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. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during that time, simply press star, then the number 1 on your telephone keypad. 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 and Corporate Communications here at Tenaya, and we are excited to share data today from our RIDGE-1 phase I-B/II clinical trial of TN-401 gene therapy for the potential treatment of PKP2-associated arrhythmogenic right ventricular cardiomyopathy, or ARVC. These data were presented earlier today as a late breaker oral presentation at the American Society of Gene & Cell Therapy. While the data we are discussing today will be described in full verbally, please note that during the course of today's talk, we will be making references to slides. A PDF file of the slides accompanying this webcast are 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 view as of today, May 15, 2026. These statements involve certain assumptions, and we caution investors not to 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 that could cause actual results to differ materially from those expressed or implied by these statements. Turning to slide 3 on the call, with me today 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. We are also very pleased to be joined by Dr. John R. Giudicessi at the Mayo Clinic, an expert in genetic cardiology and a principal investigator for RIDGE.
I would also like to note that any opinions expressed by Dr. Giudicessi are his own and do not necessarily reflect the views of the 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 options and significant disease burden. As we approach our 10-year anniversary since Tenaya's formation, our commitment to heart disease and the cardiology community has never wavered. Across the board, we have invested in the deep understanding of these conditions and in the science necessary to bring new treatments, and with that, new 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. 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 I-B/II clinical trial of TN-401 at the American Society of Gene & Cell Therapy's annual meeting. We were very pleased to see our presentation garner 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 20-52 weeks, showed that all patients on study achieved consistent, deep, and sustained reductions in arrhythmia burden. Biopsy results show that TN-401 is reaching the cardiomyocytes and achieving expression. Importantly, TN-401 gene therapy was well-tolerated at both the 3E13 and the 6E13 vector genomes per kilogram doses. We are very encouraged by these results. Before we dive into the data, I wanna take a moment on slide six to briefly ground us in the disease we're here to discuss, ARVC, and why this work and these results matter. The most common genetic driver of ARVC is mutations in the plakophilin-2 or PKP2 gene, which are estimated to account for roughly 40% of diagnosed cases.
PKP2 associated ARVC alone is believed to affect more than 70,000 individuals in the United States. Symptoms can begin early in life and often include palpitations, lightheadedness, fainting, and exercise intolerance. 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 its severity, but its impact on otherwise young, active individuals and families.
Despite the use of implantable cardioverter-defibrillators or ICDs and strict lifestyle limitations, patients often continue to suffer from recurrent arrhythmias, painful ICD shocks, 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 ARVC. 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, a discussion by Kathy Ivey and a Q&A with Dr. John Giudicessi. Whit?
Thank you, Faraz. Having touched on the disease and unmet need, I'd like to start with a discussion of how TN-401 is designed to address PKP2-associated ARVC, the design and objectives of the RIDGE-1 trial, and the newest interim clinical results. As illustrated on slide 8, PKP2 gene mutations disrupt the structural integrity of the heart. The PKP2 gene produces a key protein that provides critical support for the mechanical and electrical connection necessary for every heartbeat.
Deficiency in PKP2 protein leads to degradation of a scaffolding structure called the desmosome that helps the heart muscles hold tightly together and stabilizes the electrical channels or gap junctions that trigger each contraction. TN-401 gene therapy is designed to deliver a full-length functional human PKP2 gene using a well-validated AAV9 capsid and a cardiac cardiomyocyte-specific promoter.
Once delivered to cardiomyocytes, TN-401 produces PKP2 protein to increase levels of the missing protein and thereby address the underlying cause of the disease. In preclinical studies, TN-401 halted the disease. It maintained normal electrical stability, prevented structural damage in both the left and right ventricles, and prevented premature death.
On slide 9, we have an overview of the RIDGE-1 trial, which is designed to characterize the safety of two different doses, 3E13 and 6E13 vector genomes per kilogram body weight. In addition to dose finding, RIDGE-1 is looking at the pharmacodynamics and includes several exploratory endpoints measuring changes in key clinical parameters. We have now completed enrollment of both those cohorts, and we're currently enrolling patients in the 6E13 vector genomes per kilogram expansion cohort.
The data presented today includes safety, biopsy, and clinical results from the six patients enrolled in cohorts 1 and 2. 2 additional patients have now been dosed in the expansion cohort, will be included in future data readouts. Slide 10 shows the baseline characteristics of screening. A couple of things to point out here. First, all six patients also participated in our RIDGE natural history study. Second, they have signs of severe disease. Most were diagnosed at a young age.
Many have undergone catheter ablation procedures, all have required implantable cardioverter-defibrillators. Despite a robust standard of care therapy, all remain at risk for life-threatening arrhythmias, continue to have electrical instability manifested by high numbers of premature ventricular contractions or PVC every day. TN-401 successfully improved electrical stability in preclinical models, let's 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's 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 can trigger a life-threatening arrhythmia.
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 seven 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 two patients occurring 6-9 months after dosing, and these patients continue to have lower rates at one year.
At this most recent data cut, the average drop across all three cohort 1 patients was 60%. Cohort two has an average reduction of 67%, including patients five and 6, who had strikingly high rates at screening. Two more things to point out. The reductions in cohort one out to one year past dosing suggest a durable effect. Second, PVC counts in cohort 2 are dropping before 6 months, sooner than we saw in cohort 1. This may indicate faster onset of action at the higher dose. However, we will continue dosing more patients to confirm. As we monitor PVCs, we also gather data on non-sustained ventricular tachycardias or NSVT.
These are rapid runs of the normal heart rhythms coming from the ventricle lasting up to 30 seconds that are more severe and higher risk than PVC. On slide 13, we see that among those patients in RIDGE-1 who were experiencing high rates of non-sustained VTach, these were dramatically declined post-dose. Patient two went from an average of 78 per day to zero, and Patient five went from 43 to four per day.
Drops like these, if persistent, could reflect substantial improvement in electrical stability. The other patients in RIDGE-1 had low non-sustained VTach counts at screening, and their counts remained low and stable at post-dose. Other measures of clinical response, including QRS duration, T-wave inversions, echo parameters, and New York Heart Association class were in the normal range or remained stable. Why do these results matter?
Electrical instability is the hallmark of PKP2-associated ARVC, and 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 non-sustained 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 arrhythmias. PVCs and non-sustained VTs can be reliably quantified in a trial such as RIDGE-1 and are direct and early indicators of whether TN-401 is achieving disease-modifying effects as designed.
We are thrilled with these early, consistent and persistent results that we have shared today and look forward to presenting more clinical data with more patients and longer follow-up durations 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've obtained from our biopsies. Slide 16 illustrates the purpose of the heart biopsies, which we take at three junctures, pre-dose or baseline, post-dose, which was week eight in the first 4 RIDGE-1 patients, and week 22 for patient 5. Finally, again at week 52. Patient 6's post-dose biopsy analyses were not yet available out of our data cut. You'll note we varied the timing of post-dose biopsies in order to begin getting a sense of TN-401 kinetics. Using a catheter, a small snip of tissue about 1 millimeter in size is taken from the septum. Six to eight of these tissue samples are collected in the cath lab and receive an initial visual inspection for quality.
Each of these precious tissue samples is preserved and earmarked for specific quantitative analyses of DNA, RNA, or protein. The measurements collected during these biopsy samples analyses 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 cell to produce PKP2 protein.
Results shared on Slide 17 provide clear evidence that TN-401 DNA is consistently reaching the heart with robust vector copy numbers per host genome ranging from 1.8-5 vector copies per cell. On Slide 18, we see clear evidence of RNA expression, which is measured as transgene copies per microgram of RNA. While the totality of our biopsy results are what tell the story, the 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 expressed in cardiomyocytes by virtue of the selective promoter use and is able to do so with high sensitivity and specificity. Here we see robust levels of mRNA expression ranging from 1E4 up to 2.9E5 RNA copies per microgram of RNA. For those samples in cohort 1 where we have measurements across time, we can see that mRNA expression is the same. As we look at protein expression levels over time on Slide 19, these data show some encouraging apparent increases at different time points. The overall signal is confounded by the challenges of measuring PKP2 protein in diseased heart.
As a reminder, the PKP2 pro-protein produced by TN-401 is indistinguishable from PKP2 protein produced by the patient's one working PKP2 gene. Despite the ups and downs of the bar chart view, it does not make sense that protein levels would be lower after dosing than prior to treatment. Given the clear increases in DNA and RNA, coupled with the clinical results shared by Whit, it would believe that protein levels are staying flat. What is happening here and why are the results confounding, not just for us, but also for others using different methods? We believe that chief among the challenges in quantifying protein level changes is 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 cardiomyocytes in decline, fatty or fibrotic tissue, or a mix of some or all of the above. The image on the right shows a section of cardiac tissues from an ARVC donor heart with two encircled areas that could each represent a 1-2 millimeter biopsy. The area on the left in the dark blue circle contains a high proportion of cardiomyocytes than the area on the right in the red circle, which contains more fibrous fatty replacement. Because each collected biopsy sample is designated for a different measure, there will be variability from patient to patient, assay to assay, and time point to time point.
In an effort to minimize these variables, my team has brought significant time and effort, as well as our own and external expertise forth to develop an approach to measure PKP2 protein levels in cardiac biopsy samples. On slide 21, we review our methodology. As you may recall, Tenaya has selected liquid chromatography mass spectrometry, or LC-MS, for this purpose. In the heart, PKP2 expression is highest in cardiomyocytes, but can be detected at lower levels in other cell types, including fat cells, which are known to infiltrate ARVC hearts.
Therefore, to get the most meaningful measure of our protein of interest, we normalize the LC-MS measurement to a cardiomyocyte-restricted protein, in our case, myosin heavy chain, to provide a reliable and consistently quantified measure of PKP2 protein relative to the heart muscle content of the biopsy, where it is needed to support the structural and electrical integrity of the heart. Among our findings in the examination of PKP2 measurement methods using samples from donors without disease, we learned there is a wide range of normal PKP2 levels, as seen on the left. This tells us that differences from person to person are to be expected and that interpreting comparisons across our patients or between patients and healthy individuals requires caution. The graphs on the right show PKP2 levels measured from the same 5 normal donor hearts, but using three different methods.
LC-MS normalized to myosin or Western blot with either a standard curve to calculate absolute PKP2 levels were normalized to the ubiquitously expressed protein GAPDH. LC-MS normalized to myosin resulted in a twofold difference in PKP2 protein among these five hearts. In contrast, without normalization to the myocyte-specific protein, Western blot's results showed up to sevenfold difference between these same five normal donor hearts.
The variability that occurs when cardiomyocyte composition is not taken into account may be further intensified in samples from diseased hearts due to their more varied composition. It quickly becomes evident that protein values are really not comparable across trials using different measurement methods. Given the reproducibility of the protein quantification available via Mass spectrometry 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 sample.
The totality of the 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 decreased arrhythmia burden across all patients, gives us confidence in TN-401's disease-modifying activity. I'll now invite Whit back 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 of both TN-401's pharmacodynamic activity and PKP2-associated ARVC biology at a molecular level. RIDGE-1's primary endpoint and purpose is to establish 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 adverse 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 was classified as an SAE because it was monitored in-hospital.
These elevations resolved spontaneously without treatment, with no evidence of clinical myocarditis and no sequelae. As of the current data cut, there are 2 new grade 3 events, both associated with a medication error in 1 patient. 1 liver enzyme elevation attributed to TN-401 occurred in conjunction with an unintended interruption of steroid immunosuppression. 1 thrombocytopenia event not attributed to TN-401 was due to sirolimus overdosing with serum levels far exceeding the target range. Importantly, there has been no evidence of cardiac inflammation by imaging or biopsy, no pro-arrhythmic events related to TN-401, no clinical TMA events, and complement inhibitors have not been needed. Following a review of all safety data per protocol, the RIDGE-1 Data Safety Monitoring Board endorsed continued dosing at either dose, and we are proceeding to enroll patients at the 6013 expansion cohort. Safety is our priority.
Immuno-suppressive medications used for gene therapy administration can themselves have side effects. 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 it. As seen on slide 24, in RIDGE-1, we use prophylactic prednisone and sirolimus to manage the immune response. Importantly, the duration and total dose of corticosteroids has been comparable across both 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. Biopsies demonstrate evidence of transduction and expression.
Most notably, the clinical data show consistent evidence of reduced arrhythmia burden and improved electrical stability, which would be expected to substantially reduce these patients' 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 cardiomyopathies, 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 at today's late-breaker session at the American Society of Gene & Cell Therapy. Before opening the line to your questions, we will ask John to share insights on the care of ARVC patients and his impressions of the RIDGE-1 data. John, thank you for joining us.
Thanks for having me, Matt. It's a pleasure.
To start, 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 % have the PKP2 mutation?
That's a great question. I'm one of our now 3 genetic cardiologists at the Mayo Clinic, Rochester, and we just specialize in both clinical care and advancing research for patients with these heritable heart or muscle disorders. Currently, we have about 1,600 patients with genotype-positive arrhythmogenic and dilated cardiomyopathy, of which 220 to 230 are PKP2 variant positive. This is a substantial subset of the patients with arrhythmogenic cardiomyopathy that we treat in our practice.
Can you characterize how common genetic testing is?
In our practice, just by the nature of it being genetic cardiology, it is very common. Increasingly, it is playing a role in the diagnosis for stratification and management, especially as there is more interest in these trials that are coming forward. We are realizing how much genetics plays 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. PKP2 typically results in a right ventricular predominant disease, really characterized by a high, you know, prevalence of ventricular arrhythmias. This is in comparison to other genes such as lamin and filamin C, which are much more left 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 it particularly amenable to a gene therapy approach such as TN-401.
How would you characterize the baseline characteristics of the patient that joined, RIDGE-1 compared to PKP2 patients, generally in your practice?
Yeah. 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 three 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. Overall, you would expect that this patient population is going to have more severe or advanced disease than a typical PKP2 ARVC that I'll see in my practice.
For these patients, what are the biggest challenges of this condition, day-to-day and longer term? What are they seeking in terms of treatment goals and future therapy?
Yeah. You can divide it up into several categories. The first is obviously the ventricular arrhythmias, which we've talked about are a huge deal to these patients. They have ICDs in place. Those will often go off. That has both psychosocial implications, but also physical implications. They'll land themselves in the hospital. They're young patients who are then spending time in the hospital, really disrupting their work and their lives. That's a big consideration just from a clinical management perspective. It's just the burden of reversing this disease. In addition, we know that exercise, you know, is a trigger for both ventricular arrhythmias but also advances the disease. These patients, once they're diagnosed, are restricted from exercise.
Often, they were athletes in their prior lives, this has profound implications on their quality of life because they're restricted from those activities that they truly love. That is a consistent thing the patients in our practice that have enrolled in this study is 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, it's a genetic disease. These patients and their families, they're not the only one affected. Their children are affected. Their siblings are affected. It has a far-reaching impact on not just the patient in front of me, but their entire family going forward.
Many of these patients are really looking for something not just to help them but to help their 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 arrhythmias?
You take a look at how we risk stratify arrhythmogenic right ventricular cardiomyopathy. There are several widely used calculators, all of which incorporate PVC burden, which is the primary, you know, kind of outlook or outcome in this trial. They also incorporate non-sustained VT burden. They do predict, you know, life-threatening ventricular arrhythmias or sustained VT. They definitely play a huge role when we're stratifying patients and also when we're treating them. In conventional care, when we're using anti-arrhythmic drugs or we're using catheter ablation, our biggest metric when we're determining the success of those therapies is to take a look at the PVC burden, to take a look at non-sustained VT burden because that gives us our best predictor of whether these patients will have future events.
What would you consider a clinically meaningful reduction in PVC burden?
I think anything that we're seeing in the 50%, 60%, 70% range is a substantial reduction. We've got to realize that what was seen in this trial for RIDGE-1 is on top of conventional medical therapy. 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 NSVT. That was what was really impressive to me is those patients with the 70 and 40, you know, NSVT burden. To see that sort of reduction really tells me that there's been some more electrostability introduced by TN-401.
Of course, the daily rates in PVCs can be quite variable. How robust is the RIDGE-1 methodology to measure them and quantify them? How convincing are the results to date to you?
Yeah, I'm very pleased to see that it wasn't a spot check. Although a lot of times in clinical practice, we don't leave a monitor on for seven or 14 days. It's just a 24-hour spot check. That can either give you some false hope, right? Lull you into a false sense of security, or it can make you more worried because the PVC rates do vary. Taking it over seven days and then averaging out the PVC burden, I think gives us a pretty good sense of what these patients, you know, ventricular activity and those VT burden truly is.
You've been caring for these patients directly. What is your impression of the safety and tolerability of TN-401 to date?
Yeah, so far, I've had no concerns on the safety or the tolerability. The patients have done very well receiving this therapy. Those in my practice that have received it, they've all been very happy with the process. I think at the end of the day, aside from some slight liver elevations that we can, you know, treat very easily with increased steroids, there really hasn't been any big safety concerns. I think we're seeing more and more interest from the ARVC population about participating in these trials. It's a good reason because they're seeing that there's a safety profile. I suspect the data on the PVC burden, non-sustained burden released today is only gonna generate increased interest.
What are the biggest limitations of current therapies for PKP2-related ARVC? What motivated you to become involved in gene therapy research?
I think if you look at what's available in our toolbox right now, it's things like antiarrhythmic drugs, things like sotalol and flecainide, catheter ablation, implantable defibrillators. They're all band-aids. They do not modify the disease progression. They are not at all disease-modifying. What we end up doing is just putting out fires. That's how we're managing these patients right now clinically, is we're all sitting on edge waiting for something to happen, and we're kind of powerless to fight against the disease process. This is where a therapy like TN-401 and the PKP2 gene replacement therapies really come in, is this gives us the first hope that we have something that could be disease-modifying. It's really needed in this space. With the ventricular arrhythmias and the disease process really cause a lot of angst in patients.
To have something that we can actually fight against essentially would really be a big step forward.
John, we're incredibly grateful to you, your longstanding commitment to advancing understanding and care of patients with inherited cardiomyopathy. We're delighted to have your insights as part of today's conversation. Thanks Faraz, your closing thoughts.
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 Whit's gratitude for Dr. Giudicessi's expertise and leadership. In addition, we are grateful to all the other participating investigators 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 SADS Foundation. We'd also like to recognize the important support provided by the California Institute for Regenerative Medicine, which has provided essential financial support for the TN-401 trial. Last but not least, I'd like to thank our own dedicated team at Tenaya, who continue to work tirelessly to advance the promise of our science towards patients.
On slide 28, we'd also like to call attention to additional efforts related to our TN-401 program. A core foundation of our progress has been RIDGE, 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. RIDGE also reflects our organization's reach beyond the U.S., with sites in six countries. Of note, RIDGE-1 also has multiple nine sites open in both the USA and U.K. You heard already the ways in which RIDGE has already contributed to trial enrollment, 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 and endpoints. 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. On that note, we were also pleased to share that based on the early data, TN-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 caps off a productive first half of the year for TN-401 program. We received DSMB clearance. We continued enrollment of patients in the 6e13 vector genomes per kilogram expansion cohort. 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 for cohort 2 at later time points that will help confirm the durability of the promising clinical effects we are seeing, as well as help confirm the dose for future clinical studies. We are actively engaging with regulators in the U.S. and abroad. We also plan to provide updates on the TN-201 program in the next month, including new meaningful data. We're 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?
We kindly ask that you limit yourself to 1 question and return to the queue for any follow-ups. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Mani Foroohar with Leerink Partners. Please go ahead.
Hey, guys. Thanks for the question. A quick one here, sort of less on this data and more looking forward, since we'll get a bunch of questions around nuance of the data later in this call. Obviously, the next event from a regulatory perspective for PKP2 is gonna be the interaction that your counterparts at Rocket have for their potential pivotal study. How do you think about the sort of the goalposts around any kind of potential pivotal? What populations should you guys, Rocket, anyone, should you be studying a gene therapy in? You know, how do you think about subdividing the population by severity, baseline characteristics, PVC versus NSVT? Just how should we prepare ourselves to digest that feedback in light of all the various PKP2 gene therapy developers?
Hey, Mani. 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 see if and in case Dr. Giudicessi has a point of view on this. There's three companies. All three of them are doing PKP2 gene therapy. You know, I won't use this call to compare our results and our trial design versus others. There are some key differences between the three programs. Obviously, at some level, there's differences in dose. Clearly, there are some differences in the early clinical data. We're very pleased with the deep and consistent and sustained reductions in arrhythmia burden that we are seeing that I think compare quite favorably to the other programs.
I really can't comment in, as you know, Mani, 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. 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 in the topic of what are endpoints that are appropriate for full approval, what are the endpoints that are appropriate for accelerated approval.
That is, you know, something that's a point of active discussion. Don't know what our what our peers in other gene therapy programs are discussing and how they're thinking about it. We just know that, as I just mentioned with RIDGE, we have a level of insight into the disease. We have retrospective data on these patients, and we're following them prospectively. I think we have a bit 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 where we've landed with some of those 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. I'd like to turn it over to Dr. Whit Tingley. Whit, do you have anything more to add to that?
Yeah, I agree with what you've said. Our consistent reductions across all patients in this trial, reductions in PVC suggest that we have defined a population that can definitely respond and raise the possibility that we could expand even to a broader population of PKP2 patients. We are in conversation with regulators and look forward to sharing more about how we've aligned with them in the second half of this year.
Dr. Giudicessi, do you have anything about, you know, populations or subpopulations from your clinical experience?
I think as a clinician, we're all watching all three trials, right? We're seeing what it comes back, you know, and seeing what patients are responding, having meaningful reductions in PVCs, non-sustained VT, and other outcomes. I think it's still too early to call. Clinically, I would guess it would be patients with more early-stage disease because there's less fibrosis, 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 data, but I think it's too early to call. The nice thing about having 3 trials is there's gonna be a lot more data to compare for as we go forward and hopefully see these things enter a pivotal phase.
Thanks, Mani.
Your next question comes from the line of Yasmeen Rahimi with Piper Sandler. Please go ahead.
Thank you so much. Team, thank you for the presentation and the consistency in the data. Thank you also for kind of highlighting the variability, the inherent variability in protein levels in PKP2. I'd love to understand, you know, in patients who have elevated PVC and NSVT, which is correlated with event rates, if there's an opportunity to actually connect the dots maybe more between, in between the changes in PVC to NSVT to maybe changes in protein levels. And then maybe secondly, I like would love to understand maybe the lack of dose response on protein levels makes sense, but maybe, do you think we could have not picked it up just because patient 5 and patient 6 had such a high elevated baseline? Would love to get some color around that.
Hi, Yas. Thanks for the question. 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, you know, dose, vector copy number, RNA, protein, and then link that to, you know, specific changes in measures of electrical instability, including PVCs and NSVT. That's not only true for our program. I think that's been true for others as well as other gene therapies for other cardiomyopathies, including our own and our peers. I think we're not trying to draw too tight a 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 has others, peers. Right now, what we're very pleased is with the changes in electrical instability, which is clearly outside of noise. There's a clear effect. It's a real effect. I think we're seeing impressive changes in the electrical instability at an earlier time point, patients five and six, particularly high severe PVCs, and those have changed dramatically and faster than what we saw in cohort 1.
Yes, that's suggestive of a dose effect. You know, 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 and see if that's reproduced. Right now, not trying to draw too close a correlation between protein levels, specific protein levels and electrical instability. I'll just remind you a point that Dr. Ivey made is that even in healthy patients, there is a tremendous amount of variability in the amount of pro PKP2 protein, that, you know. 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. That's my quick reaction. Whit, I'd like to see if you've got.
I mean, on the clinical side, we don't have any non-responder, it's hard to make correlation when everyone seems to be responding. This challenge about the biopsy and the percent of cardiac myocytes versus fibrotic tissue or fatty tissue, you know, that applies to an individual patient, which means if you take different biopsies from the same patient, you're gonna get very, you know, variable results. That really confounds the ability to correlate a clinical response with, say, the protein. It also confounds our ability to correlate protein with RNA because those have to come from different punches 'cause the tissue is treated differently for the two assays. It's too early. We'll need kind of population level correlations rather than individual patient level correlations. It's a great question. We just don't have enough data to address it today.
I'll make a note that, again, not unique to us. Another program that we're aware of, they saw, in fact, all three programs, to our knowledge at this stage, have seen this phenomena where protein, in some cases after gene therapy, have gone below the original baseline level or first went up and then went down. These are three different sponsors using three different methods, as we already covered in detail. It seems like the phenomena that we're seeing with our data are, are similar to the others, with some differences being in the, the wide swing, in the protein going up or down, maybe more exacerbated with other methods versus with ours. That up and down phenomena is something that all three programs have demonstrated to date.
You know, I'm sure us and all our peers are all gonna be, you know, wrestling with that one, but we basically all need to dose more patients and generate more data. That is a consistent point. Dr. Giudicessi, is there anything you'd like to add to this sort of commentary about protein that we haven't covered?
Well, it's everyone's wrestling. As we look through the data that's publicly available, everyone's wrestling with the variability. It's clearly there in health. That's just a challenge that is gonna 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. There's protein, you know. Seeing that there's a clinical impact I think is gonna be important. Obviously, you know, if we could show that perfect correlation, that would be fantastic, we're stuck with what we've got. It's not oncology. We don't have the access to tissue like we do for other diseases. That's I think part of this, and my worry is it's gonna be patient to patient, sample to sample, institution to institution because we all do things a little bit differently.
That's all gonna confound this result. I think this is just a learning opportunity so that everyone can figure out what is the best way to assessPH pharmacodynamic outcomes. That's something that us as investigators are starting to put our heads against all three trials to try to figure out if we can get an answer from the field. It's given us some real opportunities, you know, trying to figure out exactly what's going on and give all three companies a path forward.
Thank you. Thank you, Yas. Good question.
Your next question comes from the line of Michael Yee with Morgan Stanley. Please go ahead.
Hey, guys. Thanks for taking the question. maybe just a follow-up on the PKP2 protein expression. you know, appreciating there's definitely variability there, and we've seen it with others in the space as well. Just curious what you make of, you know, the intra-patient sort of declines, you know, at week 52 versus baseline. I think there's two patients that kind of show that trend. How does that influence your thinking on the durability here longer term? Thanks.
Yeah, thanks, I think Mike, thanks for the question. I mean, this is substantially similar to what we just covered. You know, and the last one. There are differences. We have spent some time investing to show that there, the differences in methods do contribute to differences in the kind of data you're going to generate. As we said in the last response, all three companies are seeing the same phenomena. You know, this is 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 for different patients, and also, not shown today, but have presented in the past, the immunohistochemistry, the immunofluorescence, and the localization of PKP that we are able to demonstrate. We'll have more of that kind of data in the future. I think that totality of the evidence tells us we are having a pharmacodynamic effect. The durability is going to be for us less about protein and it's really going to be about the durability of the clinical effect. Honestly, that's what we're going to pay more attention to. That's the, that's, I think the response today.
Yeah, good point. That the clinical effect has been durable, but also the RNA expression. If we look at slide 18, the RNA expression is stable. It's high at the 52-week level. That said, you know, we can't make the RNA without having the DNA there. Of course, that's the RNA that's making protein.
Yeah
you can't have stable RNA without a stable AAV vector.
Perfect. Thanks for sharing that, Whit. The first two patients that actually grew with time at the 52-week, which is a phenomenon Michael, I'll remind you in our TN-201 program, we also saw. We saw that RNA levels increase over time. There is that level of consistency. The fact that with the same method, we're seeing this slightly different, you know, presentation of protein just suggests that there's a unique presentation of this disease with a very uneven fibrofatty replacement across hearts, and therefore the 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, wanted to emphasize today.
Kathy, do you have more you want to add here?
I 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. All signs seem to be pointing to we ought to have protein expression based on the transduction and RNA we see.
Got it. Helpful. Thank you.
Your next question comes from the line of Thibault Pardo with Lifesci Capital. Please go ahead.
Hi, thank you for taking my question. Congrats on the data. Moving on from PKP2 protein expression, how should we interpret the 60% mean PVC reduction in cohort one versus a 67% mean PVC reduction cohort two? Is there enough of a difference to begin thinking about 6E to the thirteen dose as a potential go forward dose, or is it still too early given the limited sample size, different follow up? Thank you.
Thanks, Thibault. 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 range. 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, in the expansion cohort at the 60-13 dose, and we'll continue to generate data from there, and that'll 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. We're intrigued that in the patients with very, very high electrical instability in patients five and six, that they saw this dramatic decrease and saw it happen faster than what we saw in the 1st dose cohort. That's a hint at a possible dose response. Again, we just need to dose more patients. We're also, frankly, we haven't talked about safety, really pleased that, you know, at 2x the dose, we are seeing a safety profile that's quite similar to what we saw at 3E13 and generally very well tolerated.
That is 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 SAEs. The only SAEs we had were related to a medication error as we described. 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 3E13 as a dose, we'd be pretty pleased with these results. In terms of putting 60% reduction into perspective on average for our cohort, I'd like to turn to you, Dr. Giudicessi.
Like, you know, what how does that sound to you?
I mean, that's huge, right? I'll just see anecdotally, you know, that patient number five, that's my patient. We have struggled to get his arrhythmias under control. He's been on the kitchen sink, right? Everything you could throw at him, ablations, every sort of anti-arrhythmic drug. To see that sort of reduction, just on an anecdotal basis, you know, it's just, you know, it's one of those things you look at and say, "Wow. We might actually have an answer for him that we have not had in the past." 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 two patients, right? The patients in number four? Has, yes, there's been a reduction, but not nearly as significant.
I'm really looking forward, as I said in my presentation, what I want to see is, you know, the next, you know, seven-day continuous ECG monitors to see if that's going to be a durable effect. Because if it is for those patients, I think those patient number 5 and patient number six, those are truly where us as clinicians, we're scratching our heads when 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 this, which is treating one disease for another. I think it's really, really, you know, promising to see that degree of PVC reduction that early.
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 for these patients.
Thank you. Thanks. Good question. Thank you. We have 3 more in line, I believe, so we'll try to get to them quickly before we lose time.
Your next question comes from the line of Whitney Ijem with Canaccord Genuity. Please go ahead.
Hey, guys. Thanks for the question. I have several, but I'll just pick one. Well, I guess this is for Dr. Giudicessi. You mentioned prioritizing patients who had electrical issues, but less on the structural side. How are you assessing that structural involvement? I guess, is it, you know, fat fraction or how are you thinking about that fibro fatty percentage, I guess, or severity in these patients?
Dr. Giudicessi?
Yeah. No, it's a great question. I think the thing that doesn't come through very clearly because a lot of centers are presenting a 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 or cardiac MRI. In fact, I think our group was the first to describe it back in 2017, that they present like a disease called catecholaminergic polymorphic ventricular tachycardia, where they actually just have exercise-induced VT or very significant exercise-induced ventricular ectopy. Those patients, we suspect, right, have a very low amount because you do a cardiac MRI and you can characterize the facets in the RV, and we don't see any, right? Their RV size, their RV dimensions, and RV function are perfectly normal.
Those are the patients, if you ask me as a clinician, if I had a bet who would get the most bang for the buck, those are the patients because it's stabilizing. Their arrhythmias are not driven by scar. Their arrhythmias are probably driven by abnormal calcium handling. The evidence that's there is the efficacy of flecainide in this disease that's really emerged over the last five years. I think it drives home the point that there may be two different arrhythmogenic drivers in this disease, both of which would be addressed by replacing that missing calculation issue.
Thank you, Whitney. Good question.
Your next question comes from Joseph Pantginis with H.C. Wainwright. Please go ahead.
Hey, this is Sarah. Thanks for on for Joe. Thanks for taking the question. I had a question looking more at the safety profile. You showed on slide 24 some variability in immunosuppression duration across patients from 12.9- 29.4 weeks on the corticosteroids. I'm just wondering if you could add some color on what's driving that. Is that mainly clinical factors like their immune response magnitude or just physician discretion? As you're thinking of scaling to a pivotal trial, how do you anticipate standardizing the IS taper more rigidly? Thank you.
Let me first turn it over to Dr. Tingley to just talk about our immunosuppression regimen across both programs, and then Dr. Giudicessi, his practical experience, you know, administering and tapering.
Yeah, it's a excellent question. I don't think our goals even in pivotal trials will be to standardize the taper. We really like the individualized taper because the goal is to get off it as quickly as possible, but some patients can tolerate that better than others. For example, patient five here who had the longest duration, it was just at the tail end. You know, not all the safety labs were perfect. Out of an abundance of caution, the immunosuppression regimen, you know, was continued. Other patients have, you know, successfully came completely off much sooner. It's the tailored approach allows us to minimize the total immunosuppression for each patient. John, do you wanna-
Yeah, just, patient five is a patient that because of that steroid interruption had that transaminitis that we had to do a prolonged steroid course. We basically restarted steroids to treat that issue, which was due to a pharmacy error. It happens even in 2026 despite all the safeguards. That patient, I think, is an outlier, right? Usually we can move patient four, also is a patient of 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.
I think leaving it open to clinicians' you know, kind of comfort level is a good thing because everybody, you know, there is different ways to skin a cat, right. I think for me, my goal going forward with these patients is I want them off as soon as possible, as soon as safe, and that's what we're moving to do. There are gonna be those patients because everybody, right, our genetic makeup, our biology is a little bit different. There are gonna be things as the AAV gene therapies come along that are gonna predict either genetically or environmentally, those that are gonna have these responses from a liver enzyme perspective or whatever. We're gonna have to have longer, you know, dosing. We just need to kind of roll with that, get more data.
I like the flexible dosing. I think standardized, you can't do it 'cause every patient's a little bit different. That's just the way of the world.
I'll make one last comment here. We recently also had a presentation at the European Society Heart Failure Conference where we also presented data that looks like this. I'm not gonna throw out that information. That'll be available, I think on slide soon. We saw a similar 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, you know, on average, a shortening the duration on steroids. And that has been replicated in both the TN-401 program and on the TN-201 program. I think this is a great example, like during the sentinel period of gene therapies, this is exactly why you do it.
You'll learn, you apply, then you can go into the expansion cohort with more confidence that you've figured it out, and how to manage these things, both on the prophylactic, then the tapering, as well as how you monitor the patients during tapering. We've put a tremendous amount of effort and thought into this with our sites into safety, and we're very pleased that we have an immune suppression 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 Gila Lipschitz with Chardan. Please go ahead.
Good morning, and congratulating on the update. Thanks for taking the questions. I wanted to follow up a little bit on the trajectory of the PVC improvements. I know you mentioned cohort 2 may be showing effects a bit faster. For the cohort 1 patients with the 52 weeks of 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 three in the prior data cut had not yet shown an improvement and now has. Yeah, additional color there would be helpful to understand expectations for cohort 2 as well.
Yeah, sure.
No, that's absolutely right. At our last data release, the first two patients had had drops in PVCs, but that was after the six-month time point. That third patient was before the six-month time point, week 20, and hadn't yet seen a drop. Now, of course, we do see a drop on that patient three, and the drops for the first two patients have been maintained for the 52-week time point. As we pointed out now in cohort 2, we are seeing drops at that earlier time point of 20 weeks. We're happy to see sustained persistent reductions in the first cohort and now early reductions in the higher dose cohort. You know, it couldn't be more encouraging.
Yeah. I would only add to that, Gila, what we really are excited about is the consistency. All six patients seeing these effects at whatever time point. The durability that we're seeing with the first two patients at one year, given the wide heterogeneity that you know are gonna see in the natural history, that wouldn't have happened by chance. We know now it's not a spot effect at any time point, but it's also not a spot effect when we're seeing it durable over a one-year period now. Just also love the consistency between PVCs and NSVT data, with, you know, patient two and five, seeing the ones who had the highest number having the most dramatic decline, and that is consistent with what we're seeing in PVCs.
As we know in other programs, we haven't necessarily seen that kind of consistency where both PVCs and NSVTs are going down versus one going up and the other going down. 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'll be the kinetics of the response, the magnitude of the response, and the consistency of the response that'll 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. 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 one-year time point by the time we do the next data release at or near the one-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.
That's an excellent day for the TN-401 program. More importantly, an excellent day for the PKP2-associated ARVC community. Thank you again to everybody who contributed to this. Thank you particularly, Dr. Giudicessi for both your presentation at ASGCT today and for spending so much time with us for your invaluable expert Q&A. These slides will go up into the public. They're already in the public domain. 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 that program as well. Thank you everybody for joining today.
Ladies and gentlemen, this concludes today's call. Thank you all for joining. You may now disconnect.