Good day, and welcome to the MyPEAK-1 Cohort One Initial Data Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would like to turn the call over to Michelle Corral, Vice President of Corporate Communications and Investor Relations. Please go ahead.
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 One of the MyPEAK-1 phase I-B/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.
Excuse me there. We are pleased to have Dr. Milind Desai of the Cleveland Clinic. For his many titles, he serves as 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 happens 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 talk, 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 17th, 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 five, 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 de-risk 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 one patient who has reached their one-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 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 de-risk 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 I-B/II trial of TN-201, and offer a promising potential read-through to our AAV9-based TN-401 gene therapy program, for which we recently announced dosing. Now, before we go deeper into these data, over the next four slides, I will briefly cover an overview of the disease, the TN-201 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 six, 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 seven 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 cause a decrease in the level of MyBPC 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 I-B/II study is provided on slide eight. As a reminder, this is a multi-center open-label dose escalation trial designed to assess safety, tolerability, and clinical efficacy of TN-201. We have completed the dosing of Cohort One, comprised of the first three 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 One 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 Two per protocol. The DSMB also endorsed our plans to expand the enrollment criteria to include adults with the obstructive form of disease and removing the ICD requirement. Cohort Two enrollment is underway. Now, turning to endpoints on slide nine. 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 two patients in Cohort One were then dosed sequentially in January and July and monitored for safety. Therefore, the available dataset we'll be reviewing today includes the week 52 assessment for patient one and follow-up assessments out to week 40 and week 12 for patients two and three, respectively. Today's dataset is a meaningful de-risking 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 three 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 number 11, I would like to share with you the details of our patients, the first three 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 three patients that we have recruited. The mean age is thought to be about 50 years. The first three patients are much younger, two females and one male. Because of protocol mandate, all three of them had a defibrillator, ICD, whereas in the national cohorts of HCM patients, that rate is about 21%.
All three patients had a prior surgical myectomy at high-volume 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 remained 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 squared. Here in patient one and patient three, it was in patient one, it was more than double. It was almost double and significantly increased LV mass index.
All three patients, as alluded to, were symptomatic with two in NYHA class two and one patient in NYHA class three. 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 treatments. So let us break down the three patients. Patient one had a grade three 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 two had a grade one adverse event at week one, and patient three had a grade one serious adverse event at week two.
Let me talk about the serious adverse event for a second. It was a mild elevation in liver function tests, 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 hospital, we decided to admit the patient to the hospital, categorized this as an SAE. Patients one and two have completed their immunosuppression regimen, and patient three 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, the majority of treatment emergent adverse events were mild, transient, or reversible. There were two 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 6E raised to the power of 13. 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 three 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 three 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 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 eight for patients one and two, and week 52 for patient one. As a reminder, we did not collect biopsy at baseline for patients one and two. We subsequently amended the protocol to collect biopsies at baseline, post-dose, and at the one-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 three, 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 dubbed vector copy number or VCN. Both patients at eight weeks had over two vector genomes per diploid genome, meaning we've delivered the equivalent of two 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 one, there's a drop in VCN to 0.8 vector genomes per diploid genome. This is expected. There are copies of the cassette still around at week eight that aren't incorporated into the cardiomyocytes. These extra capsids get cleared over time, but there's no loss in function in TN-201 because 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 soon. 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 the 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 6.7 E13. 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 this 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 three 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 factor 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 one at weeks eight and 52 and patient two at week eight, 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 zero for both patients, even without a baseline biopsy. At week eight, patient one and patient two reached transcription levels of 1.7E5 and 1.3E5 mRNA copies per microgram of RNA. At the week 52 biopsy, patient one achieved RNA levels of 2.5E5, a 50% increase. We discussed a moment ago the drop in the DNA vector copy number in patient one between week eight 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 two 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 is 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 two 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 two. 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%-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, so in red. The average patient has 60% of the normal healthy level, with patients ranging from 47%-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 had 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 cardiac gene therapy programs have been associated with clinical benefit. On slide 21, we show the protein results from the first two patients' three biopsies. At eight weeks, MyBPC protein levels for patient one were 56% of normal. At one year, patient one'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 eight 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 MyBPC 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 three, baseline biopsies will be available. Patient two at week eight had a 62% MyBPC3 protein, and their one-year biopsy will be early next year. Next year, we will also get our first glimpse at patient three and its dose cohort two, including baseline biopsies. With more time, more patients, and both doses, we will begin to understand the quantitative relationships between transduction of 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 number 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 a more advanced disease state, and in patient one, 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 one remains elevated at week 52, likely due to advanced disease. However, Patient two has normalized the Troponin I levels since TN-201 treatment. Moving on to some of the clinical signals, we observe encouraging early clinical signals, but recognize 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 one remains stable. Troponin I in patient two increased. The markers of hypertrophy and diastolic function in patient two improved, and diastolic function remained stable in patient one. Symptoms in both patients have improved NYHA Class, and KCCQ has remained stable in patient one.
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 clearer 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 results 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.
We have reason to believe that will enable enrollment, even at the sentinel dosing period for cohort two, to go faster. On cardiac delivery and expression, the vector copy numbers observed at the eight-week mark following dosing meet our expectations, whether looking at our preclinical data or that of peers who in some cases are using higher doses. The result: clear expression of TN-201 mRNA, which we can differentiate from endogenous mRNA. 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 one and two, as well as initial results for cohort two. 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 have been instrumental to dosing the first three 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.
In particular, we all owe a deep debt of gratitude to the first three patients who stepped forward to enroll dose cohort one 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.
Thank you. If you'd like to ask a question, please press star 11. If your question has been answered and you'd like to remove yourself from the queue, please press star 11 again. Our first question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.
Good morning, team. 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 one. Question two 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 two and patient three? 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 one patient's weight? Is it going to 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.
Thank you, 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 last one first, the dose. So go ahead and respond to the first one, and then we can cover liver enzymes and.
Okay, last one first. 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. We look very much forward to the results of cohort two, where we'll 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. They responded rapidly to steroids. They were asymptomatic. There was no evidence of hepatic damage, no elevation in bilirubin, simply transaminase elevations. The first patient hit CTCAE grade three, which starts at five times 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.
We have not seen a grade 3 since then.
The last one might have been on actually the serial or in the serial dosing period for.
Oh, yes.
So.
Thank you, Faraz. So in the protocol and in alignment with the FDA, we will continue sequential dosing for the first three patients at the next dose level.
Thank you, Yasmeen, for the questions. We're ready for the next one, Operator.
Thank you. Our next question comes from Mani Foroohar with Leerink Partners. Your line is open.
Hi, good morning. This is CJ on for Mani. Taking a forward-looking view, can you share whether you've dosed any patients in cohort two yet, and also how we should think of initiation timing for parallel dosing and dose expansion? Thank you.
Thanks, CJ, for the question. I'll take a first crack at this. We haven't yet announced dosing of the first patient in cohort two, and somewhat consistent with our practice in dose cohort one, 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 two. 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 then, of course, the widening eligibility has helped us, so overall, we anticipate and expect that enrollment in dose cohort two can move more rapidly than dose cohort one.
But we won't make forward projections at this time. Whit, is there anything you'd like to add to that?
I agree.
Thanks. I guess to clarify my question a bit more, now that you've completed the sentinel cohort for cohort one, can you start dose expansion now while you continue to sequentially dose cohort two?
Thanks for the reminder of that question. So technically, yes, we are open to dosing patients in parallel at dose cohort one. However, at this time, we're focused on enrolling patients for dose cohort two. 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 two and then make a decision based on the totality of data of expansion, the optional 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 appropriately.
Okay, great. Thank you so much.
Thank you. Our next question comes from Ritu Baral with TD Cowen. Your line is open.
Good morning, everyone. Thanks for taking the question. 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 do you guys have a target, a target delta, or any considerations for even a higher dose, just given this is a bump up and 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.
Thank you, Ritu. Thanks for answering the question. I'm going to ask Whit to respond to that first, and then I'll add to that.
Yeah, 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.
Yeah.
So Whitt.
Go ahead. Sorry, Ritu. I was just going to add that.
Oh, I was going to say, go ahead.
Go ahead.
Go ahead.
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 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 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 ours 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 eight 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 zero to eight 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, Ritu, 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 three, the one who started on IV steroids elevations, was there a particular reason that IV steroids were required over just orals in this case?
Good question. I'll have Whit respond to that.
So okay, go ahead, Doctor.
Actually, great one for Dr. Desai today. Great. Thank you.
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 my simple answer to that is it is our iterative experience based on the prior two 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 tapers, which could potentially very well be the case for this patient.
Got it. Super helpful. And then last question. 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 and 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 forms relating that level to function based on some sort of modifier, whether it be genotypic or whether it be patient characteristic. Thanks.
Yeah, 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 translated into 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 the polygenic risk scores do stratify risk among sarcomere-positive HCM patients. It 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.
Yeah, the only thing I would add is just a 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 of 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 will support that. Good questions, Ritu.
Thank you. Our next question comes from Michael Ulz with Morgan Stanley. Your line is open.
Good morning. Thanks for taking the question. 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? Thanks.
That's a good question, and I'll ask Whit to take a first crack at that, and I'll see if I have anything additional to add.
Yeah, 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 eight-week results is that this is still early. We're certainly not a steady state. We haven't plateaued by the eight-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 one-year biopsy reflects the steady state or whether we'll have increasing expression even beyond one year.
Yeah, 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 we'll learn a lot more through this study. It's interesting. We have seen from our peer gene therapy company in the New England Journal paper, we were pleased to see that in the Danon program, that out to three and four years, there are patients who still have stable viable 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 post-mitotic, and so they're not dividing. And that also contributes to stability. So the exact kinetics past the one-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 one-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 eight to 52 weeks, 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 at higher dose.
Got it. Thank you.
Thanks, Mike.
Thank you. Our next question comes from Cory Jubinville with LifeSci Capital. Your line is open.
Thanks for taking our questions. 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, etc., over the course of one year without intervention?
So, Faraz, I'm going to take this question since it was directed towards me.
Yeah, please. Please use Dr. Desai directed to you.
Yeah.
And we'll add if necessary.
These folks, all three patients, 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 five years, the entire cohort, but needless to say, all the three 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 their disease stability?
Hard to say, but they are feeling symptomatically better. Again, I will simply answer, 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 n, 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.
Yeah, I would only maybe mention, if you look at patient one 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 have 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 where we're operating for some of these patients.
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. 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 they're hearing that from all three 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.
Yeah, that's helpful. And can you provide a little bit more context on what you mean when you say that patient two 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 approval endpoint and similar indications. How do you think about that and that threshold in the context of these data and potentially future studies or readouts?
Great question. I'll ask Whit to take a first response there and then Dr. Desai to add.
Yeah, we look forward to sharing more data from cohort one 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 that will include patient three and longer-term follow-up for all three patients.
Yeah.
Dr. Desai?
I have nothing further to add. I agree with everything you've said.
Yeah, more details to follow. I think the only thing we would say is that when we chose this color scheme, I think we wanted our 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. 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 where it's hypertrophy, diastolic dysfunction, etc., there are many, many subcategories within that.
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.
Thank you. I'll hop back in the queue.
Thanks, Cory. Good questions.
Thank you. Our next question comes from Sammy Corwin with William Blair. Your line is open.
Hi, good morning, everyone. This is Caleb on for Sammy Corwin. We would just want 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? Thanks.
Whit, do you want to respond to that first?
As we proceed in enrolling this trial, we may see patients with less severe baselines coming in. We don't anticipate that 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 phenomena somewhat separate than the mechanisms of disease.
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?
Yeah, Dr. Desai, would you like to start with reactions from peers?
Yeah, I think so. Thank you. Yeah, 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 in the 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.
Yeah, I agree. There's increasing enthusiasm, I would say, in the baseline, very high enthusiasm for a therapy that addresses the underlying genetic cause of disease and can potentially reverse and prevent disease. And specifically in terms of involvement 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.
Yeah, 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 will dose in dose cohort two or in the expansion dose cohorts after that are less severe, right? 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 as overall more severe, and by other eligibility criteria that we're enriching for, including thickened 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 will just point out that some of these patients include we are getting referrals from outside the U.S., right? So patients are coming and traveling distances to be part of a study like this. 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 for us, if you don't mind me if I make a comment, even I think the first three 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.
Thank you, Dr. Desai. Next question.
Thank you. Our next question comes from Joe Pantginis with H.C. Wainwright. Your line is open.
Everybody, good morning and happy holidays, and thank you for taking the question. 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? Thank you.
How about we actually cover the clinical questions first, and I'll follow up with manufacturing at the end. So Whit, first, do you just endpoints and whether there would be any evolution in those endpoints?
Yeah, the measures that we show on slide 24, as I say, are summaries of the more specific endpoints. And we'll share more detail in 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 to 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 going 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 cardiomyocyte 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 the more gene therapy-oriented programs and 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 because we don't expect 100% of the patients to have a response to 100% of the endpoints 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 three 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 an 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 in my wheelhouse. So MRI potentially would have a huge role in 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, etc. Now, in 2024 and 2025, 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, five years ago, we didn't have any of these conversations. Now we have a lot of these good things happening.
Yeah, 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 the other standards.
Yeah. I mean, I would also say that there's 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 and 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 molecules. 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 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 to 200-liter and to the 1,000-liter scale. And also, importantly, we have manufactured enough drug for this phase I-B study. And so we don't have an immediate need to produce more material. So we've de-risked manufacturing at this early stage in the clinical development. What will happen in the future is to be determined, right? I think that 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 things taking longer?
I think that will dictate both 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.
Great. Thank you very much for all the color.
Great question, Joe. Thank you. Next one.
Thank you. And our next question comes from Whitney Ijem with Canaccord Genuity. Your line is open.
Hey, guys. 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've said there'll 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 peds patients, particularly in the context of the RPD. Thanks.
Great. Thanks. 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.
Yeah. 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 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 who are affected?
I mean, 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.
Yeah. We're super excited to have the 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. And we're learning more about the natural history that'll help us have 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 Lexeo, 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 rapid development in the severe pediatric population. And so we're in our planning stages for that. We're also 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 JP Morgan 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 JP Morgan, 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.
Happy holidays. Thank you, Dr. Desai.
Thank you for your participation. This does conclude the program. You may now disconnect. Good day.