at or beyond the 1-year mark. So that's an important milestone. When we talk about getting full cohort data, you're not only talking about all 3 patients, but the more mature time point. So all 3 of them will be at that more mature time point. Something important that we didn't have with regards to protein in the updates to now, we didn't have the benefit of a baseline biopsy. That was just a clear learning. We needed to have the baseline biopsy. And so now when we did the update in AHA, the third patient in Cohort 1 has a baseline biopsy and a post-dose follow-up biopsy and then all patients in Cohort 2 have a baseline biopsy.

So you're going to get meaningful new information on safety because we announced DSMB clearance, but now we'll be able to cover that in detail. We'll get meaningful information on protein for both dose Cohort 1 and dose Cohort 2. You're going to get more durability and deepening of the effect of -- from Cohort 1 patients. And then on the Cohort 2 side, biopsy safety, but we're not making any commitments on the clinical efficacy parameters because it's just too early for that right now. So it is a meaningful update even from December last year to March of this year to November of this year. It's a steady drumbeat of data update, but very meaningful updates each time.

And -- so for Cohort 2, you'll have the baseline plus some future point in time?

Baseline plus early biopsies as well as the safety and what effect, if anything, does dose have on the safety profile...

Can you remind us when you take the biopsies for the protein? Is it like 3 months? Or what's that...?

So we have flexibility. We had announced that last year that we have a lot of flexibility there. So we could take it as early as in the first 8 to 12 weeks. We could take it as late as 26 weeks. And that's the first time point post dose. And then there's another time point at about a year mark where we also have flexibility. It could be a little bit before 1 year, it could be a little bit after 1 year. But for the first dose cohort, this will be, by definition, baseline plus the early time point. Now interestingly, what we saw in the first dose cohort is an increase in RNA and protein over time. So whatever we show here will be the early time point. You can compare that to the later time point from the low-dose cohort and start to make some projections, and I think meaningful comparisons can be made.

And with the early sort of look at the biopsies, is that enough time to sort of see a meaningful change in the protein from baseline, do you think?

We look forward to talking to you after AHA, right? So that's -- I don't want to be the witness too far down the path of like what we're going to share there. But we just overall think it's a meaningful update.

And then since we're looking at sort of protein expression over time and you're starting somewhere different from baseline, what's -- I think it's difficult to answer, but just what's the change in protein expression over time that you think sort of will drive a benefit or what's meaningful?

Yes, it's a good question, actually, and we also covered this in the methods discussion that we're not trying to aim for some magical threshold. And I would say that through a couple of different lenses. So there's not like a number. We were asked this a lot last year. And luckily, because it has the benefit of being true, we've been consistent on our answer to this since even before we had clinical data that we don't think there's a single magical threshold that we need to achieve that. The goal of gene therapy is to give each patient more above what they have. We can approach -- we can see that from our preclinical data where at a certain dose, you get 100% wild-type protein, and you get maximum benefit.

But even at less than 100% wild-type protein, you're getting significant benefit. We can see that through the data from our first few patients, right? We weren't showing 50% increase in protein. We were showing 5%, 2%, 4%, like those kind of numbers, and we were still seeing some of the benefit that I shared with you that we presented at ACC. We look at it from the perspective of our peers, both Lexeo and Rocket, modest increases in protein expression, pretty dramatic improvements in LVMI and other measures of disease. So it does -- overall, the picture seems to be that a little can go a long way in gene therapy in general, but in particularly in these cardiac programs.

And the final thing I would say about protein levels and thresholds is the FDA has not asked for a threshold. So in the alignment that they have announced with both Rocket and Lexeo, they said that you can use protein as a surrogate endpoint as well as reduction of LVMI. On reduction of LVMI, they did set a threshold, greater than 10% is considered clinically benefit and outside the noise of echo. And so they said, that's your threshold. But on the protein side, there is no threshold that either of them has to achieve to convince the FDA. So I think we're just looking to continue to demonstrate that we can add protein and then show the clinical benefit measured a couple of different ways.

Got it. So after you share this update at AHA, just sort of talk about next steps for the program. Do you keep adding more patients? What does that look like?

That's a great question. And I think we'll be in a better position to talk about that after the data release. But big picture is we're glad that we have the DSMB clearance to start to dose in parallel whenever we choose to do so, whether at the first dose cohort or the second dose cohort. We're glad that we're generating the data that we're generating. We can continue adding more patients and/or we can prepare to engage with regulatory agencies about what's that path going to look like for us? And is that path -- what does that look like for children who we've been talking about for a long time? And can we confirm accelerated approval possible with protein expression and LVMI?

All of that will go into our thinking about what's the right next thing to do. Right now, I think we have an opportunity to let the dose Cohort 2 data mature and to see with the benefit of dose, do we see differences in protein? Do we see differences in RNA? Do we see differences in efficacy parameters, right? If the answer is yes, that means one thing for what you choose as your pivotal dose. If the answer is no, it's within the range of noise.

So how does that look relative to safety? So we have more to learn from dose Cohort 2 before we make decisions about what to do in terms of dosing more patients and how many more and should we do it before or after regulatory feedback. So right now, we're giving no guidance on what we're doing in terms of dosing because we've achieved what we want to for now, and we have -- we can now learn from what we've already done.

Okay. Maybe we can move to PKP2. That's your 401 program. And then maybe you can just talk a little bit of -- give us some background on that program and maybe the disease as well.

Yes. I mean it's our second program. We're very excited about it. So TN-201, that's the leading genetic cause of hypertrophic cardiomyopathy. TN-401 is addressing the leading genetic cause of arrhythmogenic cardiomyopathy. It accounts for about 40% of all ARVC cases, and that translates to about 70,000 patients in the U.S. alone. It's a severe disease. We -- one grew some statistic for this disease is about 4/4 of patients. The first manifestation of the disease is sudden cardiac arrest and death. So you find out that you have the disease when it's too late. That's just a terrible statistic. We can do better. We also understand the genetics of the disease.

It is a disease of haploinsufficiency as a result of the mutation, they're missing or have deficient levels of the protein. And so our goal with TN-201 is to simply add some of that missing protein, restore function. Now these patients will -- the hallmark of the disease is this arrhythmia. It shows up in premature ventricular contractions, nonsustained ventricular tachycardia, sustained ventricular tachycardia. They all have ICDs, eventually, they get shocks.

Incredible -- that is incredible impact on their quality of life, both the exercise restriction that they're put under as well as the shocks that they experience and the fear of shocks. And so we have an opportunity to address that. There is no treatment available that addresses the underlying genetic cause of the disease. And so we're advancing TN-401 to try to do that. Most of the patients -- in this case, unlike TN-201, all the patients are adults. So they present in their 20s and 30s and 40s. And so a very different disease in many ways from TN-201 and -- but exciting opportunity to do some good...

Yes. And you're planning to share the initial sort of Phase I data from your RIDGE study in the fourth quarter of this year. So maybe talk a little bit about the design in terms of the number of patients and as well as some of the key endpoints and...

Yes, very similar design. Very similar design as the TN-201 program, 3 patients at the first dose cohort and the dose is the same, 3E13 vector genomes per kilogram. And then we already have cleared that sort of sentinel dosing in the first dose cohort. And now we are dosing at the higher dose cohort, which is exactly the same as TN-201's 6E13. So also important from a safety context that we're generally operating at lower doses compared to some of our peers who are in the 1E14 range. And so then in terms of endpoints, look, safety first. And then -- so that's also very consistent with the TN-201 program, biopsies, all patients get baseline and post-dose biopsies.

So we'll be getting protein, RNA and measures of transduction. And then in terms of efficacy, that's where it starts getting different, right? Over here, blood-based biomarkers like cardiac troponin I, NT-proBNP less prominent compared to HCM, things like heart thickening, it does happen in these patients, but that's less of a prominent feature. The hallmark of the disease is the arrhythmia. And these patients have an incredible background level of premature ventricular contractions or PVCs, like more than 500 a day. Some of them have thousands a day.

And that is what is a leading indicator of other things that are going to end up happening, whether it's the sustained or not sustained ventricular tachycardia and ventricular fibrillation. So PVCs are happening every day. So that also provides a great dynamic biomarker [ to ] see the impact of gene therapy in addition to potentially preventing the remodeling of the heart that's happening, adverse remodeling of the heart or prevention of fibro-fatty replacement.

But that -- those are longer-term endpoints that are going to take a while to mature. But I think some of these nonsustained ventricular tachycardia, PVCs, these are things that we might be able to measure whether through a patch or through the ICDs, a lot of different ways to measure that. So those are some of the things. And of course, we'll be looking for patient-reported outcomes, New York Heart Class and other quality of life instruments.

When you share that initial look at the data, will it include all...

Well, that will include all of that. We'll clarify that. That's everything that we're studying, that design is similar to HCM. We designed the study to make sure that we are capturing all this information because there's always a chance that a program like this slips into a pivotal study and then you want to have captured all of this data and captured over many years. But the initial data release is going to be more like the data release we did last year for TN-201. First 3 patients -- all 3 patients have a biopsy with a benefit of baseline, obviously, extensive safety information.

And then it's not lost on us that 2 of our peers have already presented data and both of them shared early changes in things like PVCs. So there's probably at some level -- even though we have not guided to any clinical data, but there's probably not an unreasonable expectation that we're going to share something there. And -- but that's what we're...

And then the follow-up on the patients roughly would be out to a year or less than...?

No, less than a year. So this is the -- this is, like I said, more comparable to the cohort last year when we did our initial update on 201 is that there -- all 3 patients are not at the 1-year mark. 201, the data we're presenting at AHA, all 3 patients will have at the 1-year mark. This program is one step behind. So no, not all of them will be at the 1-year mark.

And then just interpreting the protein expression, should we think about that sort of the same way as you described for 201?

Yes. I think that's like -- the goal is to give each patient more. We're going to look at it multiple ways. We look at transduction, so vector copy number. We look at RNA expression, we look at protein. We also look at other ways, immunohistochemistry, can we look at the desmosomes, can we visualize that? So yes, we have a lot that gets from the biopsy.

And the goal is similar, get each patient above their own baseline and get closer to the normal range, but we're not trying to get into the normal range any more than any of the other gene therapy programs that have ever been approved have gotten their patients into the normal range of protein. That's just not our expectation. It's not the physician expectation. It's not the FDA's expectation.

Makes sense. And after you give this initial update, sort of what are the next steps you just...

[ Key dosing ]. Obviously, we're already dosing the patients at the higher dose cohort. We announced that as part of our release earlier this year. So we're on track to enroll the high-dose cohort. And then the other next steps, I would say is, I think among our peers, we're the first to be also beginning to expand ex U.S. So we are activating sites in the United Kingdom and preparing to dose patients there as well. And the other really important thing that's happening in the background is we do have the largest natural history study in the world. We've been quietly building that up over the last couple of years.

So we're at a point where we have more than 190 patients enrolled in the natural history study, all of them with a PKP2 mutation. And these are all patients who are alive and being prospectively followed, plus we're collecting their retrospective data, so their past history of medications, shocks, et cetera. This is a larger natural history study than the other 2 peers combined. It is a very rich data set, gives us deeper disease insights, gives us a better way of thinking about -- we think, a better way of thinking about surrogate biomarkers for accelerated approval as well as full approval.

And of course, these are patients who are at some level interested in what we're doing and could provide -- they are and have been providing patients in the RIDGE-1 study where we're dosing them and could be that source of patients for future pivotal studies, both in the U.S. and ex U.S. because we're enrolling from multiple countries.

So that's what's next for the program, continue dosing patients, continue to generate safety and efficacy data and biopsy data, continue to harvest and mine the data from the regulatory -- from the -- sorry, the natural history study, continue to monitor the data from our peers because we're not operating in a vacuum. Yes, it's all execution and data.

Yes. Great. Maybe in the last just few minutes here, I can ask sort of a couple of these macro questions, [ asking all our ] companies. So there are 3, but I don't know if we'll get through all of them, but just in terms of like China rise in biotech innovation, just how are you thinking about your competitive position there? And will this influence your sort of R&D strategy in any way?

China rising is a good thing. It's a good thing for science. There's some great science happening over there. It's not relevant to us today in that we don't have any competitors to our knowledge coming from China. So it's not a -- we have -- the competitors are right here in our backyard in New York. And so we don't worry about China from a competitive perspective nor -- I actually think that's -- there's an opportunity there. There's 1 billion people. There's a lot of patients with these mutations that we care about who are probably there and hoping to also be -- the benefit from treatment.

So I view that -- I think China rising is an inevitability. It's been happening by many different measures. And I don't think we should view that as a threat because our job is to advance science for patients. Anything that advances the science and anything that improves patients' lives is good.

And if that just means an entire nation is kind of beginning to contribute to that and put their shoulder behind that, I view that as an absolute good thing. We're not naive that increases overall dynamics and maybe in the future competitive dynamics for us. But in the near term, I think there's more to learn from and benefit from than to fear.

Yes. Makes sense. Second question, just how are you currently leveraging artificial intelligence or thinking about AI's future disruption...?

AI. I forgot about the AI question. So look, actually, I think that's another one where it's like -- we've already been quietly doing this in the background without much fanfare. So as you know, we have a small molecule program, TN-301, that's going after HDAC6. It's a highly selective HDAC6 inhibitor. So where did that come from? Well, it turns out our conviction around the cardioprotective properties of that target came from an unbiased phenotypic screening of human iPSC-derived cardiomyocytes in the background of a genetic defect, BAG3-deficient cell line.

We were screening these cell lines, characterizing their phenotype and screen like thousands of molecules against them to see which one might change the phenotype. And guess what, that was generating more images than we could possibly analyze with the human eye. So what do we use? We used imaging algorithms and AI to do that and to help characterize the improvements. And that worked extraordinarily well. And in fact, the story of that discovery process using AI is -- was the cover story of Science Translational Medicine a few years ago when they published it. So that's one way in which we're already using AI. Another way, and we have a collaboration with a very major tech company on the use of their AI algorithms for capsid engineering efforts.

So we had some of our own homegrown efforts, but now we're collaborating with somebody who's got a lot more data, a lot more algorithms and a lot more computing power to say, can we screen hundreds of millions of variants and then from that, get to capsids that are better than what we've been able to do on our own? The short answer is yes.

And that is -- so those are 2 drug discovery enabling efforts that have already happened or are happening right now at the company. I'm a huge believer in AI. I think it's going to -- but what we -- I can also say what we've learned from that process is you cannot -- it doesn't happen on its own. You need the people, you need the wet lab work for that to become real. So I view these as complementary and incredibly exciting for the future. What was your third one?

It was actually the FDA, which we touched...

We already touched on. [ There you go ]. We already covered that. It's all good.

And we're out of time as well. So why don't we leave it there?

So are we popping open the Corona now or later?

So thanks so much, Faraz. Appreciate your time today.

I appreciate your coverage. Great work for us. Thank you.

Thank you.

Hello, and thank you for standing by. My name is Lacey, and I will be your conference operator today. At this time, I would like to welcome everyone to the Measuring Protein Expression in Cardiac Gene Therapy, KOL webcast event. [Operator Instructions].

I would now like to turn the conference over to Michelle Corral, Vice President, Investor Relations and Corporate Communications. You may begin.

Thank you so much, Lacey, and good morning to everyone. I appreciate you joining us once again for our KOL webinar and hope that everybody can see and hear our presentation this time. Welcome to our KOL webinar event to discuss the measurement of protein expression in cardiac gene therapy. Joining me today on today's call from Team Tenaya are Faraz Ali, Tenaya's Chief Executive Officer; Dr. Whit Tingley, our Chief Medical Officer; and Kathy Ivey, our Senior Vice President of Research. As well as our special guest. We have with us Dr. Mike Previs of the University of Vermont.

As a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of today, August 26, 2025. These statements involve certain assumptions, and we caution investors not to place undue reliance on this information. Please refer to our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements.

I would also like to note that any opinions expressed by our guest speaker, Dr. Michael Previs are his own and do not necessarily reflect the opinions of the company. And with that out of the way, I will pass the mic to Faraz Ali for some introductory remarks. Faraz?

Thank you, Michelle, and good morning, everyone. I'm Faraz Ali, Chief Executive Officer of Tenaya Therapeutics. At Tenaya, we're driven by bold and urgent mission to discover, develop and deliver curative therapies that address the underlying drivers of heart disease. This mission is not just aspirational, but it's foundational to everything we do. So on behalf of the Tenaya team, and thank you for joining us today for our session focused on measuring protein expression in cardiac gene therapy, during which we will discuss the ground breaking work being done at Tenaya to transform the standard of care for patients living with genetic cardiomyopathies.

Today, I'm proud to share how we are translating that mission into meaningful progress for patients and families affected by devastating genetic cardiomyopathies. We were founded in 2016 with a singular focus, and the company was filled very intentionally with deep expertise and integrated capabilities. In addition to our core value of patients first, Tenaya's culture is rooted in scientific excellence and tenacity, which together have resulted in a pipeline of 3 clinical stage programs, including 2 novel gene therapies that each have near-term data readouts.

We're in a pivotal moment in our journey as an emerging leader in gene therapy for inherited heart conditions, we're advancing a pipeline that targets the root cause of disease, not just the symptoms. These are not incremental steps. They represent a paradigm shift in how we think about treating and ultimately, hopefully, curing cardiomyopathies. And they are made possible by the deep scientific expertise, relentless innovation and unwavering commitment of our team and collaborators.

Here's our pipeline. Our lead program is focused on hypertrophic cardiomyopathy, or HCM, where we're developing TN-201 and adeno-associated virus or AAV based gene therapy designed to treat adults and children with HCM due to MYBPC3 gene mutations, the most prevalent form of genetic HCM. This program is advancing through the clinic and progressing steadily towards pivotal studies. A data readout encompassing the first 6 patients to receive TN-201 is planned for the fourth quarter of this year.

Our second gene therapy program is TN-401, another AAV9-based gene therapy being developed for the treatment of arrhythmogenic right ventricular cardiomyopathy or ARVC caused by mutations of the Plakophilin-2 or PKP2 gene. Our RIDGE-1 clinical study for TN-401 is ongoing with an initial data readout for the first 3 patients coming in the fourth quarter of this year.

Both MYBPC3 -associated HCM and PKP2 associated ARVC are the result of protein haploinsufficiency, which is the lack of certain proteins that are crucial for the heart to be properly is the cause of the condition. Unlike other gene therapies, we may be more familiar with in MYBPC3 associated HCM and PKP2 associated ARVC, the vast majority of patients are heterozygous and producing some protein with their 1 working gene. That also means that the protein products produced by TN-201 and TN-401 are indistinguishable from the background protein.

As a result, the task of understanding how much background protein already exists and discerning whether gene therapy is increasing the patient's protein levels and ameliorating the cause of disease, is more complicated versus other gene therapies. This is also quite important in the context of seeking potential accelerated approvals based using protein as at least 1 surrogate marker for efficacy, for which there is recent and relevant FDA precedents.

We have learned a lot from TN-201 program that we're now applying to our second TN-401 program. Today, we hope to illuminate our learnings as we've set out to conquer the challenge of protein measurement in cardiac gene therapy. In today's session, Dr. Whit Tingley, Tenaya's Chief Medical Officer, will review the clinical status of TN-201 and TN-401 and outline expectations for the near-term data readouts.

In order to offer additional context with those readouts, Dr. Kathy Ivey, Tenaya's Senior Vice President of Research, will be joined by Dr. Michael Previs to discuss the rigorous methodology Tenaya has undertaken to measure proteins. Evidence of protein expression is a critical early sign of our gene therapy success in addressing the underlying cause of each of these conditions as well as providing a valuable clue to the therapy's durability over time.

Dr. Michael Previs is a world-leading expert in heart muscle disease and specifically, the characterizations of key proteins critical to healthy heart function. Professor of Molecular Physiology and Biophysics at the University of Vermont's, Larner College of Medicine. Dr. Previs lab uses a combination of mass spectrometry-based proteomic strategy and state-of-the-art single-molecule imaging techniques to characterize the structure and function of muscle protein complexes in health and disease.

Specifically, he is focused on understanding the molecular mechanisms by which myosin binding protein C regulates the heart's ability to contract. Finally, we will open up the call to questions from our covering analysts for Dr. Tingley, Ivey and Previs. We also invite questions from investors, which may be submitted into the chat box on your screen. With that brief overview, let me turn our event over to Dr. Tingley. Whit?

Thanks Faraz. As Faraz mentioned, this is an exciting time for Tenaya and for our lead gene therapy programs, both TN-201 for MYBPC3-associated hypertrophic cardiomyopathy and TN-401 for PKP2 associated ARVC. As of now midway through the year, we have achieved significant progress against our goals for both programs. For TN-201, we presented initial data at the American College of Cardiology in March, covering the first dose cohort, Cohort 1.

And we've announced we have fully enrolled the second dose cohort and that the DSMB has reviewed all available data from these cohorts and recommended expanding the study per protocol. For TN-401, we presented initial data on the natural history at the Heart Rhythm Society this year. Cohort 1 is fully enrolled, the DSMB reviewed the Cohort 1 data and recommended we proceed per protocol to expand that dose level and escalate to the next dose level at which we have initiated.

We will have data readouts from each program in the fourth quarter of this year. But before providing details on what to expect, let's take a moment to cover important characteristics of each condition and the aims of the current studies. Let's start with MYBPC3-associated hypertrophic cardiomyopathy. MYBPC3 is the most common genetic cause of HCM, estimated to affect 120,000 patients in the United States and many more around the world. As far as mentioned, the vast majority of patients have heterozygous mutations, though on rare occasions, infants are born with 2 MYBPC3 mutations.

Their disease is so severe, they require heart transplantation to survive even the first year of life. Heterozygous mutations can affect people at any age, affected children such as Gabe pictured here typically of earlier progression and a higher overall burden of disease than adults. We look forward to sharing a natural history data from our MyClimb study of pediatric MYBPC3+HCM patients this weekend at the European Society of Cardiology Congress. In this disease, the muscle of the left ventricle thickens and is unable to relax and fill properly limiting cardiac output and the ability to meet the body's demand for blood supply.

Initial symptoms are shortness of breath, chest pain, fatigue, syncope and palpitations from arrhythmias. Patients are at high risk of sudden cardiac arrest and death. Fortunately, for patients, the treatment of HCM has gotten more attention in recent years. However, there's still no treatment that addresses the underlying genetic cause of disease.

First-line therapy involves generic heart failure medications. Recently, cardiac myosin inhibitors have emerged, but these are only available for the subpopulation of patients with the obstructive subtype of HCM. Only about 30% of patients with MYBPC3 associated HCM have obstructive HCM. So the majority are not eligible for current cardiac myosin inhibitors. MYBPC3 HCM is caused by protein insufficiency, mutations to the MYBPC3 gene result in a lack of myosin binding protein C, which is critical for regulating the contraction and relaxation of the heart. Protein C deficiency results in hypercontractility, stiffness, thickening of the ventricle and disorganization of the muscle cells themselves, which places patients at greater risk for lethal arrhythmias and progressive heart failure.

TN-201 gene therapy is designed to address this protein deficit by inserting a full-length working MYBPC3 gene into the heart where it can produce more C protein and restore contraction and relaxation. This is expected to halt disease progression and potentially reverse disease, ultimately improving patient outcomes, symptoms and quality of life.

In November 2023, we dosed the first patient with TN-201 gene therapy as part of our MyPEAK-1 Phase Ib/II clinical trial. The primary objective of the study is to establish the safety profile of TN-201 and evaluate tolerability and performance at 2 different dose levels. In addition to safety, we are taking heart biopsies to assess the transduction and expression of TN-201 using cardiac imaging to examine changes in heart structure and function.

Following levels of plasma biomarkers associated with disease and with heart strain, monitoring heart failure functional class and exercise capacity and measuring patient-reported outcomes for symptom improvement and quality of life. The ultimate goal is to see many of these parameters of disease improving together consistently. We are often asked what will be included in our planned Q4 data readout and what success would look like.

For Cohort 1, we plan to share longer-term follow-up data building on our prior presentation at ACC in March. The 3 patients who received TN-201 at the 3E13 dose should have assessment out to 1 year and more, including heart biopsies. Success here is continuation of the positive observations we have shared thus far. We shared at ACC that TN-201 has been well tolerated with robust evidence of DNA transduction and increasing RNA expression as well as improvements in protein levels for the first 2 patients.

2 of the Cohort 1 patients saw improvements in one or more measure of cardiac hypertrophy and all 3 achieved New York Heart Association Class 1 status, meaning they were no longer expressing -- experiencing heart failure symptoms, that interfered in daily activities. For Cohort 2, our focus is going to be on safety and biopsy results. This will be the first data for the 6E13 vg per kilogram dose. We look forward to reporting baseline and post-dose biopsy data at this dose.

Success here is continued good tolerability, and we'd hope to see dose-dependent increases in DNA, RNA and protein levels. We'll be looking at clinical endpoints, but for these patients, it may be too soon to see post dose changes. The goals of TN-401 treatment in our RIDGE-1 clinical trial are similar to what we've been sharing with TN-201. PKP2-associated ARVC is a devastating disease characterized by life-threatening arrhythmias in adolescents and young adults. PKP2 mutations are responsible for approximately 40% of ARVC cases.

Current estimates are that the disease affects about 70,000 patients in the U.S. and many more globally. We believe this disease is underdiagnosed. These numbers may be higher. Nearly 1/4 of those affected present with their first a symptom being sudden cardiac death. Other early symptoms of disease include palpitations, lightheadedness and fainting. Patients often experience constant premature ventricular beats and other ventricular arrhythmias physical exertion and exercise such as sports aggravate arrhythmias and accelerate disease progression, so patients are placed on tight exercise restrictions.

Due to the risk of sudden cardiac death, most patients have implanted cardioverter-defibrillator devices, these devices restore normal rhythms during life-threatening events but leave significant emotional burden for patients sometimes described as posttraumatic stress disorder. PKP2 encodes the plakophilin-2 protein. This is an essential protein within the desmosomes complex. The desmosomes is like a fastener between heart cells, helping to hold heart muscle cells together. They also support proteins responsible for the electrical signaling in the heart coordinating each heartbeat. A deficiency in the PKP2 protein leads to the collapse of the desmosome cell adhesion structure.

Heart muscle cells are damaged, electrical signaling is disturbed and heart muscle is gradually replaced by nonfunctional fibrofatty tissue. Over time, the ventricle can distend and weaken leading to heart failure symptoms and then even greater risk of life-threatening arrhythmias. Much like we discussed for TN-201, TN-401 delivers a full-length copy of the PKP2 gene to heart muscle cells where it produces the Plakophilin-2 protein, with the goal of restoring the structural integrity of the desmosomes and improving the heart function.

Improving electrical stability, reducing arrhythmias and slowing or even halting the progression of the fibro-fatty replacement that leads to heart failure. In November 2024, we dosed the first patient in our RIDGE-1 Phase Ib clinical trial of TN-401 for the treatment of PKP2 associated ARVC. The primary objective of the study is to establish the safety profile and evaluate the tolerability and performance of 2 different doses. We've completed enrollment of the first cohort at the 3E13 vector genome per kilogram dose and dosing is underway in Cohort 2 at 6E13. In addition to safety, we are taking biopsies at baseline 8 weeks and 1 year post dose to assess transduction and expression of TN-401, we're monitoring ICD activity and gathering arrhythmia data.

We are imaging the heart for structural and functional changes. We are assessing changes in plasma biomarkers, and we're surveying for patient-reported outcomes and quality of life measures. The treatment goal for TN-401 gene therapy is to reduce arrhythmic events and halt progression of heart failure by restoring the structural integrity of the desmosome. Our initial data from the first cohort of 3 patients dosed at 3E13 will focus on safety and tolerability and whether our immunological regimen is working appropriately. We're also going to look closely at heart biopsy data at this stage from which we'll be able to see the levels of TN-401 DNA transduction, mRNA transcription and whether these increase Plakophilin-2 protein expression, success at this stage is seeing all 3 of these measures increasing from baseline. We are also monitoring for any early changes in arrhythmic activity.

And with that, I'd like to hand the call over to Dr. Kathy Ivey, who leads our research group, including a translational medicine team responsible for overseeing the analysis of our biopsy data. Kathy?

Thank you, Whit, and good morning to everyone joining us. As we've introduced, cardiac biopsies are collected as part of Tenaya's gene therapy clinical trials. And next, I'll describe what those biopsies are being used for. In the TN-201 and TN-401 clinical trials, biopsy sample analysis and the resulting measurements are our first opportunity to affirm that our gene therapy is reaching the heart that it is first entering the heart cell through the process of transduction that the healthy working gene being delivered is transcribed by the cell's machinery to produce messenger RNA.

This mRNA provides the instructions needed by the cells to produce protein. Biopsies are taken at various time points in each of our clinical trials. Using a catheter, a small net of tissue, just 1 to 2 millimeters in diameter is collected from the septum. A number of these tissue samples are collected in the cardiac cath lab, and that's where they first received an initial visual inspection for quality.

And then each of these precious tissue samples is preserved and earmarked for specific quantitative analysis of either DNA, RNA or protein. For each of the components of the biopsy that we are trying to measure specific assays have been qualified. Our DNA assay utilizes digital droplet PCR or ddPCR, and is able to distinguish TN-201 or TN-401 DNA from endogenous DNA encoding MYBPC3 or PKP2, and quantify the number of vector copies per cell.

This measure provides the first evidence that our gene therapy is reaching the heart and is reported as the VCN or vector copy number. Shortly after infusion, DNA levels in the heart should be at their highest. Over time, a decrease is anticipated as DNA is cleared from non-cardiomyocytes such as fibroblast and a durable steady state is reached that represents long-term retention of the TN-201 DNA inside cardiac myocyte.

Using reverse transcript based quantitative PCR or RT-qPCR, we can quantify the expression of TN-201 or TN-401 messenger RNA. The gene therapy-derived mRNA can also be distinguished from the patient's endogenous mRNA, encoding MYBPC3 or PKP2, RNA expression provides an important proxy for potential protein expression via gene therapy since without one, we certainly won't see the other.

Over time, we expect to see the levels of gene therapy mRNA increase and then stabilize, which brings us to the focus of today's discussion, protein measurement and cardiomyocytes, for this, we utilize liquid chromatography - mass spectrometry or LCMS, which can quantify the amount of particular proteins in a sample. Similar to RNA, we expect to see an initial rise in protein levels, but anticipate that over time, the increase will level off and endure.

In many cases, the aim of gene therapy is to introduce a protein that is entirely absent with the most established example of this being the approved gene therapy Zolgensma for treatment of spinal muscular atrophy or SMA, which occurs only when both copies of the SMN1 gene are dysfunctional. In homozygous conditions like SMA, there's no protein being produced, so the measurement is from 0 to something, in diseases of haploinsufficiency such as MYBPC3-HCM and PKP2-ARVC, patients are producing some of the needed protein from their one healthy copy of the gene is not enough of the protein.

So if we're successful, the protein produced from the gene therapy will be identical to the protein produced from the patient's own single healthy copy of the gene. And while the gene therapy RNA can be distinguished from the endogenous RNA, the resulting gene therapy proteins are indistinguishable from their corresponding endogenous protein.

With this in mind, we knew at the outset of these programs that we needed a highly sensitive tool for measuring these protein levels from cardiac biopsies, and that's where the work of Dr. Previs and his lab comes in. Dr. Previs. Thank you so much for joining us today. Before we dive into the methodology, can you tell us a little bit about how you came to be an expert in this field?

Sure. Thanks for having me, Kathy. It's great to be here with you today. So I did my PhD in cellular, molecular, biology at the University of Vermont, but I subspecialize in analytical chemistry. During grad school, I developed a mass spectrometry based platform to measure levels of protein phosphorylation, which really sparked my interest in muscle protein structure and function. To expand this expertise, I did postdoc in biophysics where I developed single molecule techniques to study your favorite protein, myosin binding protein C.

At the time, much less was known about myosin binding protein C and my work contributed to a fundamental understanding of its function and healthy hearts. When I started my own lab, I wanted to move things in a more translational direction. The big question at the time was whether the most common variant in the MYBPC3 gene resulted in hypertrophic cardiomyopathy by creating toxic protein [ fragments ] called poison peptides. Or is the variance impact in myosin binding protein C translation, resulting in a lack of functional protein or haploinsufficiency. To address this question, I teamed up with Dr. Sharlene Day at the University of Michigan and examined the expression of myosin binding protein C and what we consider it to be a large cohort of human samples that she collected in her clinic. The results from that study were Faraz and Whit referenced earlier and brought us here today.

Thanks, Mike. Can you talk us through the role and function of myosin binding protein C?

Yes, absolutely. So the cardiac version of myosin binding protein C that you're interested in is solely found in specialized heart muscle cells called cardiomyocytes. These cells are what contract for the heart to pump blood. Each heartbeat is produced by sarcomeres within these cells, which are tiny contractual units. You can think about these as microscopic machines capable of performing mechanical work.

So we returned here to that slide that -- which showed earlier, we can see that myosin and actin form filaments and these filaments slide past one another to shorten the length of sarcomere to produce each contraction. So the myosin head shown in green here, extend away from the filament backbone kind of like hands, and these are clearly the business end of the molecule.

Actin is more like a rope that is pulled by these hands and the game a tug-of-war to contract the sarcomere. So myosin binding protein C though is a long tether like protein that sits in specific part of myosin filament called the C-zone. Its positioning and interactions allow myosin binding protein C to modulating both force and speed of contraction. So while myosin binding protein C doesn't generate force by itself. It's critically involved in modulating how this sarcomere behaves and therefore, how the heart beats.

How does MYBPC interact with other components of the sarcomere to regulate contraction of the heart.

Yes. So that's a great question, and I'd love to give you a straightforward answer. But the truth is, I'm 1 of the world's experts in this area, and they're still very active way with the lots and lots of multiple questions. What we do know is that one end of myosin binding protein C is anchored to the myosin filament as shown in this cartoon. While the other end could actually be untethered to anyone it can interact with myosin head as shown here or it can interact with the actin filament. So there's the 3 options for interaction.

The balance between these interactions influences how quickly myosin heads bind to the actin filament. So we can think about this as how quickly those hands can grab the rope and start pulling. And they also modulate how long the hand stay attached to the rope and continue to pull. So myosin binding protein C essentially serves as a master regulator of both the timing and magnitude of each contraction.

That being said, there are many models in the current literature that try to explain exactly how this regulation works. But as an expert, I really want to use this platform to say, don't believe in all the hype of these models. These models often ignore data that don't fit and oversimplify things that are clearly very dynamic, and there's a complex set of interactions.

The reality is, my field is still working towards consensus, if there's really a need for more detailed studies to tease these mechanisms apart.

And what's happening in the heart with MYBPC3 mutation? And how does that insufficiency of the protein result in HCM?

Yes. That's a really important question that I think everybody wants to answer, and it's one that really continues to drive my lab's research in new directions. What we do know from our previous work is that most variants in MYBPC3 gene lead to these premature stop codons in the mRNA as Faraz and Whit said, which is responsible for making proteins. So I think if we go to the next slide. Here. Yes, that one.

Okay. So if we go to this slide, our work from tissue -- this is from our work from tissue with patients with obstructive hypertrophic cardiomyopathy. And this work shows that there's a 40% decrease in the levels of myosin binding protein C compared to donor control. This reduction in our hands appears to be independent of the location of where that premature stop codon happened in the mRNA. And we don't see any evidence of a poison peptide resulting from the translation of the variant mRNA that's associated with the disease.

We know for many animal models, human iPSCs and human tissue, that a lack of myosin binding protein C disrupt the function of sarcomere. This contractile defect then at the level of the sarcomere appears to set off this cascade of changes in the heart over time and the heart begins to remodel itself. Unfortunately, this remodeling is what is impacting people's lives and driving them into the clinic.

So I think the short simple answer here is insufficient levels of myosin binding protein C clearly leads to poorly regulated contractions, which the heart actually may be trying to fix by remodeling but the remodeling is what causes the symptoms and complications of an HCM.

And what are some approaches available for measuring protein levels in cardiomyocytes. Can you talk about that and then there benefits and limitations?

Yes, sure. I can talk about this for a day, if you want. But so -- so right now, the main approach is for measuring protein levels in any system are generally antibody-based or mass spectrometry based. Each of these methods has its own nuances and pros and cons. Antibody-based methods rely on the generation of an antibody that combines specifically to a protein of interest. You then detect that binding as an indirect readout of how much protein is present. These methods, they can be pretty straightforward and accessible at very low cost, but they depend heavily on the quality and specificity of the antibody that you're producing.

If the antibody isn't great or the binding affinity in samples, differs from what you tested this in from something like post-translational modification of your protein of interest, you could run into issues with accuracy. In contrast, mass spectrometry is much, much, much more direct, robust and unbiased approach, but it's really expensive and require specialized expertise. In most cases, proteins for mass spectrometry assays are going to be digested into peptides and those peptides will then go on to be identified and measured by the mass spectrometer as proxies for protein abundance.

The technique is really powerful, especially for the use in complex tissues like the heart, where you have many different proteins in the same tissue. With both antibody and mass spectrometry-based approaches, the readouts need to be normalized, which is just the reality of both of these assays. And if I think we take a look at the next slide, right? Oh, yes, there we go.

We can see the biggest challenge with normalization. So when working with small samples from patients with heart disease, such as a sample from your trial, the sample of the size of a tiny crystal and sea salts. So these are tiny, tiny biopsies. The size is actually indicated by the circles in this image. So you have a yellow, blue and red circle. As you can see, the number of cardiomyocytes within these circles being those cells that are in pink, can really vary in the biopsies relative to the other material in that image.

Therefore, if we use the weight of the biopsy or the total protein content of the biopsy for normalization, this isn't very desirable. So with Western blotting what you typically do is you're going to normalize your readout of your protein of interest against the readout of a secondary antibody, it's a housekeeping protein. So here again, you're at the mercy of your primary antibody to your protein of interest and to the secondary antibody to your housekeeping protein. And there's also going to be the potential that the expression of the housekeeping protein varies in your disease say, which will further skew your data.

One big advantage to the MS-based approaches is that in a single run, you can get quantitative information on hundreds of proteins giving you a wide yet detailed view of the entire sample. This allow unbias look at the overall composition of the sample and provides many, many opportunities for normalization. If the assay is designed properly, it only increases the confidence in the quality of the results .

Okay, Mike. So based on your background, you're clearly a fan of mass spec-based approaches. Can you walk us through your approach using data from human heart samples as a sort of case study?

Yes, yes, absolutely. This has really become our approach now because we've collectively -- we collectively worked to refine techniques. So mass spectrometry, many forms of mass spectrometry or the cornerstone of my labs work for many different reasons, just aside from what we're talking about here.

And we really have refined the techniques specific to this application, working in collaboration with your team over the past few years. So with your samples, what we do is we started the process by inspecting each biopsy under dissecting microscope to get a sense of its quality and then we loosen the tissue with forceps in the presence of surfactants, so we kind of loosen up those samples.

We then relax the proteins chemically and then digest them into peptides using enzyme. Again, we do this because peptide abundances, are much more manageable measure with mass spectrometry.

Next, we inject those peptides onto a chromatography column, which separates them based on their chemical properties over a 2-hour period. During this entire period, those peptides are fed directly into the high resolution mass spectrometer, which allows us to identify them and record their abundance with high accuracy and precision.

One of the unique aspects of our approach is really how we normalize the data. We normalize the abundance of myosin binding protein C to peptides shared between cardiac myosin isoforms because cardiac myosin is found exclusively in cardiomyocytes. While we validated this approach over the years in our own lab, when we started working with your team, we're asked to systematically reevaluate our methods and fully understand our reproducibility.

And I think it would go to the next slide, we have some data. Yes, there we go. So if we take a look at the slide, we see an example of where we performed the assay on several biological replicates. So these are individual samples from both donor control hearts where we had bigger pieces tissue and for the septal myectomy biopsies, again, where we have bigger pieces of tissue that are unlike what we get from your clinical trial. Of course, if we look at these individual data points, there's always going to be some variability in the number -- the numbers. But the measurements for multiple pieces of the same heart are very consistent. So across the x-axis here is individual samples, and we see this consistency in these measurements.

If we compare these data from the donor controls, which are shown in green, to that from 3 separate septal myectomy samples, which are shown in red, we can see that the variability between repeat measurements from the same heart is similar. So again, if we make repeat measurements from the same heart, we have very, very little variability. But there is some variability between septal myectomy patients, those data points shown in red.

This is similar to -- this variability is really similar to what we originally reported in 2019 in our initial study. Internal studies like these with your team have really increased my confidence in the robustness of our methods and that we are detecting real biological differences rather than just measuring technical noise.

So I think if we go to the next slide, yes, here. Here, we have an example of what happens if we try to normalize the data differently. So these are examples of similar data set that I just showed you. But the readout from myosin binding protein C is normalized either myosin -- peptide for myosin or GAPDH independently. So the data from myosin are on the left in this graph and the data for GAPDH normalization are on the right of this graph. So -- and we selected GAPDH here because this is a common house keeping protein that's used for normalization of Western blotting data and other biological systems.

And what we see is that when the readout is normalized to GAPDH, there's high variability in measurements of myosin binding protein C within pieces of the same heart and this variability between hearts is even higher. There's more disparity in these data point. Based on this data set in red, we would no longer be able to detect a difference myosin binding protein C levels between the HCM samples and donor controls using the GAPDH normalization strategy.

So to me, these data really highlights the importance of rigorously testing these methods like your team has forced me to do, to make sure that these preparations are really consistent and reproducible. And they also really introduced the concept that you need to get the normalization strategy right because even when you're working with a piece of a very expensive piece of equipment like mass spectrometer, that's capable of making these high accuracy and precision measurements. If you're normalizing the data incorrectly, you're still going to get the wrong answers.

So then, Mike, what gives you the confidence or reassurance that when there are seemingly modest increases in protein levels that those changes that we observe are not just noise?

Yes. So it's important here to say. So first and foremost, I'm a scientist. So I'm trained in skepticism. It's run deep inside of me. So I question our data constantly, which my trainees absolutely love and appreciate, they're excited to show me data and then I just start picking it apart, right? But the unfortunate reality with the collaboration with you is that when we're working with human samples, there's no real gold standard, and we've really learned this through this internal testing.

It's not like we can just take a gold clock and place it on a scale and get repeat measurements and really, really tell you what our precision and accuracy are because each piece of tissue is unique. And so there's no perfect benchmark for these measurements, right? That being said, the 1 thing that I've really appreciated working with your team is that you guys bring the same level of skepticism to these projects, which has pushed me to be even more rigorous and really created learning opportunities for my own lab.

The in-house testing has really allowed us to understand the limits of our detection methods which provides me comfort and reassurance that we're providing top quality data here. This gives me confidence and pride that every measurement I make in Vermont is good as you'll get anywhere in the world. Other big advantages in our interactions really do come by chance and by both chance and design.

In some cases, surgeon gets a large enough biopsy that we can analyze biological replicates from the same time point, right? Only a few of your biopsies are coming to me, you're using them for other things. But I really like when we have these analytical replicates from that same time point. But even in the absence of these replicates, we always get the longitudinal biopsy is from those same patients.

So when I see consistent numbers from replicate measurements and directional increases and protein levels changing over time, I believe these measurements are reflective of the underlying biology. And well, for me, as a basic scientist, the early data from Cohort 1 have been really great and super exciting. And they make me believe that maybe -- is really -- we are getting protein expression from that AAV -- but really, they've just increased my excitement for Cohort 2 and the higher doses of the AAV.

Tell us then how imaging or other measures can serve to supplement or complement the mass spec analysis?

Yes. I mean so that's another really great question. And one of my early mentors during my PhD is cardiologist, and he said to me, if you need statistics, it's not real. And I know that people don't want to hear that, but the statement is really stuck with me through the years, and I think it's real. And it's something that really we carry into all of our homework in our labs to kind of build confidence right? So when we're working on projects, we really aim for conclusions that aren't just supported by statistical measurements, I lab and the statistics are the lasting that we usually do, but our data are usually supported by complementary assays that are going to provide multiple new points or multiple angles to address that same question and that's where I get compliments. So for instant in my lab, we often pair our mass spectrometry data with fluorescence imaging or functional assays to validate the findings from mass spec.

So the really exciting thing for me about our collaboration is that our data that we're collecting proteomic data are continually being integrated with other key measurements like RNA expression levels and functional outcomes. Unfortunately here for me, unbinding this data, and I learned about them in things like this presentation. So that's the limitation I have with our relationship.

From what I've seen so far from the change of that were reported that even though that the myosin binding protein C levels have been modest, we've seen a modest increase in this levels they're reproducible and they seem to align really well with the rest of what you're been seeing at the RNA level and at the functional level. So to me, it's super exciting.

And I think that this kind of orthogonal validation that's -- it's really this convergence of data when multiple methods were telling the same story that always gives me the most confidence that we really understand the underlying biology because biology is really complicated.

So given what you know about myosin's function in the sarcomere, what do you make up the range of protein levels in the healthy samples? And how does that impact your thinking about myosin binding protein C levels in HCM patients?

Yes, this question keeps coming up. It's come offline a bunch of times, and it's a really complex question, I think, and it's much harder to talk about in the details of this protein assay, but I'll take a shot. So if I think back to my days as postdoc, one of our key findings was that even a modest change in the phosphorylation level, the phosphorylation status of myosin binding protein C could have a significant effect on actin and myosin interaction. So how that sarcomere shortens.

So to me, it's not just about how much myosin binding protein C is present. It's about how many of those molecules are functionally active and interacting with those binding partners that I talked about at any given time. So this leads me to think that normal protein levels might not be telling the whole story. While the full replacement of myosin binding protein C volume protein C in your clinical trial would obviously be a home run.

I'm not entirely sure that it's not possible that we don't even need these full levels of myosin binding protein C to restore it's function sarcomere, to get back to what appears to be a normal heart. But I think for me and the reality here is that your team, not my work, it's our team that's doing the incredibly important work of doing a study of myosin binding protein C replacement in these humans that have disease that I could have really only dreamed that as postdocs, right?

So I really, really appreciate the collaboration here. So -- in the end, I'm very confident that my data, our mass spectrometry data will provide a very, very accurate picture of myosin binding protein C levels during all stages of your trial, but these data really are going to be transformed when they're paired with their clinical outcomes.

I think it's this critical combination of data that will ultimately help us to find that question of how much myosin binding protein C is not to restore function.

All right. Mike, last question here. How does the methodology apply to measuring other cardiomyocyte proteins such as PKP2? Can you talk about what's normal for PKP2? And is there also a range?

Yes, yes, yes, absolutely. So just as mentioned multiple times earlier, mass spectrometry is an incredibly powerful tool, right? And if it's really used properly, it can quantify the abundance of hundreds of proteins across the wide dynamic range with high accuracy and precision, super powerful. So while our interactions or my interactions with their team, initially were centered around myosin binding protein C to my combined expertise in this protein and mass spectrometry it was super easy for me to extract PKP2 data from the controlled data sets on that and expert in cardiac muscle protein expression. So this is easy for me to do. However, in true form, your team wanted more validation on my end because I'm not an expert in PKP2. So I think if we go to the next slide, we could see why your team is correct here.

So what we did is we ran many additional samples. We look back at our C protein samples, and then we ran many additional samples and tested various normalization strategies that we talked about in many meetings. And although PKP2 is localized to the interpolated disc, as what said rather than sarcomere, we still settled in on normalizing its readout peptide shared between cardiac myosin isoforms. Because, again, myosin is most reliable marker for these cardiomyocytes in the samples, right? And seeing that you're trying to express this protein in cardiomyocytes, this normalization, again, gives us confidence that we're comparing apples-to-apples across samples.

So we're normalizing things correctly. So in our new internal studies like the ones I'm showing on the slide, a few really interesting things popped out. First, the variability in PKP2 levels when measured normalizing these things these 2 -- those peptide share myosin isoforms, was similar when measured in multiple pieces for -- from the same samples. So if we look, I believe we have 4 donors here, and you see there's 4 -- multiple measurements from those 4 donors and the variability is very tight.

So this was good and again, giving me confidence in the reproducibility of the assay. However, the variability between donor control patients was surprisingly large. You can see donor one levels were much, much lower. And again, to my colleagues dismay, this was statistically significant, which did give me pause here.

So we don't really fully understand what's driving this variability, but all signs point to this variability being biological. So another challenge for measuring PKP2 is that we don't have a large cohort of examples from patients with the disease. So we can't get say anything about the variability in the disease cohort. So while I'm fully confident in our ability to measure PKP2 accurately, we're still really learning what normal looks like and how normal is going to differ with disease.

And I think by the end of the TN-401 study, we're really going to be able to answer these questions. However, in the short term, just like in the TN-201 trial, we're analyzing longitudinal samples. So each patient essentially acts as their own internal control. So we really don't need these information to determine if things are working. So in summary, I'm again confident that we'll be able to tell if the AAV is increasing the PKP2 levels in this clinical trial.

So -- but again, here, your team will also benefit from pairing our proteomic data. So the protein levels might not be telling those story. So our proteomic data with the same orthogonal approaches that you're using in the TN-201 trial. And it's again, as integrated view that will really help us move from just measuring a change in protein expression to really understanding the therapeutic response. And that's really what I'm excited about.

Okay. Mike, I'd like to thank you again for walking us through this work. It's been a truly productive collaboration with you and your lab and we've learned a lot along the way about the strength of mass spec to discern potentially really subtle changes in protein levels, which is critical evidence of gene therapy's potential for success.

We're convinced that mass spectrometry is the best method to obtain direct measurements of the proteins of interest and also to quantify their levels in the sample. And it's apparent from today's explanation, the steps that have been taken to navigate the challenges of tissue quality and sample variability, we know as you pointed out that literature has examples of different conclusions being reached based on the selection of proteins for normalization and by selecting myosin heavy chain, which is expressed only in cardiomyocytes but not in other cells of the heart, we can be confident that the measurements are directly applicable to the goals of treatment.

The work in normal control heart shared here also bring home the fact that there isn't just one threshold that we need to get to, the biology of the individual matters and it will be the changes in each patient over time, that will be the most important way of looking at and interpreting biopsy data. Thanks so much again for this discussion, Dr. Previs. Operator, I think we're ready for Q&A.

[Operator Instructions] Your first question comes from the line of Cory Jubinville with LifeSci Capital.

This one for Dr. Previs. So you emphasize normally MYBPC3 levels to myosin heavy chain 6 and 7 to help kind of mitigate that biopsy, heterogeneity. Does HCM status impact the stoichiometry of the sarcomere or in the case of PKP2, the desmosome? And if so, how do you validate that myosin heavy chain 6 and 7, content is stable or comparable, whether it be across time points or disease states or sampling sites?

Thanks for the question. As always, we know that you're going to go deep, and I'm so glad that we have Dr. Previs here to talk about the methods that we use for normalization. So Dr. Previs why didn't you get started? And then after that, I'll invite either Kathy or Whit to add any more on top of your comments.

Yes. So I mean that's a great question, right? So for myosin binding protein C, the answer is very simple that myosin is in complex with myosin binding protein C, we know under normal conditions, exactly how many molecules of myosin are in thick filament. We know how many molecules myosin binding protein C are thick filament, this is rock-solid from everything from zebrafish to mice to humans, and we've measured this in all of these things.

So yes, in HCM in that case is clearly a -- due to a lack of stoichiometry of myosin binding protein C to myosin. We also get quantitative data on actin, the regulatory proteins on thin filament and all of those things are highly regulated and precise and we're only seeing loss of myosin binding protein C in the case of disease triggered by that, by mutations and MYBPC3 gene. So PKP2 is a little bit more complicated, right, because it's in the interpolated disc.

And as we showed from those donor controls, there is definitely differences from one control to the other, and we were very surprised. But if we try to say normalized to some other protein interpolated disc, which is what we've also tried to do, we're concerned that we don't know enough about biology, the normal biology of PKP2. So we -- our most consistent data are when we normalize to myosin heavy chain because it seems like the myosin heavy chain is the most representative of what is in the cardiomyocyte.

And again, from my lab, if we image, we see very -- the fluorescence imaging, we see very consistent reproducibility and the expression of myosin within the cardiomyocyte, no, there's not big gaps in expression. So I hope that answers your question, but it's a great question.

A great question. Yes, so far in HCM due to loss of MYBPC3 the goal is to restore the stoichiometry. And so the appropriate number of hands are physiologically regulated. And of course, as Kathy mentioned, the protein we express is indistinguishable from wild-type protein, so we should have all the regulatory capabilities. So that Stoichiometry that we're measuring, the ratio we're measuring is what we're trying to improve.

Now yes, for ARVC and PKP2, it's a little more complicated. You could think, well, we want to improve the stoichiometry of the desmosome. But in that case, PKP2 is a critical anchoring protein for the structure. So the whole structure falls apart. So we hope and expect that all the desmosomal proteins will increase an expression, and there'll be more on the cell surface, as we express the PKP2 protein so not appropriate to normalize to those.

And I'll say the same is actually true of the gap junctions, the critical [ tingling ] molecule in the heart, those also drop off without enough PKP2 to anchor the desmosome. So we do actually -- we wouldn't want to normalize to any of those, and that's why normalizing the myosin heavy chain makes the most sense..

Got it. That's helpful. And as a follow-up on PKP2 expression. So on the final slide, it notes the variability between -- of PKP2 expression within a patient is low, but across patients is high, but when you outlined some of that historical data across donors on MYBPC3 protein expression, it seemed pretty remarkably consistent at about 60% of normal. I guess what's the biological rationale behind this discrepancy between MYBPC3 and PKP2? Assuming these are relatively healthy donors on PKP2 expression and how should we make sense of this as it relates to evaluating the efficacy of a PKP2 gene therapy? Is it kind of less about hitting the specific threshold relative to normal? Or is it more about an individual specific improvement from baseline?

Thanks again for -- Cory for the question. I think for this one, maybe Whit, I'm going to ask you to go first to just talk about the different sort of thresholds and how we think about thresholds versus absolute protein and how we think about sort of expression relative to the normal range?

Yes. And both of our studies will really help inform how much protein makes a difference in the phenotype, but going in we don't think that there is a threshold effect. We do think that the variability across both healthy people and in these patient populations suggest that everybody has their own sensitivity to protein loss and protein reduction. So in another way of saying the same amount of protein loss of reduction could cause disease in 1 person and not in the next person. So our goal is to increase the protein level in patients towards normal, but not achieve any specific threshold.

Maybe just to add 1 more comment to that. If it's possible to go back to that slide, the last slide. Cory, it's an important question, right? This is the first time we're showing this data. I believe the first time data like this has been presented, showing sort of a range of normal using this very, very precise method.

Enjoying PKP2 protein in this way. And it is interesting to see this wide range of variability. And I think a few things are true here, right? One is that we don't think that we need to get to the top end of this range, probably don't even need to get to the middle of this range if there was like a median or an average that right? People at the very low end of this range have perfectly normal hearts. They have no disease, right? And this is from what end of '12, right? If we were to run this end of '24, we'd probably see some clustering towards a mean, and we might also pick up even more variability at the top and bottom end.

For the purposes, we hope to get patients closer to the lower end of that range because we know that at that lower end of that range, patients have completely normal heart, but we don't think it's a magical threshold effect even at that level every little bit that we give to these patients can go a very long way and we've seen this from other genetic cardiomyopathies, including from some of our peers, but a little bit can go a long way.

So the general goal is to get in the direction of the lower end of this range. But the absolute goal is to give each patient more than what they have because it appears that the heart is very sensitive to the loss of this protein for each patient in their own way. So if we give them a little bit more back, that should go a long way. So would you agree with that statement?

Yes.

Your next question comes from the line of Ritu Baral with TD Cowen.

This is Joshua Fleishman on the line for Ritu. Curious, from prior data, are there any preliminary covariates that you guys have identified, which can help predict the quantity of transgene expression needed to provide a meaningful functional benefit?

Joshua, it's a good question. And are you referring to the TN-201 MYBPC3 program?

Yes, sorry.

Okay. So are there any covariants, other proteins that are changing that might be predictive? You're the experts, Dr. Previs. I'm going to give you a first shot at answering that question, whether we see other proteins changing at the same time with MYBPC3. And then Whitt, I'll kind of ask you to follow up with that about how we think about predictors of success.

Yes. So that's a complicated question, again. And we published papers on this. The -- at the protein level, there are many proteins that are also changing. Myosin-binding protein C is lost, but there's metabolic proteins that are changing because there's complex remodeling that is happening, right?

In previous studies, we have tried to team up with geneticists to take our protein data and correlate it with their genetic data to answer that exact question, right? So is there -- is any protein that is decreased, also in combination with myosin-binding protein C? Does that have another mutation in that other protein?

And my understanding is that there is no other protein that has been shown to be -- or other genes to be co-affected to trigger the disease. But definitely 5 years ago, I went down the same path, and maybe we just don't have the technology yet for the informatic ability to kind of go through the genetic data. Whitt might be much better answering this than myself.

Yes, Just additional thoughts. So we don't have good clinical predictors of the protein level. We have looked at the heterozygous patients and compared the protein level to the age of onset and other things, didn't find a clear pattern, but we are very much underpowered for that analysis. So more to be done as we get more data.

As Mike was saying, the best predictor is the genetics and particularly the type of mutation, number of mutations occurring in the MYBPC3 gene. So if you have two truncating mutations, you probably have zero protein. We look forward to more data coming out about that, but that's the presumption of the field.

There are leaky truncation mutation. So if you have a little bit of leak, you may have a little bit of protein. And -- but those with zero protein have very severe disease. The infants I talked about need heart transplant in the first year of life.

If you have one truncation mutation and other is normal, that's the patients we've been talking about here with roughly 60%, but some variability there. And then, of course, if you have 2 wild-type copies, you averaged at 100%, but there is a range there as well. So that is the biggest predictor of protein level as the number of truncating or loss of function, mutations and their leakiness.

My understanding is that we have not found polymorphisms that regulate the level of C protein, so quantitative trait low side like that. So we can't build a polygenic model of C protein expression at this point.

Okay. And then I just have one follow-up question, please. Just to confirm, using the LCMS approach over other traditional approaches, it appears that the major benefit is just the higher sensitivity and higher specificity of the assay. But it looks like both approaches are still limited by only measuring total protein, not protein expressed solely from 201 or 401, correct.

Yes, correct. So...

Go ahead, Whitt.

So because the protein products of our gene therapies are full-length, wild-type sequences, they are identical to the endogenous. And so these techniques cannot distinguish where that protein came from, transgene or the endogenous gene.

But there are many more advantages to mass spec that Michael listed. We're measuring many peptides across the length of the protein, and we can much better control than when we're measuring a single epitope with a single antibody.

Yes, the only I'd add to that, Joshua, is on Slide 27 that was presented. It really is so telling that the -- how methods matter. We really, really have swept the small stuff here with Dr. Previs over now many years. And really, this is why we decided to select mass spec. And even within mass specs, selecting what is the -- what are we going to do myosin -- normalized to myosin, not only myosin, but specific peptides.

We actually had a whole family of peptides to select from within myosin and looking for stability, looking for things that are not going to vary as much to make sure that we're picking the right anchor against which we were measuring the changes in the Myosin-III protein. And it was a similar method that went into PKP2. If you compare the methods, you're normalizing the GAPDH versus myosin, we just wouldn't even come to the right conclusions about who is normal and who has disease.

That is the central insight for us here and why we decided to go the direction of mass spec and within that, be nearly obsessive and beyond the scope of today's presentation about which specific peptides we're measuring for each biopsy samples within the myosin.

So a lot of detail here beyond the scope of today's presentation, but gives us a lot of confidence about the mass spec method and the normalization to myosin from both programs.

Operator, let's take the next question.

Your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

This is Dominic on for Yasmeen Rahimi. Thank you for the great presentation and the helpful insights. So we just had a quick question. Considering the MyPEAK data will be helpful to inform dosing selection, how informative do you expect the additional Cohort 1 and new Cohort 2 data to be? Specifically, how do you plan to use the totality of data across the protein improvements and the safety measures to inform continued development?

Dominic, thanks for the question. Whitt, I'll turn it over to you, how do we think about the incremental data that we'll be getting and presenting in Q4 of this year relative to what we presented to date and how that informs our future direction?

Yes. The best way to choose a dose is to compare doses, and we really look forward to sharing the first data from the higher dose 6E13 vector genomes per kilogram. And of course, that comparison will be the starting work to help select the dose for future pivotal study. Safety, of course, is paramount. We want to choose the dose that is definitely safe and very well tolerated.

We are encouraged that our DSMB has reviewed the data and endorsed proceeding, indicating that both doses are well tolerated. The -- we will be sharing biopsy results from the high-dose cohort. And the biopsies for all the reasons we've said today provide very quantitative and early in the post-treatment time course data on the expression of protein, which we predict will lead to efficacy. So the dose protein expression relationship will be very informative for dose selection.

But we also want to confirm that with clinical endpoints, which take longer to mature, we are certainly following those the end of the year readout might be early to really compare the clinical efficacy across the dose cohorts. So later next year might be the time for that of that analysis. But all these factors will go into the ultimate dose selection to take forward to subsequent trials.

Yes, Dominic, the only thing I'll add to that is, it's a good question, right? We're at an exciting moment in the program. We'll be presenting early additional data from the dose Cohort 1. We're already pleased with what we're seeing from dose Cohort 1, right? We were quite pleased with what we're able to share at the ACC earlier this year, and we summarized that at the top of this call.

So we're looking forward to sharing even more from longer follow-up from these patients. What we've seen in some of our peers and what early evidence seems to bear out here is that the longer we wait, the more we see both the durability of the effect and even some additional effects over time. So we're excited with Cohort 1, we're excited for dose Cohort 2 with the biopsy.

From here, there are many directions we can go, right, from a program perspective. And we've said this for a while, we can continue exploring adults. Right now, the patients dosed to date have been mostly nonobstructive patients. There's also obstructive adults, but then there's also the children.

And we're quite excited to be presenting data, the first ever data presentation from our MyClimb natural history study of more than 200 children, both retrospective and prospective data that will be presented at the upcoming European Society of Cardiology, what will be there with the other members of the team to share that data and to really bring a spotlight on the very severe children, both the homozygous infants as well as compound heterozygotes and other severe heterozygotes.

So that's another exciting direction that this program can go. The data we're generating now helps us decide what's the right dose, irrespective of the population we're going after, whether nonobstructive or obstructive adults or children, what's the right dose that strikes the right balance between safety, protein expression and signals of efficacy.

So in Q4, we look forward to presenting the data, but we won't be sharing the direction that we're going with the program at that time, that would be more of a 2026 discussion.

Hopefully, that answers your question, Dominic. And operator, ready for the next question.

Your next question comes from the line of Mike Ulz with Morgan Stanley.

Thanks for all the details on your methods here. So I guess, maybe just with your more precise methods in terms of protein expression, I guess what's the lowest level threshold over time in the same patient where you're confident you're seeing a real change in the expression versus just noise? It sounds like maybe very low percentage difference would be meaningful with these methods.

Yes. Great question, Mike. Thanks for asking it. And for here, I'll ask Michelle to wind back one slide. And Dr. Previs, if you don't mind speaking about how do you think about the noise, right? There is a certain level of difference in the samples on Slide 29. So Dr. Previs, maybe you can speak about that for each protein in each program.

Yes, I can definitely do that. So what slide are we going to go back to?

This one. Just the variability.

Yes. Yes. Yes, yes. So I don't want to give you an actual number for what the level is because I don't want to mislead you. I've been shocked, we've done many mixtures assays where we're mixing known levels of proteins together, and our methods are even more robust than I would have ever thought or I thought at the beginning of the process here.

But you could see for donor 1 for PKP2, which, again, PKP2, I want just to keep in context here, is expressed at a much lower level in the cardiomyocyte than something like Myosin-binding Protein C or myosin because it's only in the interpolated disk rather than distributed everywhere. So our absolute signal is always a little bit lower for PKP2. So there's probably a little bit more variability in that measurement.

But the variability between repeat measurements, as shown here on the left, so these are individual pieces of heart from the same patient; is quite low. It seems like a shock on blast that we could see. And we can tell the difference between donor 1, donor 2, donor 3 and donor 4 really when the data are lined up like this.

So for me to really address your question, I think we showed for TN-201 maybe a 3% to 5% change for multiple samples. To me, that seemed real because those data came from repeat measurements of biopsies, as shown here, when they were available, and we saw that increase over time.

I think that in Cohort 2, I think we have both the access to the tissue is a little bit better than when we started, and we're repurposing them for mass spec a little bit better. And I do think that the higher dose is going to be telling.

So I don't know if that quite addresses your question.

Yes. No, that was very helpful.

Your next question comes from the line of Sami Corwin with William Blair.

I have one for Dr. Previs and a couple for the company. Dr. Previs, just curious, how low cardiomyocyte levels in a biopsy could affect the mass spectroscopy sensitivity and accuracy? And then for the company, can you validate or clarify that mass spec was used for protein quantification in the initial TN-201 data?

And then obviously, this presentation highlighted how powerful of a tool mass spec is. But given some of your competitors who are also developing PKP2-based gene therapies, have presented protein data using other methodologies, do you plan on supplementing the use of mass spec with other methods for measuring protein expression?

So those are three questions there. And we'll try to do them justice one by one. I will -- maybe Dr. Previs, you can confirm the answer to one of the questions, which is the methods. Have the methods changed at all between 201 and 401? Or have we generally used the same methods?

Yes. So the method is the sample prep, the LCMS, how the sample goes through the LCMS is all identical. Obviously, we're selecting different peptides for PKP2 versus myosin. In the background, we're also looking at peptides from collagen, from albumin to really assess the quality of that biopsy and get a sense of how many party of cardiomyocytes are there. Faraz, would you like to answer the question about how low we can go?

Yes. Well, so the other one is -- the question was now we have seen that other companies -- this is not in the MYBPC3 space, Dr. Previs, but this has been in the PKP2 side, there are two other companies, and they have different methods. And we're not commenting on the quality of their data or anything like that. But methodologically, there are some differences using Western blot versus mass spec, normalizing to GAPDH versus normalizing to myosin, two very obvious differences between our methods were there.

So the question was, would we be changing our methods, now that we know that others have presented this in a different way? And I think the answer is no on our side. No, we're not changing our methods. But do you want to add to that in any way about reaffirming the metrics that we've used compared to others.

Yes. I mean without -- as an expert here, without seeing the actual -- how the sample was handled to the output that came about, it's really hard for me to complement or comment on any other method. Kind of I make this look easy often, even with your team, right? But it's from 20-plus years of experience of handling cardiac muscle biopsy, right? And there's a lot that goes into the front end of the sample prep to make sure that these things are right.

And with your team, we've looked at -- we've taken data that was run in 2017 that was published in 2019, that I didn't even touch as a technician in my lab, and we've compared those data to the sample sitting in the freezer for God knows how many years and me doing the preparation, me running the sample and the data are virtually identical. We can't tell the difference between biological variance versus the technical variance on the data, which is fantastic.

So I think it would be premature to comment on anybody other -- anybody else's math because Western blotting is not Western blotting, the same thing. I try to make a point that mass spectrometry is not mass spectrometry. You could buy $700,000 piece of equipment, you could try to do this yourself, but you need the expertise to do that in that area.

And it's -- it kills me when faculty members tell the student, "Oh, just do mass spec on this." It's its own specialty in that.

So the last part of the question -- go ahead.

As a grad student, I did a lot of Western blotting back in the day, and I'm really impressed with mass spec and its level of -- not the sensitivity, but accuracy overall for so many different reasons. But they're are apples and orange, very difficult to compare and different labs, different samples, that would be a very hard crosswalk to do.

But please do, Mike, go ahead, and I'll answer the other question about how we...

Well, and also, I think that -- if you don't mind going to Slide 24 because there was also this question about the sample. And if depending on the content of that sample, how does the method handle that? And so I think this was sort of glance at the very beginning 3 hypothetical pinches with varying levels of cardiomyocytes in there.

And so Dr. Previs, do you mind just sharing how the method adjusts to this in mass spec better than other methods at quantifying the protein in the backdrop of fibrofatty replacement or fibrosis?

Yes. I mean so you -- these are very critical. They're very special samples. There's a lot of anxiety whenever one of these samples arrive, right? And I think from your end, we had a sample that produced no data, right? And when we look at that sample, there is no -- there's very little myosin heavy chain in that sample, which is the most abundant protein, right? And that raised an alarm in my mind that the quality of the sample is really critical.

The surgeon is blind when they go in and take these biopsies, right? They're sampling wall, they can get some fatty material, they can get fibrotic material, right, and they're tiny. So that's exactly why we use myosin because, again, it's a marker of how many cardiomyocytes in there.

And we are now in the process of just revising exactly, so we know exactly what level of myosin we need to be able to see on the mass spectrometer to be able to know that we're detect -- we're able to detect PKP2 or Myosin-binding Protein C.

So to your question, it's very low. Like it's very sensitive, but we do need cardiomyocytes. If the biopsy is a vessel or a collagen or fatty material, we are not going to get data from that biopsy. That's the reality.

And I believe what you're referring to is in our TN-201 program, the third patient [ C1 P3 ] had a baseline biopsy, the initial post-dose biopsy, we weren't able to really quantify protein from that because there were simply just not enough cardiomyocytes in there.

But of course, we have a second shot at a biopsy of that patient, which is the second biopsy, which will be part of the data readout in Q4 of this year, where we do have meaningful data for that patient as well as subsequent patients in the high-dose cohort.

So Whitt, was there something else that you were trying to add before I jumped to the slide?

No, this was exactly it.

I think we may have time for one last question before we get to the end of the allotted time. Operator?

Your final question comes from the line of Joe Pantginis with H.C. Wainwright.

So my first question out of two is a bit layered, and I'll qualify it by saying your views as of today because it could certainly change tomorrow. As the program moves forward, I wanted to get your sense of the role of biopsy, say, the level and frequency in later-stage studies versus just assessing clinical parameters. And what your views might be regarding the commercial and regulatory scales for mass spec?

That's an interesting question, Joe. Thanks for asking that. Let me first turn the second part of your question. I'll address the first part of your question with Whitt's help. But for the second part, the scalability of mass spec, imagine a future world, Dr. Previs, where we're analyzing a lot more samples in parallel. Is this -- are these methods scalable?

Yes. The short answer is, absolutely. The method is scalable, it's transferable to different mass spectrometer, different [ tolerogenic ] setup where the data could be produced even faster, right? It's very scalable.

Go ahead, Whitt.

Yes. The vision is not to need a mass spec or tissue samples for commercial use. These protein levels are very, very valuable for showing the efficacy of the gene therapies, and we're very encouraged by increasing enthusiasm at the FDA for mechanism-based approvals for these types of therapies. So replacing protein in disease is caused by protein, so very valuable for dose selection, for demonstrating activity and for approvals of gene therapies at this point.

But at commercial launch, we'll use the genetics. As I said that the genotype really predicts whether there is insufficient protein causing disease. And so it will be the genotype pathogenic, likely pathogenic mutations in MYBPC3 or PKP2 that would determine eligibility for clinical use without requiring heart biopsy.

I appreciate that. And my second question is...

Joe, I do want to be fair. There's I think somebody else is waiting in queue.

And the other thing I just want to be clear, in a commercial setting, we think that protein biopsies are going to be really important for the potential for accelerated approval based on protein as a surrogate marker that's been done with many gene therapy programs, including some of our peers, as well as, obviously, there have been some high-profile cases in the Duchenne muscular dystrophy space.

So protein is really important when you're seeking that initial regulatory approval based on a surrogate marker. However, in a commercial setting, right, we don't see that biopsies continue to be necessary. So it's really important at this stage when we're trying to understand the relationship between protein and benefit, but not something that we would be doing at commercial scale later.

So I just wanted to sort of put that to rest because that was -- I thought that might be linked to your question about scalability of the method. We would not be suggesting to do baseline biopsies and post-dose biopsies on thousands and thousands of patients in a commercial setting.

We do -- we are over, but there was one more question from one of our analysts. And operator, if you don't mind opening it one last time.

We have a question from the line of Geulah Livshits with Chardan.

Maybe just another question on normalization. Again, you showed the nice intrapatient and a little consistency across the different samples. So when you think about the trial interpretation, I'm wondering if the longitudinal data showing consistency over time for MYBPC3 and perhaps less so than for PKP2?

And also for the trial, could there be an impact of the immune regimen on the protein expression dynamics, for example, myosin heavy chain or the MYBPC3 and the PKP2 that could affect the interpretation of the data?

Good question. Maybe, Whitt, can I first ask you just immune regimen and whether you had any reason to believe from our work or the work of others that the immune regimen might in any way complicate these measurements? And I'll ask you, Dr. Previs, to also add to that.

Yes. So great question. Thank you. Obviously, in the gene therapy field, there has been a question about the immune system removing cells that are expressing the therapeutic protein.

We don't believe that will be a concern. We have not seen any evidence of reaction against the protein probably because these are heterozygous patients that are [indiscernible] positive, meaning they're already tolerant to all the peptides in the MYBPC3 and PKP2 proteins. Also these are intracellular proteins. So that makes it that issue less likely.

Now to your question of inflammatory cells potentially being there, of course, we do heart biopsies, we do not really see that. So that's not going to be a problem. Theoretically, that would be compensated by the methodology that Mike has developed to normalize to that myosin heavy chain. So I guess no across the board.

Dr. Previs?

Yes, I don't think I can add anything to that. But again, that's the reason why we're normalizing to myosin because it is in the cardiomyocyte. And I think it does take care of those questions.

To address the other part of your question, Geulah, it's a good one, and it's come up before, so it may be worth putting to rest.

Michelle, do you mind going to Slide 22? Because this is your original work, Dr. Previs. And one thing that struck us when we first saw this, and while we approached you even about using this method and our -- prospectively in our studies is how remarkably consistent it is, but isn't one insight from here.

These are different patients, all had MYBPC3 mutations, all had myectomies. They were at different stages of their disease, right? And so some might have been 30 years old, somebody might be 40 years old, somebody might have been 50 years old. So this idea that these data may fluctuate a bit over time longitudinally, it feels like the tightness of this measurement suggests that if there is any such thing, it would be within a very tight range.

Is that a fair assessment of this data set?

Yes. I mean absolutely. I am always shocked in healthy animals, healthy individuals. I am shocked by how consistent that number is between mice, again, rats, humans. And the one thing that did come out of my work post publishing this paper with you is I do think that the data points that are high here above this blue line were consistently high from biopsies. I think that's just what's in the person, what's in that person.

Again, we don't have multiple biopsies from that person over time. So we don't know how much it will fluctuate. I think the coolest thing about the collaboration with you is we get those multiple labs to describe, so we'll see if the level increases, if it continues to be increased, how it varies between biopsies and that sort of thing.

So although you're doing clinical trial, me as a basic scientist, I am super excited about basic science, the basic science aspect of this also, which is kind of what some of these questions are touched.

Yes. And the only last thing I'll add to that, it is important, it's a relevant question. I would say that Obviously, we'll have, Geulah, two shots on goal here for each patient for which we have the baseline biopsy and one post-dose biopsy as well as sort of more immediate, for example, in the PKP2 program, 8-week biopsy. And then we'll have another d at the 52-week.

So we'll be able to see if there are any changes with time, but there's always going to be a certain amount of pinch-to-pinch variability. That has nothing to do with the time course of the disease, the changes in the disease. So we just have to have the humility there that there will be changes from pinch to pinch over time. But we'll have a chance to see that.

I'll also remind you that it's not just a protein and this normalization of myosin, but there's other things like RNA that we're also looking with the totality of the data that we're looking at. And so there may be small differences in RNA from time to time or protein from time to time. We'll be able to see some of that. But overall, we don't think that there is meaningful changes over time, and that's what this data set seems to tell us.

Final thing I would say is in our peers who published in the New England Journal last year, had some excellent work done in Danon disease; they were able to show longitudinally over many years, they showed RNA and protein, and there were changes over time. Some of that may have been biological variability, some of that may have been methods. And so the importance of getting your methods right upfront cannot be overstated, and that has been the whole point of today's presentation.

So I think we're over time, we're so glad that there was some good Q&A here, an opportunity for back and forth with our speakers. I want to thank you, Dr. Previs, for lending your time and your expertise to us today and being such a wonderful -- for committing your career to these methods. And and that enables us and our mission to move forward towards patients and really enable us to make sense of the data that we're getting from these studies.

So thank you for your work. Thank you for your partnership over many years. And thanks to Whitt and Kathy for adding their voice to this, and thanks to all of you for attending today.

Our analysts had a chance to ask questions, and we are able to respond not everybody on the webcast. If you submitted a question, had a chance to do so, but you have an opportunity to do so later. You know how to reach us, Michelle Corral, our VP of Investor Relations, or e-mail is in the public domain.

Please, if you have burning questions that came from today's presentation, please don't hesitate to reach out to her, and then we'll find a way to answer that. This is just setting some stage for data releases in Q4, more to come. It's an exciting time for Tenaya.

We thank you for your attention, and looking forward to the second half of the year and these data releases and the discussion that will follow. With that, operator, I think we can close.

Thank you. You may disconnect.