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

Good day, and welcome to the MyPEAK-1 Cohort 1 Initial Data Call. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Michelle Corral, Vice President of Corporate Communications and Investor Relations.

Thank you, Michelle. Good morning, everyone. I'm Michelle Corral, Vice President of Corporate Communications and Investor Relations at Tenaya. Today, we look forward to sharing the initial readout from Cohort 1 of the MyPEAK-1 Phase Ib/II clinical trial of TN-201 gene therapy for the potential treatment of MYBPC3-associated hypertrophic cardiomyopathy. Joining us on today's call are Faraz Ali, Chief Executive Officer; and Dr. Whit Tingley, Chief Medical Officer at Tenaya. We are pleased to have Dr. Milind Desai of the Cleveland Clinic. To remind his title, he serves at the Haslam Family Endowed Chair in Cardiovascular Medicine; Vice Chair, Heart Vascular Thoracic Institute; and Director of the Hypertrophic Cardiomyopathy Center. Dr. Desai is also an investigator for the MyPEAK-1 trial and happened to have enrolled and treated the first cohort of patients. While the data we are disclosing will be described in full verbally, please note that during the course of today's call, we will be making references to slides. A PDF file of these slides is available on the Tenaya website in the IR section under Events and Presentations. As a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of today, December 17, 2024. 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. With that introduction complete, let me please turn the call over to Faraz Ali for opening remarks. Faraz?

Thank you, Michelle, and good morning, and thanks to all of you for joining us today as we share early and promising results from the first cohort of our MyPEAK-1 clinical trial of TN-201 gene therapy. TN-201 is the first gene therapy being developed to treat the underlying genetic cause and protein deficiency in MYBPC3-associated hypertrophic cardiomyopathy or HCM. While early, these data mark a meaningful and exciting milestone in our journey of developing this innovative approach. On Slide 5, you will see a summary of the data that we will present in some detail during the call today. On safety, TN-201 was generally well tolerated at the 3e13 vector genome per kilogram starting dose with a safety profile that is consistent with other gene therapies. These results derisk TN-201 for safety, which alone is an important starting point in any gene therapy study. The biopsy data obtained to date demonstrate robust rates of cardiac transduction. These compare favorably to our preclinical data at this dose that was associated with significant efficacy and also compare favorably to the published clinical data of other peer AAV gene therapies for genetic cardiomyopathies. Importantly, we are clearly able to detect measurable expression of RNA specifically from the TN-201 transcript. And these data also compare favorably to the published clinical data of other peer AAV gene therapies for genetic cardiomyopathies. Moreover, in the 1 patient who has reached their 1-year time point, we can see that RNA expression levels increased over time and that increase is also accompanied by a protein level increase over the same time period. Overall, we believe these early biopsy results further validate the selection of AAV9 as a capsid of choice for robust delivery, distribution and durable expression in the heart. Though it is too soon for a full clinical picture to emerge, circulating biomarkers have been stable overall and certain parameters of disease appear to be stable or improving, offering encouraging, albeit early signals of clinical activity in these very sick patients. We believe these initial data derisk the safety of TN-201, further validate the selection of AAV9 for cardiac delivery, provide us with increased confidence for the continued success of this ongoing Phase Ib/II trial of TN-201 and offer a promising potential read-through to our AAV9-based TN-201 gene therapy, TN-401 gene therapy program for which we recently announced dosing. Now before we go deeper into these data, over the next 4 slides, I will briefly cover an overview of the disease, the TN-01 product candidate, our clinical study design and our endpoints. These slides should look familiar from our corporate deck to those of you who have been following our story. On Slide 6, we provide a brief overview about MYBPC3-associated HCM. As a reminder, this is the most common genetic form of HCM associated with 57% of familial HCM cases and estimated to affect 120,000 adults, adolescents and children in the U.S. alone. As you will hear more about today, this is a very severe and progressive condition in which the heart walls continue to thicken, leading to serious complications, including fibrosis, abnormal heart rhythms, cardiac dysfunction, heart failure and sudden cardiac arrest or death. There are no approved therapies that can address the underlying genetic cause of this condition. Slide 7 provides a brief overview of TN-201. TN-201 is Tenaya's lead gene therapy program and the first ever being developed to address the underlying genetic cause of HCM. It has been well established that mutations in the MYBPC3 gene causes a decrease in the level of MYBPC3 protein, an essential regulatory protein in the sarcomere of every single cardiomyocyte in the heart. Our TN-201 product candidate uses the AAV9 capsid to deliver a fully functional MYBPC3 gene that is intended to restore levels of the MYBPC protein. By doing so, our hope is to potentially halt disease progression and reverse some overall symptoms after a single dose. A brief overview of the MyPEAK-1 Phase Ib/II study is provided on Slide 8. As a reminder, this is a multicenter, open-label, dose escalation trial designed to assess safety, tolerability and clinical efficacy of TN-201. We have completed the dosing of Cohort 1, comprised of the first 3 patients treated at the 3e13 vector genome per kilogram starting dose via a one-time infusion. As announced back in October of this year, the safety results from Cohort 1 were reviewed by an independent data and safety monitoring board that recommended the trial proceed with dose escalation at the 6e13 vector genome per kilogram dose level for Cohort 2 per protocol. The DSMB also endorsed the plans to expand the enrollment criteria to include adults with the obstructive form of disease and removing the ICD requirement. Cohort 2 enrollment is underway. Now turning to endpoints on Slide 9. Consistent with prior guidance, the data reported today are first look focused on TN-201 safety, PK activity as measured via cardiac biopsies and circulating biomarkers. We will also use this opportunity to share early observations and changes from baseline in plasma biomarkers and other study parameters. The first MYBPC3-associated HCM patient in the world received a one-time infusion of TN-201 in October of 2023. The subsequent 2 patients in Cohort 1 were then dosed sequentially in January and July and monitored for safety. Therefore, the available data set we'll be reviewing today includes the week 52 assessment for patient 1 and follow-up assessment out to week 40 and week 12 for patients 2 and 3 respectively. Today's data set is a meaningful derisking milestone in TN-201's progress and we will have substantially more data in the first half of 2025. With that, we'd like to introduce Dr. Milind Desai in today's call. Dr. Desai is a renowned cardiologist working out of the Cleveland Clinic and specializing in HCM with expertise in multimodal cardiovascular imaging. He is among our most esteemed roster of clinical investigators and just happens to have enrolled the first 3 patients whose initial data we will be reviewing today. Dr. Desai, thank you for joining us.

Thank you very much. Good morning, everybody, and congratulations to the Tenaya team for this important day. First and foremost, I would like to thank our patients and my research team for helping us get to this day. If you look at Slide #11, I would like to share with you the details of our patients, the first 3 patients that we enrolled in MyPEAK trial. The second column here is an important column as it details what we know about an average HCM patient. And I want to put that in context of the first 3 patients that we have recruited. The mean age is thought to be about 50 years. The first 3 patients are much younger, 2 females and 1 male. Because of protocol mandate, all 3 of them had a defibrillator, ICD, whereas in the national cohorts of HCM patients, that rate is about 21%. All 3 patients had a prior surgical myectomy at high-volume centers, recognized centers outside of the State of Ohio before being referred for gene therapy to Cleveland Clinic. All patients had successful relief of LVOT, outflow tract obstruction and still remain symptomatic in spite of a successful surgery. That is evidenced by significant elevation in the biomarkers. If you look at the NT-proBNP, the average in the databases is thought to be around 563. Each one of our patients had significantly elevated NT-proBNP as well as cardiac troponin. I want you to focus also on the LV mass index to understand the extent of disease. The average in female mass index is thought to be about 89 grams per meter square. Here in patient 1 and patient 3, it was -- in patient 1, it was more than double -- it was almost double and significantly increased LV mass index. All 3 patients, as alluded to, were symptomatic with 2 in NYHA Class II and 1 patient in NYHA Class III. Moving on to Slide 12. TN-201 was generally very well tolerated and reported adverse events are consistent with known gene therapy infusions and known side effects of immunosuppression. So let us walk through this. TN-201-related events were reversible elevated liver enzyme, which occurred in all the patients and normalized in response to steroid treatment. So let us break down the 3 patients. Patient 1 had a Grade 3 adverse event at week 15, which was mitigated based on the lessons learned from the first patient, we mitigated that issue by increasing monitoring throughout the immunosuppression tapering. Patient 2 had a Grade 1 adverse event at week 1. And patient 3 had a Grade 1 serious adverse event at week 2. Let me talk about the serious adverse event for a second. It was a mild elevation in liver function test, but we classified it as a serious adverse event because a clinical decision was made to administer IV steroids in the hospital. So the fact that we had to admit the patient to the -- we decided to admit the patient to the hospital categorized this as an SAE. Patients 1 and 2 have completed their immunosuppression regimen and patient 3 is undergoing an expected and a rapid down taper of the immunosuppression. In terms of other safety findings, we did not observe any thrombotic microangiopathy or TMA, no thrombocytopenia, no signs of cardiotoxicities, no myocarditis, arrhythmias and the ejection fraction of the left ventricle has remained stable. Importantly, no patient has discontinued study. In terms of events unrelated to TN-201, majority of treatment-emergent adverse events were mild, transient or reversible. There were 2 SAEs unrelated to TN-201, which also occurred. To summarize, DSMB had access to all the data and they reviewed everything and have cleared us to proceed with dose escalation to 6e13. All patients, as I alluded to, remain on the study. I think I will hand it over to Dr. Whit Tingley to discuss the biopsy findings. Whit?

Thank you, Dr. Desai. Let's pick up at Slide 14, biopsy samples. In the biopsy samples, we are measuring 3 key stages in the mechanism of action of TN-201, namely, delivery, also known as transduction of TN-201 DNA to the heart. RNA expression or transcription in which we measure the specific messenger RNA produced by TN-201. And protein expression via translation of messenger RNA into protein in which we look for increases in MYBPC protein levels over time. The 3 measurements of DNA, RNA and protein together tell us whether TN-201 is working as it should. On Slide 15, on the left, we describe the methodology for measuring DNA, RNA and protein in the heart. TN-201 DNA and TN-201 mRNA can be distinguished from the patient's own endogenous MYBPC3 gene and RNA using PCR assays. On the other hand, the protein produced by TN-201 gene therapy is indistinguishable from the patient's own endogenous protein. We use mass spectrometry to measure the abundance of total MYBPC protein, which is normalized to myosin heavy chain. On the right of Slide 15, we describe what we are expecting over time from each of these elements. Shortly after infusion, DNA levels in the heart are at their highest. Over time, a decrease is anticipated as DNA is cleared from non-cardiomyocytes such as fibroblasts and a durable steady state is then reached, representing long-term retention of the TN-201 DNA inside cardiac myocytes. As the TN-201 and MYBPC3 gene is transcribed in the cardiomyocyte, TN-201 mRNA quantities increase. And as the mRNA is translated into MYBPC protein, protein levels will increase from baseline levels. Slide 16 summarizes our biopsy findings. We are very pleased overall with the biopsy data available thus far at our starting dose of 3e13 vector genomes per kilogram. We're seeing clear evidence of robust delivery of TN-201 DNA to the heart, resulting in increased TN-201 mRNA expression and accompanied by an increase in protein level over time. Cardiac biopsies have been performed at week 8 for patients 1 and 2 and week 52 for patient 1. As a reminder, we did not collect biopsy at baseline for patients 1 and 2. We subsequently amended the protocol to collect biopsies at baseline post dose and at the 1-year mark, which will allow us to better understand the increases in kinetics of protein levels over time. That change in protocol went into effect ahead of patient 3. So their baseline and initial biopsies will be included in future updates. Slide 17. We're extremely pleased with the TN-201 transduction rate as measured by DNA copies in the heart, also vector copy number or VCN. Both patients at 8 weeks had over 2 vector genomes for diploid genome, meaning we've delivered the equivalent of 2 MYBPC3 genes per nucleus in the heart, substantially more than was needed for efficacy preclinically. In preclinical models, a VCN of 0.3 was sufficient for significant efficacy. At the week 52 biopsy in patient 1, there is a drop in VCN to 0.8 vector genomes for diploid genome. This is expected. There are copies of the cassette still around at week 8 that aren't incorporated into the cardiomyocytes. These extra capsids get cleared over time, but there's no loss in function in TN-201 as the active episomes in the cardiomyocyte nuclei are stable. In fact, the activity of TN-201 actually increases in this patient over time as we will see with the RNA results. To put these results in more context, we turn to Slide 18, where we plotted the same TN-201 transduction results along with data from another AAV9-based cardiac gene therapy, specifically RP-A501 for Danon disease, recently published in the New England Journal of Medicine. With these -- with an important caveat that these are distinct constructs in different disease settings, we see that TN-201 appears to perform favorably. At a dose of 3e13 vector genomes per kilogram, TN-201 achieved a similar rate of heart transduction to the other product at a dose of 6.7e13. That dose, which is more than double our starting dose, has been selected as the final dose for pivotal studies. Of course, we cannot determine the optimal dose for TN-201 based on the comparison because these are different constructs, different genetic targets and different diseases. The other product has a drop in VCN over the first year, similar to TN-201. It then stabilizes through at least 3 years as expected. We anticipate that TN-201 will yield similar long-term stable transduction. Overall, we are excited to see this robust cardiac transduction by TN-201, which reinforces that the AAV9 vector is well suited for cardiac gene therapy. Next, we look at TN-201 expression as measured by mRNA on Slide 19. Based on available biopsies from patient 1 at weeks 8 and 52 and patient 2 at week 8, we see clear evidence of RNA expression, which is measured as transgene copies per microgram of RNA. As a reminder, the PCR assay used here detects only mRNA produced by TN-201 and is high sensitivity and specificity. We know that the baseline mRNA level must be 0 for both patients even without a baseline biopsy. At week 8, patient 1 and patient 2 reached transcription levels of 1.7e5 and 1.3e5 mRNA copies per microgram of RNA. At the week 52 biopsy, patient 1 achieved RNA levels of 2.5e5, a 50% increase. We discussed a moment ago the drop in the DNA vector copy number in patient 1 between week 8 and week 52. So this 50% increase in RNA confirms that there was no loss of DNA function. We see this phenomenon in preclinical studies as well. Once again, on this slide, we've included 2 points of comparison to contextualize our mRNA results. As noted by the green dotted line at the top of the chart, the mRNA levels detected in the patients were below those observed for the same dose in the knockout mouse model, which achieved near maximal efficacy. We know from our work and many others that AAV expression varies significantly between species. It's very typical to get higher expression in the mouse than in humans. To place our data in context with others' clinical experience, we have included the plum colored box, which shows median levels of RNA expression from 2 cardiac gene therapy peers. Here, we see that our mRNA expression levels are very similar. We anticipate the potential for greater transgene expression and more clinical efficacy at higher doses of TN-201. This was one of the drivers behind our decision to escalate to the 6e13 dose. All in all, we are encouraged by the increasing expression of TN-201 RNA in these initial biopsies and to be in the same range as published data from others. Bear in mind, TN-201 is being administered at a relatively low starting dose for an AAV9-based gene therapy, 3e13 vector genomes per kilogram. We expect from experience with our preclinical models and others that in this low part of the dose response curve, a twofold increase in dose can yield more than a twofold increase in expression, which bodes well for Cohort 2. Now to protein expression. Before we look at the biopsy results from our study, let's discuss the range of MYBPC protein levels in healthy people and patients with MYBPC3-associated HCM. On Slide 20, we see that levels of MYBPC protein in healthy individuals are variable, as shown in green. The protein levels on this graph are normalized to the average healthy heart, so an average person has 100%. However, there's a discernible range among healthy people from 78% up to 109% in our data. This represents biological variability among people rather than assay variability. Seeing that some healthy people can have just 78% of normal MYBPC protein tells us that levels of 100% aren't necessarily required for normal heart function. There's also a range of MYBPC protein levels among 19 patients with MYBPC3-associated HCM, shown in red. The average patient has 60% of the normal healthy level with patients ranging from 47% to 79%. In this data, there was no apparent correlation between the MYBPC protein level and markers of disease severity in these patients. Overall, the variability indicates that individuals have different sensitivities to or tolerance for low MYBPC protein levels. From this, we conclude that the primary treatment goal for TN-201 is to increase each patient's MYBPC protein level from their individual baseline, not to achieve 100% level or a specific threshold level. We note that modest increases in protein levels in other cardio gene therapy programs have been associated with clinical benefit. On Slide 21, we show the protein results from the first 2 patients 3 biopsies. At 8 weeks, MYBPC protein levels for patient 1 were 56% of normal. At 1 year, patient 1's protein levels increased to 59% of normal. This detectable increase in protein level is consistent with the robust delivery of TN-201 DNA in this patient and correlates with the increase in TN-201 mRNA between week 8 and week 52 that we discussed earlier. Taken together, we believe this is a positive indicator that TN-201 is being transcribed and translated into MYBPC3 protein. Because we do not have a baseline biopsy for these patients, the 3% increase measured here may well underestimate the total increase in protein from TN-201. Starting with patient 3 baseline biopsies will be available. Patient 2 at week 8 had a 62% MYBPC protein and their 1-year biopsy will be early next year. Next year, we will also get our first glimpse at patient 3 and at dose Cohort 2, including baseline biopsies. With more time, more patients in both doses, we will begin to understand the quantitative relationship between transduction DNA, transcription to RNA, translation to protein and resulting improvements in heart function and clinical signs and symptoms. I'd like now to invite Dr. Desai back to share initial observations of clinical endpoints at this early stage. Dr. Desai?

Thank you. Again, that was very good. So I would like to point your attention towards Slide #23, which discusses the results of the circulating biomarker. These were overall stable at this early time point. And let us walk through, first, the NT-proBNP levels on the left side of the slide. Essentially, MyPEAK baseline NT-proBNP levels were observed higher than those in other non-obstructive HCM trials, suggesting in a more advanced disease state. And in patient 1, from baseline to week 52, the NT-proBNP remained elevated. But as we have discussed, immunosuppression is known to influence NT-proBNP level in both the patients thus far. Upon completion of the immunosuppression regimen, the NT-proBNP levels returned to baseline. In terms of cardiac troponin, again, we observed that the baseline troponin I levels were much higher than in the other non-obstructive HCM trials. Patient 1 remains elevated at week 52 likely due to advanced disease. However, patient 2 has normalized the troponin I levels since TN-201 treatment. Moving on to some of the clinical signals. We observed encouraging early clinical signals, but recognized a simple fact that we need more follow-up, we need more patients, and clearly, we also need data from higher dose cohort. But to summarize, the color-coded slide, dark green represents significant improvement, light green is stable and the gray color is declined or mixed results. NT-proBNP in patient 1 remained stable. Troponin I in patient 2 increased. The markers of hypertrophy and diastolic function in patient 2 improved and diastolic function remained stable in patient 1. Symptoms in both patients have improved NYHA class and KCCQ has remained stable in patient 1. The KCCQ score was confounded or unavailable at the last time point due to an unrelated adverse event. The data on cardiac function is -- so in terms of cardiopulmonary exercise testing, we are still awaiting, not yet interpretable. So to summarize, initial improvement and/or stabilization was observed across several domains. We are still seeking directional improvements in multiple parameters over time. And as mentioned before, overall clinical picture will become clear with time with longer follow-up and more patients. I will hand it over to Faraz Ali for closing remarks and Q&A.

Thank you, Whit and Dr. Desai for that detailed review of the MyPEAK-1 results to date. As we had anticipated, these are early but meaningful data and more follow-up over time will be required to get the full story of TN-201's potential. Nevertheless, we are very encouraged by a number of promising success factors and their implications for the future of the program. On safety, TN-201's emerging safety profile is looking good. The primary AE associated with study drug is one that is typical of gene therapy and one we were prepared for and able to mitigate. And our monitoring and mitigation strategies are continuing to improve. The result in October, based on all the data available at that time, the DSMB endorsed our planned dose escalation as well as the expansion of eligibility criteria to allow a greater diversity of patients to be enrolled and we have reason to believe that will enable enrollment even at the sentinel dosing period for Cohort 2 to go faster. On cardiac delivery and expression, the vector copy numbers observed at the 8-week mark following dosing meets our expectations, whether looking at our preclinical data or that of peers who in some cases are using higher doses. The results, clear expression of TN-201 mRNA, which we can differentiate from endogenous mRNA and further mRNA is increasing over time. Meaningfully, we are also seeing protein levels increase over time in a disease where insufficient protein levels are the underlying cause. In the context of other cardiomyopathy gene therapies, a growing body of data is emerging where a relatively small amount of protein expression is able to achieve meaningful clinical changes over time. With a strong caveat that our initial MyPEAK-1 results require reinforcement from additional follow-up, more patients and higher doses, we are further encouraged by the early signals across multiple parameters of potential improvement or stability in the face of a severe and progressive condition. Today's readout is an important first step on our climb, decreasing certain program risks and increasing our confidence in TN-201's potential. We're excited to share substantially more data in 2025, including longer follow-ups and serial biopsy results for patients 1 and 2 as well as initial results for Cohort 2. 2025 will also be an important year for our TN-401 gene therapy program that uses the same capsid with the first patient dosed and enrollment ongoing. Before we transition to Q&A, we at Tenaya wish to offer our gratitude to several groups. We wish to thank our investors, some of whom may be listening, for your sustained support, encouragement and feedback. We wish to thank the dedicated teams of researchers, clinicians and partners working at scores of clinical sites across both the MyPEAK-1 and MyClimb studies. We wish to extend a special gratitude to Dr. Desai for joining us today. Your unwavering enthusiasm, dedication and expertise has been instrumental to dosing the first 3 patients in the world with TN-201. We wish to thank our dedicated employees who bring their best to Tenaya every day as a One Tenaya community. We wish to extend our gratitude to the HCM community for your engagement, for your support and for your inspiring stories. You are truly the reason why we do what we do. And in particular, we all owe a deep debt of gratitude to the first 3 patients who stepped forward to enroll dose Cohort 1 of the MyPEAK-1 study. We can say with all sincerity that we would not be here where we are today without you. We applaud your courage, your commitment to the HCM community and your contribution to the potentially transformative science that TN-201 gene therapy represents. With that, operator, we are ready to open the call to questions.

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

Congrats on the data. A few questions. I think the first question is, could you talk on the degree of the liver enzyme elevations that were reported? I know it was transient, whether these were 2x, 3x, 4x or 5x? Question 1. Question 2 is, the encouraging protein expression increase of 3% is encouraging. How should we be thinking about the inherent variability? And what we should be hoping for to see in patient 2 and patient 3? And is there a way to model out what the expression levels would be if we move on to a higher dose? And then the third question is, congrats on getting the green light to dose higher. Do you need to dose 1 patient to wait to kind of do a staggered event or could you actually start rapidly dosing several patients at the same time? And I'll jump back in the queue.

Yasmeen, good to hear your voice. Great questions. And for these, I'm going to turn to Whit. And perhaps, Whit, we can cover the first -- the last one first, the dose. So go ahead and respond to the first one and then we can cover liver enzymes.

Okay, last one first. So we are in the low part of the dose response curve where we do expect more than a twofold increase in expression with a twofold increase in dose. So we look very much forward to the results of Cohort 2 where we will have baseline biopsies at the higher dose and we'll be able to see the full extent of elevations in protein levels. In terms of the transaminase elevations, these were all transient and responded rapidly to steroids. They were asymptomatic. There was no evidence of hepatic damage, no elevation in bilirubin, simply transaminase elevation. The first patient hit CTCAE Grade 3, which starts at 5x the upper limit of normal. This was late in the tapering period and we mitigated future events by increasing the monitoring frequency during the late tapering period so that steroids could be initiated or increased sooner. And this -- we have not seen a Grade 3 since then.

The last one might have been on the serial dosing period for...

Yes. So in the protocol and in alignment with the FDA, we will continue sequential dosing for the first 3 patients at the next dose level.

Thank you, Yasmeen, for the questions. We're ready for the next one, operator.

Our next question comes from Mani Foroohar with Leerink Partners.

This is CJ on for Mani. Taking a forward-looking view, can you share whether you've dosed any patients in Cohort 2 yet? And also, how we should think of initiation timing for parallel dosing and dose expansion?

Thanks, CJ, for the question. I will take the first crack at this. We haven't yet announced dosing of the first patient in Cohort 2. And somewhat consistent with our practice in dose Cohort 1, we won't be giving blow-by-blow patient-by-patient updates necessarily. And then we are making forward-looking projections of enrollment for dose Cohort 2. Now having said that, we've already mentioned that we're in the serial enrollment period, as Whit just mentioned, where we dose, we pause review data with DSMB before dosing the next patient. We are encouraged by the number of patients who have come forward since the announcement of the last DSMB clearance and the growing pipeline of patients that we have. And based -- and then, of course, the widening eligibility has helped us. So overall, we anticipate and expect that enrollment in dose Cohort 2 can move more rapidly than dose Cohort 1. And -- but we won't make forward projections at this time. Whit, is there anything you'd like to add to that?

I agree.

I guess, to clarify my question a bit more. Now that you've completed the sentinel cohort for Cohort 1, can you start dose expansion now while you continue to sequentially dose Cohort 2?

Thanks for the reminder of that question. So technically, yes, we are open to dosing patients in parallel at dose Cohort 1. However, at this time, we're focused on enrolling patients for dose Cohort 2. The data that's been presented to date suggests that we could get more expression, as Whit mentioned, at a higher dose. And therefore, we'd like to dose patients at dose Cohort 2 and then make a decision based on the totality of data of expansion, the optimal dose expansion and in which dose cohort to do it and how many to do it. So I think that's our current plan. Whit, anything you would add to that?

Absolutely. The protocol gives us flexibility once we have data from both doses to expand one or both dose levels.

Our next question comes from Ritu Baral with TD Cowen.

On the next dose cohort, the 6e13, what are your expectations? You mentioned that you could see greater than 2x increases in mRNA. As you look at your expectations for the higher dose, is it centered more around the RNA expression? Is it centered more around protein levels? And how -- do you guys have a target, a target delta or any considerations for even a higher dose just given this is a bump up in -- a 2x bump up from the low dose, and as you mentioned, you're still sort of at the low end of the dose response curve? And then I've got a follow-up.

Thanks for asking the question. I'm going to ask Whit to respond to that first and then I will add to that.

Yes. We track the RNA and the protein levels very closely. At the end of the day, it is the protein that's doing the job in the cell. So that's what matters most to increase. We don't have specific target levels. As we get more data from more patients at both dose levels and of course with the natural variability in patients, we will learn much more about how much protein increase is required to move the needle symptomatically for our patients. We are encouraged by other cardiac gene therapies where a little bit of protein can go a long way, but each disease is different and we will be learning as we go.

Sorry, Ritu, I was just going to add that...

Does a 2x increase in dose likely suggest a linear 2x increase in protein levels? How should we be expecting those protein levels when we do get the first high dose update?

Again, I would just add to what Whit has already said here that it's -- we are -- we certainly have reason to believe from our preclinical data that with higher dose we could get more vector copy number, that's certainly been seen in the Rocket study. And then with that higher vector copy number, additional RNA and protein. However, we also know that human clinical data may vary from our preclinical models. And so we have the humility to know that there is more that should be possible with a higher dose, but not to project quantitatively exactly how much that could be. In the Rocket study, I think higher dose was -- it's unclear whether that was associated with an exactly a twofold increase in protein expression, their assays and RNA varied. And same with the other peer gene therapy studies. So we need to see for -- ultimately, this is a different gene, different protein. It may have its own kinetics of expression and magnitude. And that's what we have to learn from our own study. We're pleased that we do have evidence of increased expression from 8 weeks to 52 weeks from the first patient who was evaluable. We don't know what their baseline biopsy is and how much they may have increased from week 0 to 8 weeks post dosing. So with the benefit of a baseline biopsy, we will learn -- and with taking the biopsies at different time points, which our protocol now allows us to do, we will learn a lot more about the expression kinetics of protein and then really start to understand we think with data in 2025, the relationship between dose, vector copy number, RNA, protein and clinical symptoms for this condition and how that may be similar or differ from our peer cardiac gene therapies. We're pleased with what we have. We don't think we need to get to 100% wild type, as we've mentioned. We believe that it's all about adding more protein above the baseline, starting baseline for each of these severe patients, but we can't make quantitative projections at this time.

Understood. My next question is for Dr. Desai. Patient 3, the one who started on [Technical Difficulty] was there a particular reason that IV steroids were required over just orals in this case?

Good question. I would respond to that. Actually, great one for Dr. Desai to take.

No, go ahead, please. Whit, go ahead.

No, go ahead, Dr. Desai. You're the one who did it. So please go ahead and respond to that.

So this is -- my simple answer to that is it is our iterative experience based on the prior 2 patients. I'll make it simple by saying, we wanted to get ahead of the conversation and not have a higher level elevation of LFTs. And I think in looking back at it, that was the right strategy. Whit, please go ahead.

Yes, I agree. There is increasing discussion in the field about whether treating harder, earlier and faster will lead to faster overall steroid taper, which could potentially very well be the case for this patient.

Got it. Super helpful. And then last question. Any -- are there any modifier genes or modifier baseline characteristics? I guess, this is a question for Whit and Dr. Desai. But any sort of modifying characteristics that we should be thinking of in relation to MYBPC protein level? As you guys mentioned on the slide, there's that wide variability of expression in HCM patients. I'm just wondering, if there's anything new in the literature on [indiscernible] relating that level to function based on some sort of modifier, whether it be genotypic or whether it be patient characteristics?

Yes. I would say, in the big picture, there's clearly correlation between protein level and severity of disease in addition to the 60% level we talked about for heterozygous patients. There are infants born that are homozygous, have no functional protein and require a heart transplant in the first months of life. So no protein is extremely severe, extremely early onset. Heterozygous state with 60% protein is variable but can lead to requirement for defibrillators and open heart surgery and risk of premature death at young adult ages, and in some cases, in pediatrics. Within the range of the heterozygous patients that we showed you, there isn't good data to show that those smaller differences in protein are directly translating to differences in severity. And in fact, that small data set we have, we didn't find those differences. So it does suggest that individuals have different individual sensitivity to a particular level of C protein. This could be due to other genetic factors. We do know that polygenic risk scores do stratify risk amongst sarcomere-positive HCM patients, could also be due to environmental factors as well.

Dr. Desai, is there anything that you would want to add to that?

No, I think Whit covered it. I was going to say we are learning every single day about the influence of polygenic risk scores and environmental factors. So I think the story is still being written as we speak. I have nothing more further to add beyond Whit.

Yes. The only thing I would add is just the quarter of a century now in rare diseases, this is not an uncommon phenomenon at all that for the same genetic mutation, you can see quite a lot of variability in the underlying expression of patients and that there's not great correlation with the disease severity. And so I think this is -- what we're seeing is quite a common phenomenon, not unique to MYBPC3 positive gene therapy. And therefore, I think then to the extent that this is true with many genetic conditions, and despite that, many genetic conditions have had the same phenomena where with the addition of the functional gene and the production of missing protein, the increase in protein not achieving wild type levels has still been meaningful for many patients and many gene therapies across many conditions despite maybe the background variability and sensitivity to individual protein levels. And we hope and look forward to demonstrating that, that will be true for us in TN-201 and the data in 2025 we hope will support that. Good questions, Ritu.

Our next question comes from Mike Ulz with Morgan Stanley.

Maybe just a follow-up on protein expression, and I know this is a bit challenging to answer at this point. But just generally speaking, when would you expect the protein expression to begin to increase post dosing? And when might that reach sort of peak levels?

That's a good question. And I'll ask Whit to take the first crack at that and I'll see if I have anything additional to add.

Yes. The kinetics in humans is different than the kinetics in mice and it is this study where we will learn far more about the true kinetics. As part of the protocol amendment where we added the baseline biopsy, we also adjusted the timing of that first post dose biopsy. So we will get a fuller curve. What we've learned from the 8-week results is that this is still early. We're certainly not a steady state. We haven't plateaued by the 8-week time point, probably not in terms of RNA and protein likely lags behind the RNA. So we will get a much fuller picture of the kinetics over time. We do not yet know whether even the 1-year biopsy reflects the steady state or whether we'll have increasing expression even beyond 1 year.

Yes, I agree completely. Mike, it's a good question. And I think both our preclinical data had predicted that there would be some increase during the first year. We haven't looked much further beyond that. And so this is -- we'll learn a lot more through the study. It's interesting, we have seen from a peer gene therapy company in the New England Journal paper, we were pleased to see that in the Danon program that out to 3 and 4 years, there are patients who still have stable, if variable, protein expression over time. And we think that's partly a function of the durability that comes with AAV9 gene therapy. We also think that's partly as a result of the fact that cardiomyocytes are postmitotic, and so they're not dividing, and that also contributes to stability. So the exact kinetics past the 1-year point, we'll learn more from the next couple of patients. The protocol allows us to do samples even a little bit past the 1-year mark. And like Rocket, over time, we will learn more with long-term data. So again, we're pleased with where we are today and the evidence of increase from 8 to 52 week that is meaningful information even in the absence of a baseline biopsy, but more to be written on the protein biopsy and protein expression story over time with more follow-up, more patients and higher dose.

Our next question comes from Cory Jubinville with LifeSci Capital.

Congrats on this update. For Dr. Desai, maybe you could help us better understand the context around the likelihood of data in its totality that we've seen today and how we should be thinking about that in the absence of a baseline biopsy. So when you think about an HCM patient with an MYBPC3 mutation that has similar characteristics to the patients that you've enrolled in this first cohort, how likely is it that these patients would have improved or even remained stable on metrics like NYHA class, cardiac troponin, hypertrophy, diastolic function, et cetera, over the course of 1 year without intervention?

So Faraz, I'm going to take this question since it was directed towards me.

Yes, please. Please do so, Dr. Desai. Directed to you. We'll add if necessary.

These folks, all 3 patients were -- remember, as I alluded to, they all had what was perceived as definitive treatment, meaning open heart surgery to relieve their HCM-related symptoms. They remained fairly symptomatic despite that and sought us out for the trial because they were progressively getting worse. Now it is impossible to predict how they would have progressed or regressed over the year of doing nothing additional beyond gene therapy. And that's something that will pan out in the next few years because we are following these folks up over 5 years, the entire cohort. But needless to say, the -- all the 3 patients -- the third one is still too early, but both the first patients had issues with activities of daily living, which precluded them from doing stuff. And at this time point, each one is symptomatically feeling better. And so is it the therapy? Is it there's disease stability? Hard to say, but they are feeling symptomatically better. Again, I will simply answer, we are -- as I alluded to in the slides, we are still too early in the phase of the disease and there's a lot of stuff that we need to understand further.

I agree. Thank you, Dr. Desai. We still have a small end and a short follow-up time period and just one dose level. So we will be learning far more in 2025. Too early to say anything conclusive now.

Yes. I would only maybe mention, if you look at patient 1, and the baseline characteristics were offered on Slide 11, that patient had a myectomy at the age of 24, which means their disease had started before that and had already progressed quite significantly to get to that point. Then they had an ICD implantation in 27, and that's where we find her when she came into this study. I don't know if anybody would have a priori predicted that after a myectomy their LVMI overall would be as high as it is, that the troponin and cardiac levels are as high as they are. So clearly, this is speaking to the underlying progressive nature of a genetic defect that couldn't be addressed with a myectomy. So that is the backdrop against we're operating for some of these patients. So it becomes hard to predict what would have happened to this patient without the gene therapy when we have this incredible progressive disease in a very short period of time for a relatively young patient. That's why we do believe that in the context of such a severe disease and in a progressive disease, stability is a good thing. And then any early signs of improvement is also good, but we're not going to declare success until we've had more time, more follow-up in these patients and more patients at a higher dose. We're pleased with where we are today, but hard to predict I think, Cory, and I think you're hearing that from all 3 of us, where these patients would have been without treatment. We just know that they have been pretty bad despite everything that has been thrown at them in terms of current therapies and medical interventions and ICDs. That's clearly not been enough for them.

Yes. That's helpful. And can you provide a little bit more context on what you mean when you say that patient 2 improved on hypertrophy and diastolic via imaging? Is this left ventricular mass index, septal wall thickness? What's the magnitude of improvement here? And what's your threshold that defines improvement in this case? I mean, we've seen in peer cardiac gene therapy programs that the FDA has kind of really keyed in recently on this 10% improvement threshold on LVMI as an approvable endpoint in similar indications. How are you thinking about that and the threshold -- that threshold in the context of these data and potentially future studies or read-outs?

Great question. I'll ask Whit to take a first response there and then Dr. Desai to add.

Yes. We look forward to sharing more data from Cohort 1 in the first half of 2025, including more specifics on the quantitative changes in the individual metrics. What we're sharing today is an early and sort of summarized look. So to your specific question, hypertrophy here is measured by echocardiography and combines mass index and wall thicknesses in an overall sort of summarized view. Similarly with diastolic function, there are several parameters behind that as well. So again, we look forward to sharing more specific information in the first half of next year with -- that will include patient 3 and longer term follow-up for all 3 patients.

Dr. Desai?

Yes. I have nothing further to add. I agree with everything you've said.

Yes. More details to follow. I think the only thing we would say is that when we chose this color scheme, I think we wanted it to represent -- dark green to represent something that was outside the noise level associated with the measure. Of course, that is different for each of these measures. So that was a consideration in coloring. So any improvement wouldn't necessarily qualify as a dark green that might -- a modest improvement within a certain level would be stable. You do have to be above a threshold in our mind that is supported by external reference points to qualify as a dark green. Again, our further future updates will clarify more what we mean by that and we look forward to sharing more. Any one of these measures, whether it's hypertrophy, diastolic dysfunction, et cetera, there are many, many sub-categories within that. And that's why we're not giving all of that information today. We're saving some of that for a future data update. And we look forward to being able to do that, Cory, in 2025. We haven't yet guided to exactly when we will do so.

Our next question comes from Sami Corwin with William Blair.

This is Caleb on for Sami Corwin. We just wanted to ask, as you enroll less severe patients in future cohorts, are there any assumptions you can make about the transduction kinetics of TN-201 and maybe the MYBPC protein expression? Do you expect that to vary to the data we saw today or do you expect that to be a little bit more consistent with the low dose data? And then also, if you have shared this data with the physician community, what's sort of been the receptivity to the data been?

Whit, do you want to respond to that first?

As we proceed enrolling this trial, we may see patients with less severe baseline coming in. We don't anticipate that will translate to significant differences in their baseline protein levels for the reasons we've said. It doesn't seem to be a clear correlation among heterozygous patients between the baseline protein level and the severity of disease. Also, we don't expect the severity of disease to affect the kinetics or the max achieved levels of RNA and protein expression. These are driven by phenomenon somewhat separate than the mechanisms of disease.

And do you want to speak to receptivity, both you and Dr. Desai, just the receptivity in the other physicians that you have communicated with so far?

Yes. Dr. Desai, would you like to start with the reactions from peers?

Yes. I think it is like everything else, any new therapy, new technology, there is some trepidation. But after the first few experiences, and like in this case, learning opportunities and positive experiences. I think there is enthusiasm and people and physician community willing to sort of expand the notion that this is clearly -- we are on the right track and there are patients who will benefit from this line of therapy. So I think, yes, to summarize it, there is a lot of enthusiasm in this space. And we look forward to continuing to expand the thought process and research, and then hopefully, clinical access down the road.

Yes, I agree. There's increasing enthusiasm. I would say, this baseline very high enthusiasm for a therapy that addresses the underlying genetic cause of disease and can potentially reverse and then prevent disease. And specifically in terms of enrollment and participation, the enthusiasm is only going up as we share more information about the trial, first with the announcement earlier this year that the DSMB reviewed the safety data and endorsed escalation to the 6e13 dose based on an appropriate safety profile and now starting with this data.

Yes. One thing I just want to just add is, I don't think we have a reason to believe that just because we expanded our eligibility criteria that, that means that subsequent patients that we'll dose in dose Cohort 2 or an expansion dose cohorts after that are less severe. The fundamentals haven't changed. Whether you're obstructive or non-obstructive, you have severe disease. Whether you have an ICD or don't, you still have severe disease. So that we expect that the patients, both by virtue of having a genetic form of HCM, which has overall been demonstrated in the literature is overall more severe and by other eligibility criteria that we're enriching for, including thicken hearts and elevated circulating biomarker levels, I think we're going to continue to get severe patients. I agree with Whit that we don't expect that the data and the response to therapy would change significantly with subsequent updates. So I just want to continue to emphasize that we think we will continue to get severe patients. And I support everything that's been said about the enthusiasm, and that has only gone up certainly among the various communities we engage with. I would just point out that some of these patients include -- we are getting referrals from outside the U.S. So patients are coming and traveling distances to be part of a study like this. And we have other markers of enthusiasm, the number of patients who contacted us once we expanded the eligibility criteria. Who couldn't be in before, but are eligible now, patients who enrolled in their serostatus study, which is where we got the neutralizing antibody data that we've shared in the past. We fully enrolled all 100 patients in that study and got the data for that. So we have multiple markers speaking to the enthusiasm of the community. And of course, the support of some experts like Dr. Desai and other centers of excellence for HCM, who despite the availability of existing therapies that are approved as well as other investigational therapies that are exciting, they wanted to be part of this study and have actively screened and now dosed patients. But we have lots of markers for enthusiasm in the overall community and they seem to be only going up. And we look forward to addressing as much as we can as this study progresses, but we're very excited where we are.

And Faraz, if you don't mind me, if I make a comment. Even I think the first 3 patients, not one of them was from the State of Ohio. They were at least 300 miles away from my center. So they were willing to travel, they traveled, they have followed up. So there is enthusiasm not just amongst referring physicians, but amongst the HCM community for this line of therapy. I cannot underscore the importance of that.

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

So my questions deal with the near-term and longer term profile of the gene therapy here. So first, in the near-term and as the program develops, can you just remind us sort of your current manufacturing capacity and some of your additional needs going forward as the program expands? Second, I was curious, will you be adding or showing any newer clinical endpoints as the study progresses, both with longer follow-ups and more patients? And then third, and this is really over the long-term, do you see a potential benefit or even a need for potential combinability with other broader HCM therapies?

How about we actually cover the clinical questions first and I'll follow-up with manufacturing at the end. So Whit, first, just endpoints and whether there would be any evolution in those endpoints?

Yes. The measures that we show on Slide 24, as I say, are summaries of more specific endpoints, and we'll share more detail, specific values for those in the first half of 2025. Functional capacity, for example, where we don't have data that you can summarize here at this point will be added. But otherwise, these endpoints fully characterize the types of endpoints that we will be sharing in 2025. Longer term, of course, there's room to amend the protocol if there are additional things that become important measure.

Is there anything you want to add to that, Dr. Desai, regarding these endpoints and any other endpoints we might consider over time?

Again, look, I never say never because I'm always willing to iteratively learn and adapt. But I cannot emphasize, at least at this very early stage, how crucial it is to have biopsy data. And as we learn more, as more and more patients get enrolled, then we can -- if everything is rolling in the same direction, then we could conceivably look at some additional future markers, more diastolic function, more compliance type things, more -- I don't know, more. More is always good. But first, we have to get to brass tacks. First, we have to get to the basic, basic data that we are after.

I'll just add a few comments to that question before we transition to the other questions you asked, Joe. One, just a reminder that how did we select these endpoints. We always said we were designing this to be a data-rich study. So the endpoints we selected are both endpoints that were used by a myosin -- a cardiomyosin inhibitor program for HCM and that led to a successful approval for that program. So we know it's an approvable endpoint. Other data points were derived from were the more gene therapy-oriented programs than our peers, including Rocket, which we know also includes potentially approvable endpoints. So that was partly the thinking that went into the design of this and making sure that we're collecting it quite a bit early in our time course. Which of these endpoints end up being the ones that we end up selecting for subsequent potential pivotal study? Possibly not all of them. We will learn through this study which of these respond at the doses we're testing more robustly and more consistently, and because we don't expect 100% of the patients to have a response to 100% of the endpoint just by the virtue of variable disease progression and patient-to-patient variability. So I think that's the selection part. The other thing maybe to think about what might be in the future, right now, we're doing all of our imaging using echo because the first 3 patients had ICDs. We noted from some recent comments from Rocket that the FDA did want to see some MRI data where patients did not have ICDs because MRI has the potential to be more sensitive. So that might be something to consider in the future of layering in MRI where possible among patients who do not have ICDs, which now that we've changed our eligibility criteria might be possible in the future. So that's an additional data point or response, Joe, to that second question you asked. The third question that you asked was the benefit or the need looking forward for combination therapy, particularly with other small molecules. And maybe for this one, Dr. Desai, maybe I'll ask you to respond to that one first and Whit may add something on top of that.

Yes. So I will address first the imaging question, obviously, right around my wheel. So MRI potentially would have a huge role or regional assessment of myocardial changes. So I'm going to use the global term strain which can be done using echocardiography as well as on multiparametric imaging on MRI, looking for myocardial fibrosis, discrete fibrosis, diffuse fibrosis as well as strain and subtle changes in chamber dimensions, et cetera. Now in 2024 and '25, we can do MRIs in pacemaker ICD patients, but there's a fair bit of artifacts. So the fact that these folks -- now we can infuse gene therapy in people without these devices, we significantly reduce the chances of artifacts and getting a lot of reliable longitudinal data. So yes, absolutely, wholeheartedly look forward to those days. The second question about using in combination, for the record, the current subgroup, the current patients were on background therapy, maximally-tolerated background therapy, each and every one of them. So could we conceivably see a future where you try background therapy or even some of these new precision cardiac myosin-specific -- cardiac myosin inhibitor therapy. And if they do not respond, then add gene therapy as an adjunct or use in combination. All kinds of permutations and combinations could be done once we ascertain safety and efficacy of all these new therapies. Remember, 5 years ago, we didn't have any of these conversations. Now we have a lot of these good things happening.

Yes, I agree. There's nothing about the AAV gene therapy that precludes use of combinations. Another way to think about it is that maybe CMI would be a bridge as the gene therapy is kicking in. So a variety of different ways to think about it. Ultimately, gene therapy has the promise to prevent disease, in which case you wouldn't need other standard of care.

I mean, I would also say that there's so much -- so many different types of patients within the HCM population, obstructive, non-obstructive adults, adolescents, even pediatric and children. We know that there are some very severe children with very rapid and severe disease progression in the first months in years of life. In those patient populations, what will be the likely best first approach, I think that will be learned over time and the role for gene therapy versus small molecule. So it's an exciting period. I agree with everything that's been said. And it's not too early to speculate, but the data will have to speak for itself, both for the myosin inhibitors and other options in the different patient populations as well as for gene therapy. And then the medical community, I know people like Dr. Desai will do their best for patients and find the right things for their patients. The last -- the first question that we will address last now was, Joe, a good one you asked about manufacturing. And so just a reminder for those who aren't familiar with this, we're very proud that we internalized manufacturing capabilities early in our history that TN-201, the entire process, analytical development, quality control, all of that was internalized. We have our own cGMP manufacturing facility. And all of the material for the MyPEAK-1 study was produced in our own facility using our own proprietary process manufactured at the 1,000 liter scale. So we're quite pleased that we successfully scaled all the way from shake flask to 50 liter, 200 liter and to the 1,000 liter scale. And so -- and also, importantly, we have manufactured enough drug for this Phase Ib study. And so we don't have an immediate need to produce more material. So we've derisked manufacturing at this early stage in the clinical development. What will happen in the future is to be determined, right? I think at some point, we will learn where we are with this program. Are we in a phase where we're rapidly expanding and rapidly progressing towards a pivotal study based on early biomarker data consistent with other peer gene therapy programs? Are we -- are things taking longer? I think that will dictate both our -- any expansion plans, future production plans. But we're super excited and pleased to be at the point where we are, where we have the drug produced in our own facility with our own process, very well characterized and compares very favorably to product attributes from other gene therapy products, including those that have been approved by the FDA. So at an early stage in clinical development, we're quite proud of where we are on manufacturing, Joe. And then the future to be determined based on the evolution of the clinical program.

And our next question comes from Whitney Ijem with [ CGF ].

Congrats on the data. I'll just squeeze a quick one here in on kind of the strategy in the pediatric patients. Can you talk a little bit more about that? I know you said there will be data next year from the ongoing natural history study in pediatric patients. What should we expect to learn there? And again, just kind of strategy in the ped patients, particularly in the context of the RPD?

Great. Great question, Whitney. Good to hear your voice. I'll ask Whit to say anything he wants to first. And then Dr. Desai, if you'd like to say something. And then we'll see if I close anything additional.

Yes. So we've had great enthusiasm for enrolling in the MyClimb natural history study in pediatric patients affected by MYBPC3 patients. We look forward to sharing the data in the future and we look forward to collaborating with investigators, pediatric cardiologists and the FDA to pursue drug development in the pediatric population. As a reminder, kids can be very severely affected by this mutation. The age of onset definitely correlates with the severity of disease. And so both heterozygous and homozygous patients can have severe consequences in childhood or even infancy, as I mentioned before. So huge unmet need, very high potential for a gene therapy that addresses the underlying cause and a lot of enthusiasm among those different stakeholders, as I said. So we look forward to working on the pediatric development strategy and then implementing it shortly and then keeping you all informed as we go.

Dr. Desai, anything you'd like to add? I know you're not a pediatric cardiologist, but any comments on the families you know and the children?

I think I echo what Whit has said. I mean -- and what you said a few minutes ago, this disease appears in a full spectrum. And there are cases, there are patients, children as well as young adults who have a very aggressive phenotype because of significantly reduced protein burdens. And my expectation is they may benefit tremendously rather than going towards early morbidity, mortality or cardiac transplantation. So like you said, the future is bright. First, we need to ascertain safety and efficacy in adults and then expand our horizons.

Yes. We're super excited to have them at MyClimb natural history study. Like Whit said, more than 200 patients enrolled, including prospective patients who could provide a run-in to a future pivotal study. We're learning more about the natural history. That will help us have a potentially a synthetic control arm for a potential pivotal study. We are very encouraged by the consistency of FDA orientation to our peers in both Rocket and Lexio where with a handful of patients, less than 10 patients in each case and with evidence of clinical benefit and protein expression, the potential alignment and the potential for an accelerated approval based on protein expression and LVMI improvement greater than 10%. I think that read-through of that FDA feedback is strongest for our severe, rapidly progressive pediatric population. And so we're quite excited to explore that opportunity and approaching the FDA at the right point after dosing enough adult patients, including the high-dose cohort patients to talk about that potential for a rapid development in the severe pediatric population. And so we're in our planning stages for that. We've also are gathering more clinical data from the MyClimb natural history study and look forward to sharing more of that in the future. So Whitney, I think this is an area that we are looking forward to telling you more about in the future, an exciting potential next phase of development for the TN-201 gene therapy program and more. So stay tuned for more in 2025. I think that's all the time we have for questions today. And so just out of respect for everyone's time, just first of all, thank you again for joining us today. We welcome follow-up questions and hope to connect with many of you over the coming days and/or potentially in person next month right here in San Francisco where we're located during the Annual JPMorgan Healthcare Conference. If you'd like to connect with any of us after the call over the coming hours or days or in person at JPMorgan, please do reach out to Michelle Corral. Again, thank you to Dr. Desai. Thank you to the community. Thank you to all of you for your attention today and for excellent questions. Have a great day.

Thank you, everybody, and happy holidays.

And happy holidays. Thank you, Dr. Desai.

Thank you for your participation. This does conclude the program. You may now disconnect. Good day.