Tenaya Therapeutics, Inc. (TNYA) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. My name is Krista, and I'll be your conference operator today. At this time, I would like to welcome you to the Tenaya Therapeutics Interim Clinical Data for TN-201 Conference Call. [Operator Instructions] I would now like to turn the conference over to Michelle Corral, Vice President of Corporate Communications and Investor Relations. Michelle, please go ahead.

Thank you, Krista, and good morning, everyone. As introduced, I'm Michelle Corral and your point of contact should you have any follow-up questions after the call or be interested in speaking further with the team. It's been an eventful few days, and we are looking forward to reviewing the interim data from our MyPEAK-1 Phase Ib/IIa clinical trial of TN-201 for MYBPC3-associated HCM. These data were presented this weekend at the American Heart Association's scientific sessions during a late-breaker session devoted to the topic of advancements in HCM care. Joining us on today's call are Faraz Ali, Tenaya's Chief Executive Officer; and Dr. Whit Tingley, Chief Medical Officer. While the data we are disclosing will be described in full verbally, please note that during the course of today's call, we will be making references to slides. A PDF file of these slides is available on the Tenaya website in the IR section under Events & Presentations. Speaking up on Slide 2, you'll see a reminder, the information discussed during this call will include forward-looking statements, which represent the company's views as of today, November 11 -- November 10, 2025. These statements involve certain assumptions and we caution investors not to place undue reliance on this information. Please refer to today's press release as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements. And with that introduction complete, let me turn the call over to Faraz Ali for opening remarks. Faraz?

Thank you, Michelle, and thank you to everyone for joining us today. Tenaya has made significant progress over the last year across our 2 gene therapy programs, TN-201 and TN-401 and we are pleased to be sharing the first of 2 meaningful data readouts with you today. After some brief stage-setting remarks and a regulatory update, Whit will be walking us through the status of the TN-201 gene therapy program for MYBPC3-associated hypertrophic cardiomyopathy and today's main event. A recap of the data presented this past weekend, the discussion of why we are excited about the continued strong emerging data package from the Phase Ib/IIa clinical trial. On Slide 4, on Saturday, at the American Heart Association's 2025 Scientific Session, Dr. Milind Desai, a renowned cardiologist, Director of the HCM Center at the Cleveland Clinic and an investigator on the trial, presented interim data from the MyPEAK-1 clinical trial of TN-201 gene therapy. This was a late-breaker presentation on the main stage at AHA during the session dedicated to advances in hypertrophic cardiomyopathy care and also in genetic medicine took a commended spotlight. Simultaneous with Dr. Desai's presentation was the publication of these promising data in cardiovascular research, which you can see on Slide 4. Links to both the slides from AHA, which we are presenting to you today and the publication are also posted to the Tenaya website. Today's presentation will also include a few extra slides of data and content that we believe are important, but that could not quite fit to the 10 minutes available to Dr. Desai at the AHA presentation. Moving on to Slide 5. The data presented from MyPEAK-1 included longer-term follow-up from Cohort 1 patients and the first look at results from Cohort 2. For those following along with the presentation accompanying this call on Slide 5, we're jumping right into the results at a high level. First, all patients on study really have objectively severe disease and significant [indiscernible] levels that we will be putting into perspective over the course of this presentation. The unmet need is high. Second, TN-201 has been well tolerated at both the 3E13 vector genome per kilogram and 6E13 vector genome per kilogram doses. Further, through our experience in dosing patients, we have optimized our prophylactic immunosuppressive regimens and monitoring such that we have reduced steroid use without increasing AEs or sacrificing safety. Importantly, from the biopsies, MYBPC3 protein levels increased in all patients, including, we can say confidently exactly with the benefit of baseline biopsies. And they did so in a dose-responsive manner in fact, with twice -- 2x higher transduction and expression observed in the first evaluable Cohort 2 patients. And importantly, the positive indicators of TN-201's activity from the biopsy that we reported earlier this year are deepening over time and we're seeing multiple measures of disease moving towards normalization, including circulating biomarkers and hypertrophy and measures of burden of disease on daily living. We'll put the changes in hypertrophy findings into broader context towards the end of this presentation since it really defines this condition. We are very encouraged by the emerging safety profile and biopsy results that we can share with you today. And then on safety and biopsy, we're pleased by the early but meaningful signs of clinical activity observed. Our next steps are to continue to follow the maturation of clinical data in these patients and to resume dosing once we have implemented certain changes to our protocol requested by the FDA. With that, we are transitioning -- I'm being told that my audio is a little bit choppy. I will -- not sure why. I will try to make a modest adjustment here if that improves things and my team will tell me if it does. On Slide 6, before we go deeper into these data, I'd like to briefly address a surprising but ultimately benign action taken by our reviewers at the FDA. In the course of proactive outreach to regulators to discuss data obtained to date, the FDA made a request for certain protocol amendments in order to minimize potential site-to-site variability. Most of these changes are intended to standardize patient monitoring and individualized immune suppression that we have successfully put into practice. During this time, while we're making those protocol changes, the enrollment in MyPEAK-1 is on clinical hold. We have submitted a revised -- we have already submitted a revised protocol to the agency in respect to their request. We agree with the recommended changes, which were consistent with our plans anyway as we look ahead to TN-201's future development.# Importantly, there have been no recent safety events of concern related to TN-201. Prior to the FDA communication, the MyPEAK-1's independent DSMB endorsed growing patients in expansion cohorts at either dose level and continue the trial with no changes. We are working very collaboratively with the agency to resolve this matter swiftly and currently do not anticipate this action will have any impact to our overall data development milestones and near-term data milestones and development time lines. On Slide 7, given the lack of any recent treatment-related adverse events, the whole action was quite unexpected. But given the backdrop of certain safety events reported in the field, the FDA's caution is understandable. As we've shared with many of you since the summer when other gene therapy sponsors reported deaths or other severe events that appear to be associated with their respective approaches to immune suppression and the underlying disease, we do not see any direct read-throughs from those situations to our program. We believe gene therapy safety is multifactorial and we have taken a very comprehensive approach to safety summarized on Slide 7 that takes into consideration factors like capsid selection, cassette design, dose, immune suppression agents, all against the backdrop of the condition being treated. Each of our trials include its own panel of independent experts in cardiology, hepatology, immunology and gene therapy. The DSMB reviews the safety data for each patient following dosing and looks per protocol at results from each cohort. FDA is also kept informed periodically of any and all adverse events in our study, whether treatment-related or unrelated. As we prepared for IND, we even surveyed other sponsors to learn from their experiences and designed our immunosuppression and monitoring protocol accordingly. Both -- as a reminder, for both TN-201 and TN-401, we utilized prophylactic sirolimus and prednisone that are administered in the weeks ahead of dosing and then continued thereafter and then tapered. I thought to have the option of a C5 complement inhibitor that can be used reactively on demand if needed. But to date, we have not had a situation where that has been warranted. We keep patients in hospitals for close monitoring of any signs of unusual activity. And as we've run along in the clinic, we've increased the frequency of lab assessments and patient monitoring to enable swift interventions and to inform individualized tapering. We have learned a lot so far and our learnings from patient monitoring and tapering are what we've been asked to protocolize by the agency, such that should we expand to new sites in the future, variabilities -- we minimize the variabilities and the potential for variabilities in how immunosuppression is administered, monitored and tapered from site to site. With that under our belt, I'd like to ask Dr. Whit Tingley to tell us about the TN-201 development program and specifically the data presented this weekend from the MyPEAK-1 clinical trial at AHA.

Thank you, Faraz, and good morning to everyone on the line. Thank you for joining us. Those of you who have been following Tenaya will likely recognize Slide 9. But as a reminder, MYBPC3-associated HCM is the most common genetic form of hypertrophic cardiomyopathy associated with 57% of familial HCM cases and estimated to affect 120,000 adults, adolescents and children in the U.S. alone. As you'll hear more today, this is a severe and progressive condition in which the heart walls become significantly thickened, impinging on the capacity of the ventricle to expand until it is too stiff to pump enough blood to meet the body's needs. The disease also causes fibrosis and leads to abnormal heart rhythms, heart failure, sudden cardiac arrest and in the worst cases, death. In spite of innovations in the field, there is significant unmet need, particularly among patients with the nonobstructive form of hypertrophic cardiomyopathy. Nonobstructive disease accounts for 70% of all MYBPC3 cases. There are no approved therapies that address the underlying genetic cause of this condition. Our lead gene therapy program, TN-201, is the first treatment being developed to address genetic mutations that cause this disease. Slide 10 offers an illustration of its intended mechanism. Causal variants in the MYBPC3 gene failed to produce protein, resulting in low levels. MyBP-C protein is essential for regulating heart contraction. It determines the force and speed of each contraction and relaxation based on the body's current needs, a little at rest, a lot during exertion. It does this by coordinating the thick and thin filaments of the sarcomeres in the muscle tissue. When there is not enough MyBP-C protein, sarcomeres produce too much force overall, ultimately leading to cardiomyopathy. TN-201 directly addresses this phenomenon by delivering a full-length healthy and functioning copy of the gene to heart cells, which then produce MyBP-C protein. The overall vision and design of TN-201 is to increase MyBP-C protein levels, fix the cause of disease, halt progression and potentially reverse symptoms and do all this with a single dose of onetime IV treatment. A brief overview of the MyPEAK-1 Phase Ib/II study is provided on Slide 11. This is multicenter open-label dose escalation trial designed to assess the safety and tolerability of TN-201. It is also designed to identify the optimal dose. Finally, it collects numerous data points for an early look at TN-201's activity, though the study is not powered for efficacy. I'm happy to say we've completed the dosing of both cohorts 1 and 2. Over the summer, the study's Independent Data Safety Monitoring Board reviewed all available safety and activity data across both of these cohorts and recommend the trial proceed per protocol with dosing of additional patients at either dose level in the expansion part of the protocol. There have been no meaningful safety events since that DSMB review in the summer. Now we'll turn to the new data presented Saturday at the American Heart Association meeting underway here in New Orleans. Slide 13 shows the baseline characteristics for the 6 patients from cohorts 1 and 2, consisting of 5 women and 1 man between the ages of 27 and 63. All have objectively severe disease. All 6 have nonobstructive disease and are at high risk requiring implantation of a cardiac defibrillator device to prevent sudden death. 4 of the 6 have previously undergone myectomy and open heart surgery to directly treat extra heart muscle at the outflow tract. But despite this, they remain symptomatic. All were experienced symptoms of heart failure, interfering with daily living and meeting New York Heart Association Class II and III. Left ventricular mass index, a key measure of hypertrophy is higher in these study participants than in most HCM patients. The data in this presentation includes over 1 year of follow-up for all Cohort 1 patients. Cohort 2, on the other hand, has a shorter follow-up of 26 weeks or less. Unfortunately, patient 5 has decided to withdraw from the study for unclear reasons and stop participating in assessments at the study center. However, she did successfully complete the immunosuppression regimen and local safety laboratories have been very reassuring. All other patients remain on study and compliant with the protocol. Patient 4's early post-dose biopsy was postponed for unrelated reasons, though it is not included in this presentation. Subsequent to this data cut, a seventh patient has been enrolled at the 6E13 vg per kilogram expansion cohort. MyPEAK-1's primary objective is to establish the safety and tolerability of TN-201 at the 2 doses being tested. On Slide 15, we detail the events observed on study across both cohorts. TN-201 was generally well tolerated at both the 3E13 and 6E13 doses. No dose-limiting toxicities were observed. Nausea was the most common adverse event reported on study of the treatment-related adverse events, reversible and asymptomatic liver enzyme elevations, grades 1 through 3 were the most frequent, occurring in 4 patients. One of these, a Grade 2 transamination elevation was classified as a serious adverse event because extra steroids were administered and monitored in the hospital setting for pragmatic reasons. The patient's enzyme elevation normalized rapidly following this treatment. Within Cohort 2, 2 patients have experienced lab abnormalities of complement activation starting a week after dosing. One of these was deemed Grade 1, mild, but classified as an SAE because the protocol-defined hospitalization was extended for further monitoring. All complement activation is resolved spontaneously without the need for any additional therapy or intervention. There were no signs of cardiotoxicities, including no declines in LV ejection fraction, no clinical myocarditis and no ventricular arrhythmias. All 6 patients have successfully tapered off immunosuppression. Slide 16 summarizes our experience and progress optimizing the immunosuppressive regimen. The immunosuppression used in the first patient successfully controlled the immune response to TN-201. So we chose to make some changes in order to reduce the total amount of immunosuppression used. Over the course of Cohort 1, we switched to starting sirolimus earlier, but at the same dose. We lowered the starting dose of prednisone and we increased the frequency of monitoring at the end of the taper. These minor adjustments resulted in faster tapers and lower total cumulative doses of steroid. As a result, the total immunosuppression used in Cohort 2 was lower than Cohort 1, better tolerated with better control, all despite the doubling of the TN-201 dose. Given the time constraints of the AHA presentation, TN-201 transduction of the heart data was not presented, but we have included it here for you today. Slide 17 shows robust transduction of the heart with TN-201 DNA levels well above the threshold set by our preclinical models. The mean vector copy number is 2.1 early post-dose in Cohort 1 and this increased in a dose-dependent manner in the first patient at the 6E13 vg per kilogram dose as expected. As was shared at ACC in March, mRNA levels are clearly detectable early post-dose and increase over the course of the year. I note that our assays used for both DNA and RNA are specific to TN-201. They do not detect the patient's original DNA or RNA. And so the assays are 0 at baseline and everything we show here is derived from the gene therapy. The therapeutic protein, on the other hand, is indistinguishable from endogenous MYBPC3. On Slide 18, we have the results of MyBP-C protein analysis. Protein levels increased above baseline in all patients over time and the higher dose of 6E13 resulted in the largest dose response, a 14% increase. In Cohort 1, patient 3 is the first to have pre- and post-dose protein levels and the levels increased by 5% at 1 year. In Cohort 2, patient 6 MyBP-C level increased 14% from baseline within just 12 weeks, so more protein produced more quickly. Patient 6 is the only Cohort 2 patient with post-dose protein available, patient 4's biopsy was delayed, as I mentioned. We look forward to seeing additional protein data from Cohort 2 in the near future and watching for the impact of these protein level changes across all patients. Turning next to measures of TN-201 activity starting on Slide 19. We see some positive and promising early results on circulating biomarkers. All Cohort 1 patients had abnormal cardiac troponin levels at baseline. These troponins improved by as much as 74% to normal or near normal levels by the most recent visits. As a reminder, troponin is a plasma marker of ongoing cardiac injury. Among HCM patients, elevated troponins predict worse outcomes such as ventricular arrhythmias, sudden cardiac death and progression to end-stage heart failure. NT-proBNP, on the other hand, is a marker of heart muscle strain and it can be sensitive to steroids. So it does increase in some patients at early time points in the trial. We are happy to see NT-proBNP levels improved at the latest time points, the most recent visits in most patients with at least 26 weeks of follow-up. AHA measurements of hypertrophy improved or remained stable in patients with at least 26 weeks of follow-up. Most notably, as shown on Slide 20, the reductions in posterior wall thickness that were observed when we reported data at ACC have further improved with time and with more patients. All 3 Cohort 1 patients have seen meaningful reductions in posterior wall thickness, ranging from 21% to 39% at week 52. Left ventricular posterior wall thickness is an established risk factor for reduced long-term survival after septal myectomy in HCM patients and these patients all fit that description. We are all encouraged by the changes we're seeing in LV mass index with reductions in overall mass ranging from 12% to 22% for the Cohort 1 patients or 2 of the Cohort 1 patients at week 52. New York Heart Association class improvements were measured briefly in the AHA presentation. On Slide 21, we share more data showing the consistent improvements over time. New York Heart Association is a well-established classification of the impact of heart failure on symptoms affecting activities of daily living. At week 26 post-dose, NYHA had approved and improved in all patients. And by 1 year, all patients were Class I, the best class, indicating no limitations from symptoms. The first 2 Cohort 1 patients now out at 78 weeks, the change in New York Heart Association class has endured. In summary, on Slide 22, TN-201 has been well tolerated at both doses. Our immunosuppressive regimen is working well and it is now working with lower overall amounts. TN-201 is working as intended, delivering DNA to the heart and expressing mRNA and protein. Protein levels increased dramatically at the 6E13 dose in just 12 weeks. We look forward to seeing Cohort 2 data mature with time to learn whether the higher protein levels accelerate and increase the response to TN-201. We anticipate sharing this data as early as the first half of next year. Perhaps most exciting among those patients with at least 26 weeks of follow-up, multiple measures of disease are moving together toward normal at the 3E13 dose level. We see responses deepening over time, consistent with other cardiac gene therapies for other diseases. We believe the improvements in troponin posterior wall thickness in New York Heart Association class may be clinically meaningful as these are all known risk factors for serious cardiovascular complications and reduced survival. On Slide 23, before handing the line back to Faraz, I'd like to acknowledge all the contributors supporting this trial. First and foremost, the people with HCM who have participated in MyPEAK-1 and their families. Their contributions and efforts are fundamental to our shared mission of creating a gene therapy to stop this genetic disease. As part of the session at AHA, the very first patient in the world to receive gene therapy treatment for MYBPC3-associated HCM shared her remarkable story of resilience in the face of severe disease, which took her mother, unfortunately, at a young age. In my book, she is a hero. In addition, our mission would not be possible without the leadership of our investigators, the dedication of the site staff, oversight and guidance from our expert DSMB members and careful data analysis from our partners at the Previs lab at the University of Vermont, the Brigham and Women's Cardiovascular Imaging Core lab and of course, our tenacious Tenaya team. Faraz. Faraz?

Thank you, Whit, and thank you for your leadership as well and your contributions to bringing this all together, both internally and externally. I will now make some comments over a few slides to try to put our program and our data into strategic and kind of clinical perspective. I'm going to now refer to Slide 25, where we're putting the disease epidemiology into perspective. This slide provides a reminder that the indications that we're pursuing, including MYBPC3-associated HCM that we're discussing today are important in part because they represent significantly larger indications versus those being pursued in other gene therapy clinical trials for genetic diseases, whether approved or in later stages of clinical development. The epidemiology of MYBPC3-associated HCM has been very well established through independent studies. And all of that work leads us to believe that there are an estimated more than 120,000 patients with this mutation in the USA alone. This is at least one reason why we think there is strategic and overall interest in this program and why the data we are presenting today are important. On Slide 26, we're now trying to put the disease severity into perspective. And we're doing so here by comparing the average LVMI, Left Ventricular Mass Index and the range of LVMI for the first 3 patients in Cohort 1 that have been dosed in our study and we're comparing that to other studies. Those peer studies include contemporaneous cardiac gene therapy studies or cardiac myosin inhibitor studies in the obstructive or nonobstructive HCM population. And what these data help illustrate is that at least as measured by LVMI, Cohort 1 patients enrolled in the MyPEAK-1 study are significantly more affected and severely affected than those that have been studied by our peers and other studies. In fact, comparing the results of hypertrophy using LV mass or LV posterior wall thickness would lead to similar comparative results. As reminded us early in this presentation, these patients have continued to progress despite access to standard of care medications and despite successful myectomies that debulks the heart tissue and provided transient but important relief. We think this analysis speaks to the relentlessly progressive nature of this genetic condition that we believe can only be fully addressed with a genetic intervention like TN-201 that is trying to address the underlying genetic cause of the disease in these patients. Finally, on Slide 26, we're trying to put the early performance of 201 into perspective as measured by both the relative and absolute decrease in both LVMI and LV posterior wall thickness as compared to the same peers referred to on the prior slide. On the left portion of the Slide 26, we're showing the improvements in LVMI shared at the AHA. For 2 of 3 patients in Cohort 1, the relative reductions in LVMI are in line with cardiac gene therapy peers and the average absolute reduction across all 3 patients in Cohort 1 is in line or even higher than what has been observed in studies of the cardiac myosin inhibitors, such as mavacamten or aficamten. On the right portion of the slide, we're similarly showing that the improvements in LV posterior wall thickness, the relative reductions in hypertrophy. The relative reductions in hypertrophy here are better than all peers and the absolute reductions are significantly higher than virtually all peer comparisons. Importantly, the reductions we're seeing in left ventricular posterior wall thickness are associated with improved long-term survival in HCM patients post myectomy as all 3 patients are now well below the threshold for left ventricular posterior wall thickness associated with higher mortality in patients post myectomy. To be clear, our intention of presenting these data is not to take away from the clinical significance of the data from our peers. Quite the opposite, the data from these peers represent product candidates that have either already been approved in the case of mavacamten or are in late stages of clinical development and product candidates that represent meaningful improvements in the lives of those patients. It is precisely for that reason that we feel our data, while early and only in 3 patients with at least 1 year of follow-up, represent a true signal of something quite meaningful. In summary, today, we have had the opportunity to present clinical data from the first 3 patients in dose Cohort 1 of the MyPEAK-1 study of TN-201 for MYBPC3-associated HCM. Against the backdrop of the uniquely high disease severity described on the prior slide and the comparisons we're making against our peers on this slide, we believe that the changes we're seeing in measures of hypertrophy are truly compelling. We are excited by the data being generated by TN-201 in adults with objectively severe nonobstructive HCM. At 1 year or greater, we're seeing robust and durable DNA transduction and mRNA expression as well as protein level changes that track to the TN-201 mRNA expression. Clinically, there's evidence of multiple parameters moving towards normalization across different domains with biomarker changes, reduction in hypertrophy and improvements in the burden of heart failure symptoms. And with that, we're going to transition to Q&A. And operator, we're ready to open the call to questions.

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

Congrats on the really strong data, and thank you for the comparative slides that you put together, very helpful. Team, I guess, given Cohort 2 showed remarkable protein expression, help us understand with really almost tripling of the protein, how we should conceptualize sort of what the clinical cardiac biomarkers and data points are potentially going to look like when you report out early next year, maybe -- and obviously, it's very clear from Cohort 1, the longer we go, the greater the treatment response becomes. So just help us conceptualize what expectations should be for Cohort 2. And then the next one is based on your prepared remarks, it seems like the procedural paperwork submitted to the FDA is already in process. I just want to make sure that these commentaries that were made with -- in regards to immunosuppression protocol for 201 and therefore, there's no need for them to review the protocol for 401. Just a clarification. And then the third one is how soon can you engage with the agency on pivotal design and come back?

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

Yes, we have very productive discussions with the FDA on 201. They have not expressed any concerns about 401. We are partnering with them to basically formalize what we've been doing by interacting with sites directly, formalize that in the protocol in terms of just precise monitoring of these patients. And this will benefit the 401 protocol as well. So we will voluntarily update that protocol as soon as we have finalized the 201 protocol with the FDA. But again, FDA has not expressed any concern about TN-401.

Yes. And Yas, to add to that, really, most of the things that were -- there was no new information on either 201 or on 401 and we -- many of the changes, as I mentioned in my opening comments, we are aligned with that because those are things that we were thinking about doing anyway. You're always thinking about ways to tweak your protocol as you think ahead to future development, which we are in both programs. And so some of the changes that we had already intended to put in motion or already had put in motion, we'll certainly do that once we have got the final alignment and final review with the agency. And all of that has been going very swiftly and rapidly. So we don't anticipate any knock-on effects on TN-401 where patients continue to get dosed. To your first question, which is how do the changes in protein, how might that show itself in clinical data in Cohort 2. We are very pleased with the high both transduction and expression from the first evaluable patient. And you're asking whether that might translate to different kind of clinical benefit. And I think the short answer is time will tell. We don't want to project too soon whether we will see a greater magnitude effect or a faster kinetics of effect from the Cohort 2 data. Frankly, Yas, we're just thrilled with what we're seeing from Cohort 1. So -- and I would also say that based on our experience and the experience of peers, it's sometimes hard to draw a straight line between dose, vector copy number, mRNA expression, protein and clinical benefit. There's so much patient-to-patient variability. And so we're pleased with what we're seeing from Cohort 1. We're optimistic for what we're going to see from Cohort 2, but don't want to speculate too soon with too early a time point and not enough patients about what the trajectory, magnitude and kinetics of Cohort 2 data may look like. Is there anything you'd like to add to that, Whit?

I agree.

And then, Yas, to your third question, which is about future plans, I think we stand by our -- what we have been saying all throughout this year and is captured in our public statement that in 2026, we aspire to have both the quantity of clinical data as well as the quality of clinical data that may allow us to engage with the regulators on this program for either future late-stage development in adults and/or in pediatric, severely affected pediatric patients on whom we've presented data quite extensively about the burden of severity in the pediatric population. We believe we're still on track for that. In fact, this data presentation at AHA is a wonderful marker of progress of where we are. We will have full cohort sets for those Cohort 2 next year. And at that point, if we're based on the experience of our peers, we may be in a position to engage with the regulators about what the design of future studies may look like, the use of surrogate markers, et cetera, et cetera. Too early to speculate now. We don't believe that the regulatory action taken has any impact on that for those forward-looking plans because the data from the patients already dosed is what we think will be most relevant. And of course, we're going to resume dosing once we've implemented changes. Clearly, we're thinking ahead to the future, Yas, because it was our -- it was our own proactive reach out to the FDA with our current data set that resulted in this request for protocol changes on -- before we dose additional patients and we're aligned with that and we're doing that. Hopefully, that answers all 3 of your questions. Thank you. Great questions.

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

Maybe just a follow-up on the clinical hold and it sounds like you should be able to make some quick progress there, but any thoughts on when that hold could potentially be lifted? Is it weeks? Or is it months? And then secondly, just prior to the hold, were you able to dose any patients in the expansion cohort at the higher dose? Just trying to get a sense of when you might get a couple more patients at that higher dose, which looks very promising.

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

Yes. We have dosed 7 patients to date. So we completed the planned Cohort 2 and have expanded that by 1 patient before the hold and we do have patients in the queue waiting. And we are optimistic about resolving this with the FDA quickly. We appreciate and share their mission to optimize for safety. And we acknowledge they have moved very quickly. We've had more than one back and forth round with them and exceeding their usual time lines. So I can't say when this will be finalized. We have submitted a revised protocol that we believe addresses all of their requests and they are actively reviewing now. So we are cautiously optimistic that this will be resolved very soon.

Mike, with comments. It has been very productive, very collaborative and very swift rounds of discussion, I think, in part because we're aligned with their thinking and in part because there is a shared understanding that the things that we're doing, while individually small, collectively, they will just add up to more consistency in the conduct of our studies and we're quite aligned with doing that. So there's really no kind of pushback between us and the FDA on the things that they're interested in learning more about and implementing. And so we are hopeful, but we've never put a date on it, Mike.

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

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

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

Yes, you said exactly -- well, that's a great question, but a very clear answer, no. These modifications are not major at all. We are not changing the immunosuppression regimen of prednisone or sirolimus nor are we changing the doses. It has been a good discussion sharing with the FDA all the progress we've made with the adjustments, the minor adjustments that I described during the presentation part of the call. My sense is that they also find that very reassuring. And the protocol amendment is more about making sure that stays consistent across all sites and it's formalized in the protocol. As I said, we talk with sites regularly and we've been managing this with them and it will be good to have it all explicitly spelled out in the protocol. There are other minor tweaks, but this does not affect the population that we're enrolling and it certainly doesn't -- won't affect the interpretation of the results.

Yes. I think the only thing I'll add to what Whit just said is, once, just -- this is a new review team for us. So they're becoming familiar with the program for the first time. We -- they respect that we know our product and our study very well. And then we respect that they are seeing things across sponsors that maybe they want to harmonize, right? Not only site-to-site variabilities left at the site level in our study, but maybe there are things that they're seeing across programs that they just like to tighten up based on the information that they have. So I think there's a lot of mutual respect. We know our product and its profile and they know what is going on across studies. So I think there's a lot of mutual respect here. The other thing -- so no changes are being made, as Whit described. However, I'd also like to point out that even in situations where changes have been made, which is not the case for us, that doesn't seem to have changed the ability of that data to be pooled for future pivotal studies. And I'm just referring to our cardiac gene therapy peers in this regards that even changes in manufacturing platform, changes in immune suppression regimen, changes in dose, that has not gotten in the way of data being pooled for the purposes of pivotal studies and looking at the totality of the evidence, which is very much on course for rare disease drug development and particularly for gene therapy drug development. So we do not have any concerns in that regard.

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

Congrats on the data update. Can you just speak to the differences that we're seeing in left ventricular mass index versus LV posterior wall thickness? I know typically, LVMI is seen as what could be an approvable endpoint in these types of cardiac indications. Posterior wall thickness demonstrated these really profound improvements, but this wasn't the case for all patients in LVMI. Intuitively, I anticipate that these 2 endpoints would be pretty lockstep with one another. I guess are there any factors in your view that would drive a robust improvement in posterior wall thickness, but an increase in LVMI? And I guess, in your view, is one measurement more objective or cleaner to measure for lack of a better term?

Whit?

Yes. It's all objective that the wall thickness is cleaner than LVMI, a great word, a great question also. So the wall thickness is a one-dimensional measurement. You just put a ruler onto the image. LV mass index has to be calculated from several measurements that are multiplied. And so small errors in each one of those can multiply out. And two, it is more sensitive to the physiologic what we say is the volume status of the patient, whether they're dehydrated or have extra fluid volume, extra blood volume, that just changes the shape of the ventricle and it's that volume or size of the ventricle is part of the equation for LV mass index. So with small numbers like we're talking about now, we are really very focused on the wall thickness as we're showing terrific improvements and consistent across patients with a consistent time course. And as we get more data with more patients, we expect the LV mass to follow.

Yes. That's a great question, Cory. And the only thing I'd add to that is it is actually quite remarkable when you look at the patient that has not yet had an overall reduction in LVMI is patient 1. And you look at that LVMI and it's at 203. And if you were to plot out all HCM patients, you'd see what an outlier that number is. It's incredible. It's maybe one of the largest ever seen. And so this is a patient who spoke eloquently at AHA, her mother died before the age of 40, runs in her family, had a myectomy, felt better, still had symptoms and really just felt like she needed more than what she had from the medications and from the myectomy. And we're super pleased that in a patient that really would be described as refractory and as Dr. Desai said at AHA headed towards potentially heart transplant, a single dose of TN-201 is producing the protein and we're seeing a dramatic reduction in at least the left ventricular posterior wall thickness at this time. And who knows what will happen over time with this patient. This is -- with the other 2 patients who are also objectively severe, we see that consistency of both LVMI and LV posterior wall thickness. And we'll see more with time, including from dose Cohort 2. So we're not overreading too much into one data point from one patient. Overall, it seems like directionally, many things are moving in the right directions for Cohort 1 patients, the circulating biomarkers, measures of hypertrophy, New York Heart class and it's still at a relatively early time point with a small number of patients. Too early to say whether we will always have consistency between LVPWT and LVMI or other measures of hypertrophy over time. It's a good question.

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

Congrats on the data. Given the FDA's clinical hold is based on the protocol uniformity, I was curious what the protocol is for using the complement inhibitor given the laboratory signs of complement activation were seen in Cohort 2. And then on Slide 29, you suggest that you could have multiple pivotal studies, including one in pediatrics. So I guess I was just curious if you plan on treating a pediatric patient in the MyPEAK-1 study prior to those discussions with FDA.

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

Yes, absolutely. So to be clear, we have not had any cases of clinical TMA, any organ involvement. We can detect innate immune response as expected to TN-201 and that does include complement activation. As Faraz was saying, the FDA can't say, but we suspect and hope that they're integrating information across multiple AAV programs to improve safety for all participants across all studies. And part of the discussion is how to best monitor the complement activation and be ready to use a complement inhibitor if it were to be needed. Again, we are very aligned with their thoughts on this and happy to implement the minor changes that they have proposed.

Yes. It's a good question, Sami. And in the past, this is something that may not have even been caught in early studies of gene therapy, including high-dose gene therapy, as patients were being discharged before the time we now know that the lab values are increasing. And we're fortunate that maybe there were not more cases of full-blown TMA and aHUS, but that had clinical [indiscernible], but that was not the case for us. And everybody, I think, is more consistently and I think that's where the FDA is trying to get to, that everybody more consistently monitors the same things, whether it's the specific points in the complement cascade, platelets, whatever, they just want to make sure that everybody, I believe, is kind of consistently looking at the same things and then consistently responding in the same ways, right? And so that -- we're 100% aligned with that and we're glad to be implementing the changes. And we believe that the changes that they're suggesting are with data from other programs that suggest that there may be a emerging kind of best-in-class approach to doing this in a more consistent and safe way across programs. And frankly, that's a gift to us now before we go into pivotal studies. We've seen some products in the case of Sarepta in the commercial domain and then having to make changes in their immunosuppression regimen by the addition of sirolimus, which we already have. In the case of Rocket, they had the unfortunate situation of adding something during the pivotal study to manage complement. And so I think that we are being handed a gift here with the opportunity to implement changes that the FDA thinks are the best for these patients and doing it now before we are in those late-stage clinical developments and before we are rapidly dosing many patients maybe in expansion cohorts. So that's another perspective on all this. It's quite positive. And then the other thing regarding pivotal studies, adults and children, I think too early to say, Sami, about whether we would first have to dose a patient in children before going into pivotal studies. Just a reminder, our current study is only focused on adults. It would require a change to the current study in order to start dosing children. So we're not open to do that. And frankly, the endpoints are quite different and quite unique in some of the severe pediatric populations. And so it may not be as simple as just changing our current study to go to those, for example, very, very severe homozygous infants that die within the first days, weeks and months of life. And so one thing it is in the public domain that we have actually opened ourselves to compassionate use approaches. So families or patients around the world through their physicians can approach us about a compassionate use for those very, very severe, very rapidly progressive patients who frankly, cannot wait until we are in a pivotal study in children. So that is in the public domain. It's on our website. And it is possible that we end up dosing a patient through a compassionate use pathway before we've aligned with the FDA on a pivotal study. But that is one indication of intent. We do believe with these data that we have in the adult there's justification, there's equipoise between efficacy and safety to give a shot to very young children who would otherwise die within the first days, weeks and months of life unless they get a heart transplant, which is quite complicated for such young patients. So hopefully, that answers your question, Sami.

Yes, very helpful.

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

I guess one key one for me. Just looking further out, there's been a lot of questions around the specific state of the programs now. More broadly, when you think about regulatory path, we've seen from a couple of other companies in the space, a mix of protein and LVMI, the co-primary endpoint. Would you expect that to be similar for you guys? Or would you expect a different approach in terms of endpoints, co-primary analysis as opposed to some other arrangement of the endpoints? Like how do you think about potential regulatory path and endpoint construction here?

I mean, we're pleased, Mani -- I'll say good question. We're pleased that both of our cardiac gene therapy peers for whom we have a lot of respect, Rocket and Lexeo and their respective programs, Danon and Friedreich's ataxia, that both under the new administration, under new leadership at the FDA, both reaffirmed the alignment with the FDA that their co-primary endpoints of any level of expression of protein, not with any quantifiable threshold, any level of expression of protein, along with an improvement in LVMI reductions of greater than 10% are sufficient for -- or could set them up for potential accelerated approval based on surrogate markers. We're glad to see that reaffirmation. There have been some surprises in the space recently. And so it's nice to know that this was relatively recent. And in the case of Rocket, it was reconfirmed after a very unfortunate safety event in their study that no dramatic changes were proposed to their study to the best of my knowledge from the public statements we've made. So it seems like there's some consistency here, Mani. And what we certainly hope is that what's sauce for the goose will be sauce for the gander and that will be also true for us. But look, each program needs to make the case for their own study, right? And so we have pointed out that the levels of hypertrophy we're seeing in these patients is uniquely high. And if you look at the comparative data with Rocket and Lexeo, you can see that we're glad to see that our peers have gotten that alignment with those endpoints. We also are seeing changes in hypertrophy and a pattern that maybe some of it is similar to theirs and some of it is unique to us, including those changes in posterior wall thickness, which does have a mortality benefit that is predicted based on the data of others. So I think too early to declare exactly what our future pivotal designs will look like. Will it be LVMI? Will it be LVMI or any other measure of hypertrophy associated with long-term benefit? We're hopeful that we are going to, in 2026, have the quantity and quality of data, Mani, that will allow us to have that discussion with the FDA. And so we can continue to come back to that guidance over and over again that this is a 2026 problem for us, not problem, but opportunity and nothing about the regulatory action changes that. Is there anything, Whit, that you'd like to add to that to those points or to make different points, including for the pediatric population?

No, I agree.

Mani, does that answer your question?

Yes, it does.

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

Congrats on the data again. Just to follow up on some of the previous questions on the left ventricular posterior wall thickness. And you mentioned these patients declining below that threshold that's associated with mortality. Can you maybe elaborate a little bit on that from your discussions with investigators or clinicians, expand on maybe the relative importance of that and the degree of risk reduction that you might see with incremental improvements there? And also, what about any other hypertrophy metrics that you're collecting? I think in the past, you may have reported data on septum thickness and things like that. So any other metrics that we can look forward to in future updates?

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

Yes, absolutely. So yes, there is data specifically for patients who have undergone septal myectomy as our Cohort 1 patients have, showing that that posterior wall thickness is predictive of survival. And so we're very encouraged to see the reduction in posterior wall thickness consistently across all these patients, which could correlate with survival benefit in the future. We're cautiously optimistic about that. The other measurements of the septum, as you noticed, has stabilized in these patients. It is interesting seeing the magnitude of improvement in the posterior wall being numerically greater than in the septum in these patients at this point. But as I just mentioned, all of these patients have had open heart surgery on that septum. So it's possible that leftover scarring and so forth means it will take longer for us to see large reductions in the septal wall thickness. That is something we'll have to monitor with time. And as discussed at the beginning of this call, the higher protein expression we've seen so far in the second cohort, that could lead to faster improvements and potentially larger improvements, although we don't know. We're very happy with what we're seeing with the 3E13 dose and look forward to sharing more data from the higher dose in the first half of next year.

Yes. And Geulah, the only thing I'll add to that is the specific paper that we referenced there will point out that the threshold is 1.3 centimeters or 13 millimeters for posterior wall thickness, but above that post-myectomy [indiscernible] thrombectomy, you still have that much or more than that is associated with higher mortality. And of course, there is still elevated mortality in those patients, all patients because they have genetic disease and they have thickened hearts. But within that, there is an even higher risk of mortality if you have a posterior wall thickness of 1.3 millimeters or more -- centimeters or more. And so in our first 3 patients dose in Cohort 1, patient 3 is objectively above that threshold and comes down below that threshold by 1-year mark. And then for patient 1, they were very close to that threshold and have come down to almost the normal range with dramatic reductions there. So that's partly why we're -- and then patient -- 1 patient, patient 2 was below that threshold and yet further, but still hypertrophy and came down well within the normal range. So that's why we're pleased in focusing in on those measures of posterior wall thickness is partly because of that experience in the literature. I would also say that with septum wall thickness, in addition to what Whit said, we've also analyzed septum wall thickness across all of these programs. And what we see consistently is septal wall thickness is something that everybody has seen varying degrees of changes and our changes are very much in line with others. And the -- but the septal wall thickness is also more -- it seems to be more recalcitrant to major changes in the way that other walls of the heart are and that sometimes -- and I don't exactly know the full biology behind it. In our case, it could be because the patients had myectomies. And so there may be some scarring in that, but that doesn't explain that for all the programs that are represented here. But it seems like a ventricular IBS or ventricular septum thickness is something that doesn't move quite as much as other hearts or other walls of the heart. But the data, the pattern that we would be showing here would be very similar. The reduction seen with TN-201 are quite consistent with and in many cases, better than both on an absolute and a relative basis than in these other studies. And we've also made these comparisons with things not represented here like ATTR cardiomyopathy and Fabry cardiomyopathy. So we now have quite a deep data set of understanding and this is partly what will go into our thinking as we thoughtfully approach the agency with our data in 2026 is what arguments we want to make about the best markers for potential further approval and with what logic. And that logic may overlap with what some of our gene therapy peers have done, but there may be some differences that are based on the data that are available in other studies as well as in our study and in the HCM population.

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

Yes. Thanks for staying here. I know we've gone over and this is -- thanks for joining us today and all the great questions. We've had an outstanding year of performance. I'm now referring to Slide 29, the last slide in the deck. We only have one more exciting milestone left to check here for 2025 and we're looking forward to doing that -- doing this again soon for the initial readout from our RIDGE-1 clinical trial for TN-401. And as a reminder, those data will provide a first look at Cohort 1 safety and biopsy results. And so we have, of course, we've already been referencing several times on this call, exciting milestones ahead of us in the first half of 2026. And as a reminder, these data milestones have not changed as a result of any recent regulatory interactions and they're not impacted by the hold that we mentioned because these are data from patients who have already been dosed. That's what we're looking forward to in the first half and of course, adding to that with the dosing of additional patients and that data set would be more likely to mature later in 2026. We look forward to more data from the TN-201 program for Cohort 1 and maturation of clinical data from Cohort 2, including more biopsy data and changes in clinical parameters. We continue to believe that we have an exciting year ahead of us for both programs in 2026 and we welcome the follow-up questions. I'm sure we didn't get to all of them today and we hope to connect with many of you over the coming days. Please reach out to Michelle, if you'd like to schedule some one-on-one time with our team to discuss these data and Tenaya's progress and our forward-looking plans. And with that, we will close. Thank you, everybody, for your time and attention, and thanks to the patients who have contributed to our results today.

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