Tenaya Therapeutics, Inc. ($TNYA)

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.