All right, good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce Faraz Ali, CEO of Tenaya Therapeutics. Just a reminder, format for today is a fireside chat, so if anyone has a question, please feel free to raise your hand and we will get your question addressed. Before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, Faraz, thanks for joining us today, and maybe I'll just quickly hand it over to you to make any introductory comments, you know, for those that maybe aren't familiar with your story.
Yeah. Great. Well, good morning, and thanks for having us here. Seven A.M. is always a tough slot for the presenters and for those who are going to join in the audience. This is an exciting time for us as a company. We obviously a clinical stage company, three programs at the clinic, and exciting for two of them in particular. One, our lead TN-201 gene therapy program, which I know we'll talk about, on track to provide initial data update, clinical data update on that program in the second half of this year. And then for the other gene therapy program, TN-401, on track to dose the first patients in the second half of this year.
So we're just entering into an important period in our corporate history, where the next six to 12 to 18 months will give us the first set of data on two gene therapy programs, which people have been waiting for a while. And, so it's an exciting time for us, and things are going well, and we're gonna if t alk about it today.
Yeah, great. Thanks for that introduction. We're looking forward to the data as well. Maybe we can start with your lead program, TN-201, you know, gene therapy for HCM, but, you know, maybe you could just describe some component... key components of the construct, what's unique about it, you know, how it works, and maybe anything that you've seen in preclinical studies that sort of give you confidence in the program.
Yeah, sure. So TN-201 is an AAV gene therapy program. And so it's intended to address the leading genetic cause of hypertrophic cardiomyopathy, which is due to the MYBPC3 mutation. We'll talk more about that later. I know, so any gene, the AAV gene therapy program is gonna have, you know, a couple of main components. It's gonna have a capsid, it's gonna have a promoter, and a few other regulatory elements. For the capsid for this program, we chose AAV9. Made that choice several years ago and have been glad that we did it. It's the capsid that has the most validation in general. It's been used to dose more patients than any other currently used capsid.
It has validation in the human heart, and that's courtesy of our the good work of our friends, Rocket, and their Danon program. And the safety database is incredible. So Zolgensma, using AAV9, has been approved several years ago. At this point, more than 3,700 patients, infants, have been dosed with either the 14 dose AAV9 in more than 50 countries. So good safety database, good human validation for biodistribution in the human heart via Rocket. And look, the preclinical data that we have produced sort of supports that choice.
We have done extensive experiments in both human cells as well as an in vivo murine model, and across all of those programs, we've been able to demonstrate that we can reverse the symptoms of the disease and/or prevent decline. We've shown reduction in heart mass, we've shown improvement in contractility, we've shown improvement in ejection fraction w e've shown an extension of survival. And so time and time again, within relevant doses of three to thirteen seems to give us the maximum efficacy in mice. It's a very, very high bar model because these mice don't have any protein. Whereas the average human is a heterozygous with some protein on board, I know we'll talk about that later. We've been able to produce 100% of the wild-type protein and 100% of the treated animals survive. So, the preclinical package is very robust, and obviously, that led to a smooth clearance when we submitted our IND. So yeah, that's the construct. The last thing I would say about... We've talked about the capsid, talked about the preclinical data. So what makes this program special and, in part, is the MYBPC3 gene is large. It doesn't optimally fit-
... within an AAV, with all the regulatory elements. So on the regulatory elements and the promoter, in particular, we had to do some innovation to make everything optimally fit and express in package. So, we have a novel promoter that has a more robust expression than a standard off-the-shelf promoter, but still allows for, exquisite expression in the cardiomyocytes of the heart versus other organs. We have, at this point, three, four different IP filings have been issued. And so I'd say, you know, validated capsid, novel promoter, and overall design of a cassette that is innovative, that is protected by IP.
Yeah. Great. Maybe before we start getting into the clinical study you're running, can we talk a little bit about just HCM in terms of what causes the disease, how those patients are identified?
Unfortunately, it's a terrible disease. Hypertrophic cardiomyopathy, about 600,000 patients estimated in the United States alone. Then, the MYBPC3 represents the leading genetic cause of HCM, and it accounts for about 19% of all patients. Back-of-the-envelope math, that's how we come to say that there's about 120,000 or more patients in the U.S. alone. That makes it a pretty large market opportunity and unmet need.
... compared to other gene therapy programs that are mostly focused on ultra-orphans. The hallmarks of the disease are enlargement of the heart, thickening of the ventricles, but there's also fibrosis, you know, downstream of that fibrosis and arrhythmia. The patients experience maybe early on with, like, you know, dizziness and faintness and lightness of breath, but eventually, those symptoms are presaging something much more severe, including early morbidity and mortality, patients needing transplant, experiencing heart failure, and needing ICDs to prevent sudden cardiac arrest. On average, patients with a genetic form of the disease, like MYBPC3, present with a much more severe course.
They're typically diagnosed more than a decade earlier than people with a non-genetic version of the disease, and they typically progress faster and have worse outcomes. There's a lot of heterogeneity here in this disease. Most of the patients are heterozygous adults, but you also have adolescents and pediatric patients, and even neonatal infants who have the homozygous form, and those kids don't survive past the first year of life.
So there's a lot on our plate. What is common across all of these patients is that they have a mutation in the MYBPC3 gene. They're not producing enough of the MYBPC protein, and that is, it's a disease of haploinsufficiency. We know all the terrible effects of the disease are downstream of that missing protein. And so TN-201 has got a very simple thesis: use AAV9 to deliver a working copy of the MYBPC3 gene, you know, produce some of the missing protein, prevent disease progression, restore some function, and hopefully prolong the lives of these patients and improve their quality of life.
Makes sense. Maybe you can talk a little bit about the treatment landscape. You know, you've mentioned unmet need, you know, where is that, and you know, how could TN-201 fit in?
Yeah. So in the past, most of these patients, unfortunately, were just given the standard cocktail of, you know, beta blockers and antiarrhythmic medications, most of which might provide some symptomatic relief, but don't really address the underlying cause of the disease. More recently, myosin inhibitors, or at least a myosin inhibitor, Camzyos, was approved, previously, mavacamten, has been commercialized by Bristol Myers Squibb. That is, been approved for the obstructive form of the disease. Nothing else has recently been approved. Now, Cytokinetics is coming with a second-in-class myosin inhibitor. What I would say is that that is outstanding, that there's some new options for these patients, 'cause as I mentioned, they are in bad shape. And so the approval of Camzyos was a real game changer, and also gave us a regulatory roadmap.
- of what's gonna be necessary for us to get to our own approval down the line. But there's a lot of unmet need. You know, the response rate on Camzyos in their pivotal study was 40%, 20% in excess of placebo. And so there were a lot of non-responders. But the bottom line is, the CMIs are not addressing the underlying cause of the disease.
It is relaxing the heart, but it's not treating the disease. It's not addressing the fact that these patients are missing MYBPC3 protein, which is an incredibly important protein responsible for the appropriate contraction in the sarcomere of every single cardiomyocyte of the heart. So I would say from a treatment landscape perspective, there's a lot of unmet need both on the pharmacological side. Also, surgical interventions are used for the obstructive patients, but for the non-obstructive patients, that's not an option. And as it turns out, patients with this MYBPC3 mutation, 70% of them have the non-obstructive form of the disease-
... and 30% have the obstructive form of the disease. So the obstructive - the patients with the obstructive form of this disease, they might benefit from a myectomy, but that's also not addressing the underlying genetic cause. Their hearts will still progress. They might benefit from a myosin inhibitor, also not addressing the underlying cause of these. On the non-obstructive type, they have even fewer options. They don't have the benefit of surgical options, and the myosin inhibitors have not yet been approved-
... and have not yet demonstrated the same efficacy that they have on the obstructive side of the equation, so we just see a lot of, you know... It's a large population with severe disease and a lot of unmet need and opportunity-
Yep
- to address.
Makes sense. And is the strategy, I think, it's, you know, target non-obstructive first and then kind of maybe move into obstructive later, is that?
Yeah, that's the. From a clinical development perspective, all of this heterogeneity that I described earlier, adults, adolescents, children, homozygous, heterozygous, obstructive, non-obstructive, what they all share in common is that they have the MYBPC3 mutation, and they're missing the relevant protein, and so we think TN-two hundred and one is gonna be relevant for all of those populations. Having said that, we have to start somewhere, and so we chose to start with the non-obstructive patients first, for all the reasons I just described.
That's where most of the patients are. That's where the unmet need is highest. And so we're gonna start there. I know we'll talk about our study design in more detail in a second, but start there, but very much with the intention, we've been very consistent on this point.
... with the intention to expand into obstructive patients and also to expand into adolescents, and pediatrics, and children. We've already had conversations with the regulators about that, and so there's really no reason for us not to. That was sort of self-imposed to try to take all this heterogeneit and say, let's focus the first couple patients here.
Yep.
But from there, branch to the other patient populations. So from a clinical development strategy, we very much wanna see how TN-201 performs in different populations, and we don't have to have, like, 10 or 20 patients treated. We just need to sample the different populations and see where we see the most promise and which endpoints, and then use that to help design a future pivotal study.
Yeah. If you're successful in non-obstructive, you know, is it the expectation you'd also be successful in obstructive, or are there different, you know, different amounts of expression you may need for some reason, or differences there that might impact that?
Excellent question, right? I mean, I just said that they, they all share reduction in protein in common. There's no doubt that there these diseases present a little bit differently. The homozygous infants, they have zero protein and they die within the first year of life. The heterozygous adults have anywhere from 40%-70% of the native protein, and they present differently. So, it is very possible that we need different levels of overall transduction and expression in different populations, or different endpoints may move more robustly, or less robustly in response to, you know, different doses of the therapy. So that's part of what. Like, we're the first in the world to be doing this. We dosed the first patient in the world in the myPEAK-1 study in October last year. That was an exciting milestone, not only for us as a company, but for the entire field. But what we're doing has not been done before, right?
Gene therapy has been done, gene therapy and cardiomyopathies have been done, but for this specific condition, you know, with this sarcomeric mutation, this is the first time we're doing it. So we have the humility to know that the phase 1a/b study is intended to explore these kind of questions. What is the dose that gives you some symptomatic relief? What is the dose that gives you dramatic symptomatic relief? What is the dose that's equivalent to a cure?
What does that look like for different patient populations? It's possible that obstructives respond differently than non-obstructives. They certainly did with the myosin inhibitors.
Right? They saw a dramatic benefit with the obstructive population, not as much in the non-obstructive, but that was because of the unique mechanism of myosin inhibitors and how that intersected with the obstructive patient, in a very unique way. So, so it is, it is fair to say, well, gosh, myosin inhibitors worked in obstructive, haven't worked quite as well yet in non-obstructive. Could the same hold true the other way around? And I would say what's different for us, is, again, I go back to the lock and key nature of what we're doing. We are addressing the actual underlying genetic cause of the disease in all of these populations and subpopulations, where, you know, we're, increasing the protein levels, and so we expect there to be benefit in all patients.
It just may be that the time horizon for any given endpoint for any given patient may take a while to... and it may be that the protein levels need to be different, but that's exactly what the phase II, phase Ib and subsequent studies are designed to address.
Yeah. So a lot of questions, and you'll answer those with your-
With our data.
myPEAK study first.
Maybe let's move there and just talk about the design there and kinda what are some of the endpoints.
Yeah, we've addressed, started to address some of that. The myPEAK-1 study is initially focused on non-obstructive patients. Obviously, everybody has to have the MYBPC3 mutation documented. We've tried to enrich for patients who have some symptoms, so the New York Heart class II or III. They also enrich for a more severe initial population who have ICDs on board, and as well as have a certain threshold of NT-proBNP. And that's all designed to, again, both homogenize the population a little bit, but there's still a lot of heterogeneity, and to enrich for patients where the severity really will justifies starting something and trying something the very first time, but then we'll expand and loosen the criteria after that.
And of course, they have to have no neutralizing antibodies to, or low neutralizing antibodies to AAV9. We've produced data on that front from our serostatus, showing that the vast majority of patients do not have neutralizing antibodies to AAV9 and would qualify for a study on that basis. In terms of endpoints, I've joked that you can take the mavacamten pivotal study and marry that up with the Rocket-
... Danon study, and there you go. We've got the endpoints. It's a data-rich study. For each patient, we are capturing a lot. We're capturing, obviously, safety first and foremost. We're taking biopsies, so that'll give us vector copy number, RNA, and protein expression. We're capturing circulating plasma-based biomarkers that can be measured, you know, very easily. We're capturing echo, and there's a lot you get from an echo.
You get the size of the heart, the mass of the heart, the dimensions of the ventricles, the thickness of the ventricles. You get ejection fraction, you get measures of strain. We're measuring functional capacity in two different ways: six-minute walk test, as well as CPET. We're, of course, measuring quality of life using the same Kansas City Cardiomyopathy Questionnaire that MyoKardia used for their pivotal study, so each patient, we're gathering a lot of information, obviously, at different time points, so a different cadence for the different endpoints. There's a lot, and that's precisely to make sure that we are learning as much as humanly possible.
... from each patient that we treat, that's quite precious, and find those signals, what's moving faster, what's moving slower? What's the relationship to dose? Again, you could look at pretty much everything that, but there's nothing that we're doing that is unique in that way.
And I say that not with any. I say that with pride because it's good. We are using endpoints that have been validated and actually have supported the pivotal study and approval eventually of MyoKardia's mavacamten, now Camzyos, and some endpoints that were agreed to with the FDA, with Rocket on their Danon program for the potential full approval, as well as potential for accelerated approval. You know, while it's just a phase 1b, there's a lot we will learn, and from that things could move quickly once we determine that right relationship between dose and certain endpoints. So we're excited. That's a first step in a journey, but it's a journey that could move very quickly once we start seeing movement in some of these endpoints.
Yeah. I think you plan to share some initial data from that study later this year. Maybe give us a sense of what we should expect in terms of patient numbers, you know, what endpoints?
Yeah. So one thing we didn't mention with the design of the study is there are two dose cohorts: dose cohort one, three E thirteen vector genomes per kilogram; dose cohort two, six E thirteen vector genomes per kilogram. And that, those doses were chosen deliberately. We saw near maximal efficacy with our three E thirteen dose in our preclinical studies, so that's. We were very pleased the FDA allowed us to start there, and then we go to six E thirteen after that. And there's sentinel dosing over there. So we dose a patient, pause DSMB clearance, dose again, pause. And after dosing three, we get to escalation and/or expansion, and same at the end of six E thirteen, we can get to expansion.
So serial dosing to begin with, and then after that, you know, parallel dosing, and that's pretty consistent with the design of other gene therapy studies. So I bring that back to what does that mean in terms of data expectations? We've been very consistent with the expectations we've set, for about a year now, which is the first data release is the first step in a journey. It's gonna be the first couple of patients in the dose cohort one. And then in terms of the endpoints that we'll get from that, of all the things that I mentioned, which is a data-rich study, safety, biopsy, circulating biomarkers is what we've committed to.
Other things like echo, functional improvement, New York Heart Association class and quality of life, those are. We're not committing to those for this first data release. There's a chance that we will share. We wanna make sure. We believe it's gonna be a meaningful update, but it's an early update. Right. The first patient was dosed in October, that means that first patient reaches their one-year mark in October of this year.
And so I use that to bookend, you know, first couple of patients from the first dose cohort, the first patient will be at a one-year mark in October. That means everybody dosed subsequently will be before their one-year mark. And so that starts setting boundary conditions for setting appropriate expectations, that, you know, everybody, one patient can be at one year and everybody else will be, you know, before the one-year mark. But we think that that's a meaningful horizon certainly to assess safety, certainly to get early reads from the biopsies. We take two, one at eight weeks and one at 52 weeks. That's, we've mentioned that in the past.
The circulating biomarkers are collected more frequently, and some of the other measures are captured quarterly or biannually or annually. That gives you a feel for... We'll have a mix of different data, some of which will be more. There'll be more of that for several patients, there'll be less of that for other patients.
So that's why we're being deliberately and appropriately, setting expectations of how much we're sharing. Meaningful update with a lot more to come in 2025, with both these initial patients and more mature data sets from the other endpoints, as well as then subsequent doses. So, the next dose cohort up. An exciting early update, managing expectations of how much we're gonna give. The comparison we make with this initial data release is Rocket circa December 2020. They did their first data release, three patients, about 18 months after initial dosing.
And then, in that, they provided similar things: safety, biopsy data, and then on the circulating biomarkers, and then on the echo side, they did not provide LV mass or any evidence of LV mass reduction. That came in subsequent data releases. And so we've kinda modeled our initial data release after theirs. It's at an earlier time point.
than their initial data release, but, you know, qualitatively, it is represents the same thing, the initial step in the journey. We all know that the journey that Rocket went on after that, where then they showed subsequent to that LV mass reduction, that looked better the year after that.
By 2023, with six or seven patients, they were in alignment with the FDA and the design of a pivotal study. So it shows that in this space, really dramatic improvements in a few endpoints, in a few patients over time, can be enough to get into a pivotal study discussion with the FDA. We don't know yet what our bar will be-
... but it's an exciting precedent for us, and so this initial data release is similar to theirs, and we hope that our journey with maturity of the data will be similar to theirs as well.
Yep. Makes sense. Maybe we can dig into a couple of those sort of updates, maybe starting with safety. Just, you know, you mentioned earlier, AAV9- sort of well-validated and understood these days, but anything on the safety side that, you know, we should be looking for?
I mean, so people have asked us about that, and we generally say, "No news is good news. So we haven't had to announce that we're on clinical hold, and that's a good thing. That means we haven't yet experienced anything that elevates to the level that it would pause our program and So, you know, we're looking for some signals that we expect are consistent with almost every AAV gene therapy, elevation of liver enzymes. The point isn't whether they have them or not, it's like, can they be managed
... with immune suppression and corticosteroid steroids? So that's something we're looking for. We're certainly looking to avoid TMAs altogether or mitigate if they have them. The study has been designed to do both of those things. We have ICDs on these patients, and that's partly to enrich for a population, but also as a safety measure, and to make sure that there's no unintended proarrhythmic consequences, no myocarditis and other things. So I'd say those are some of the obvious things that we're looking to have. We want a profile that's as good as any other gene AAV gene therapy program, but with- We've designed the study to mitigate the worst things that have been seen in the
... in the field, including, you know, TMA, and acute liver toxicity. So, knock on wood, so far, so good. We haven't had to make any of those kind of announcements.
We've had smooth, smooth clearance with the FDA, no clinical hold at that point. And that's important, by the way, because if you recall, when we started, it was against the backdrop of a lot of clinical holds in this field. That kinda set the field back at some level. And we haven't heard that as much in a while, and that's good. And we have certainly internalized all the learnings, and designed this study to be as safe as possible.
.W hat about just, cardiac biopsies, I know you're gonna be measuring a couple things there, including protein expression. So maybe just walk us through some of those and kind of what would be a good result there. And then on the protein expression, I know it's a little bit unique. It's not zero protein, and then show some protein expression. There's some level to begin with. How do we think about that?
Yeah. So, biopsy gives you a lot of information, and we're collecting it at two different time points for these patients, at 8 weeks and 52 weeks. Each patient, they're at centers of excellence, where they, they're taking actually multiple punches, so it's not. I had to answer this question to somebody yesterday. We're not relying on a single biopsy, with a single sample, and that, like, was it in the right spot or not in the right spot? But they're actually. These are experts who know how to take multiple samples, and so we're not gonna have, like, a single point of failure with a single biopsy.
But then from that, we get vector copy number, which is a measure of distribution and the relative infection of the AAV9-based product in the heart. We get RNA, and we get protein. So we get three different things. Obviously, you wanna see high vector copy numbers. That's actually the starting point, really, of the journey. Then you wanna see some expression in the RNA and protein. This is where, like you said, you know, what does good look like? That's hard for us to state clearly. We have our ideas, we have our hypotheses, but as you mentioned, these patients are heterozygotes, so they have some amount of protein on board. So they have anywhere from 40% to 70%.
And there seems to be no direct relationship that we can tell with genetic mutations and protein levels, and so we're kind of again, this is the first time that anybody's doing what we're doing before. We will learn a lot. We certainly don't expect 100% protein expression
We've got in the animals, because nobody in gene therapy gets-
100% protein expression, and nobody gets exactly what they saw in their animals. So it's not a matter of getting at 100%. It's like, what - how much do we get, and does it achieve the threshold? As I mentioned earlier, what amount gives us some symptomatic relief? What amount gives us dramatic symptomatic relief? What amount translates to a cure? We don't know what the answer is. So for a patient whose starting baseline is 40%, will it be 5% or 10% or 20%-
-that moves the curve? There's another patient who's already sitting at 60% and has disease, so what, what will move the needle for them?
One thing we'll learn from this study is, is there a single level that, you know-
you need to achieve for all patients?
Or is it relative to your baseline, given that they're all starting at different baselines? That's what makes this study a bit unique compared to others. Most other gene therapy studies and ultra-rare for an indication, their patients starting with no protein, right? And then you're delivering something on top of it. And what we've seen, including with Rocket and others, is that a small amount can go a long way and have a lot of improvement over time. So we have to figure out what that looks like for us against the backdrop of a heterozygous with a certain amount of protein. We've got the right tools. We know how to measure RNA, we know how to measure protein, we know how to quantify that.
We feel we've got the right tools at our disposal to do that. But we have to be careful about setting expectations that this is the percentage-
-point that will result in this, because we have the humility to know, that that is, exactly what we're gonna learn through this process. I will say that there's clear evidence of threshold effects, even in the mice, we know that if you have 85% wild type protein, which is what the heterozygous mice have, they have no symptoms. Zero. Like, we can't even induce symptoms on them if we tried. So we know that at least in mice, you don't have to be at 100%, even at 85% and possibly lower, we just don't know what that is, they are asymptomatic.
We know in humans, there are patients with a mutation, and they don't have symptoms, but we don't know what their protein levels are—
... because there's no, you know, justifiable reason to take a biopsy from asymptomatic patients.
We know that there's threshold effects. We've hypothesized that you know, if the average patient is 60%-70% wild type protein, and in the animals, we see that you know, 80%-85% and below, you're in. It could be that there's a narrow range in which there could be a dramatic effect, that every small, every incremental bit of protein could have a dramatic effect on each patient, and that there's certainly, we don't need 100%. Could it be 10%, 20%, or 25%, where you go from being in disease state to asymptomatic?
That would be very exciting.
If that proves to be true.
And like I said, it could be that every 5% between 0 and 20 or 25 could lead to dramatic improvements, but we don't know.
We got to prove this via clinical development, and we will not answer all those questions with the first data release. That's why we keep on saying this is the first step. We will answer more of these questions with time.
Yep. Maybe just a quick follow-up. Will patients have baseline biopsies or just the eight-week and 52-week?
The initial patients don't have a baseline biopsy. They have eight-week and 52-week.
Part of the rationale there was to spare the patient-
... from too many biopsies because they already have delicate hearts, especially the initial intent to treat population, but that may change with time.
And one thing we liked about what we've seen from others is taking different biopsies at different data points, and then you learn about the kinetics of expression. Not only the magnitude-
... but the kinetics of expression. You know, some cases, expression goes up with time, in some cases, stable. For other disease areas, it declines. We know this is the first time we're doing what we're doing, so nobody's done, so this is what the exact kinetics of expression for this protein, the sarcomere protein, are, both the magnitude and the directionality, that has to be determined. So over time, we'd love to get more data points, and that means biopsies at different data points at times. So this space will change.
We will—and it'll change deliberately because we're gonna be actively exploring and trying to understand that expression kinetics curve, but for the first couple patients, you can't tell them that you're gonna take a baseline and two months, and four months, and six months, and eight months. Like, we would pretty much not have-
Not only
No patient will sign up for that, especially patients who already have pretty compromised hearts-
and no expert would sign up for that.
So you kinda have to be patient and do that over time.
Yep. Maybe we can move to just biomarkers quickly. You know, what's a positive result on those? Is it just directionally the way they move, and is that the way to think about it?
You know, biomarkers, circulating biomarkers are informative.
-and we're overall looking in this study for directional improvement and consistency across multiple parameters. And so that'll be true for echo, circulating biomarkers. But in this initial data update. Look, we've seen circulating biomarkers. Really it depends on the nature of the product and the nature of the disease. We saw, in the case of mavacamten, you know, CMIs in obstructive-
Those came down dramatically. Like, within two weeks, you saw a dramatic reduction in NT-proBNP, for example.
And that was because of the unique mechanism of that product that provided immediate relief in those patients, less pressure, less strain, and so that brought NT-proBNP. But in Rocket Danon, it took time.
It was more on the horizon.
of 12-18 months, more associated with the overall remodeling of the heart. So I would say that for those circulating biomarkers, we think it's less like mavacamten, which was quite a unique situation or the other myosin inhibitors, and more like Rocket, where the gene therapy will take time to express and to reach optimal expression levels, and for the heart to start experiencing-
-that relief and that remodeling, and then you would start seeing things like NT-proBNP and cardiac troponin I. So, it's certainly possible that we will see those signals in this initial data release, and that those signals could get better with time, but it's not going to be like the myosin inhibitors-
-that within 14 days, you're seeing a dramatic benefit. So that's some of the expectation setting there.
Yep. Maybe just in the last minute, just the echo parameters and LV mass, maybe just talk about, you know, if we get that, for example, like, you know, what's a good result there?
Reduction is good. How much reduction is... And more reduction is better. You know, the... Again, we're going to be cautious. We haven't committed-
-to providing echo data in this first data release, and as I mentioned, Rocket, in their first data release, 18 months after dosing, did not share LV mass and LV mass reduction, that came later. So echo is great. It's also a bit noisy, so you just-
-gotta be careful. There's a lot of. We've tried to control for some of that noise by having central labs, but it's just an inherently noisy measure, which gets better when you have more patients and more time, and more data points to really help interpret the data. So, that's partly why we've been cautious about committing to that early on. But of course, we'd love to see reduction in mass. Going back to the Rocket example, they showed that that LV mass data initially was promising-
and it just got better and better and better with the continuous expression.
-of the protein in the background over time, leading to more dramatic reductions than have been seen in almost any modality in other cardiomyopathies. That's a great story to be able to tell. Again, the humility, we know that they didn't have all of that in their first go, and then that matured with time.
Not setting expectations of a certain, is it LV mass, or is it LVMI, or is it LV dimension, or is it LV wall thickness, and is it like a reduction of 10% or 20%? We are not setting any of those kinds of expectations, certainly not for this initial data release.
We're not even committing to providing echo. But over time, our preclinical data and the experience of others both lead us to certainly have the hope and aspiration that there will be a relationship between protein expression and LV mass, and that could lead to interesting conversations with the FDA, not unlike the kind that Rocket had-
-with, the regulators on their Danon program.
Yeah. Okay, great. Looks like we're out of time.
Yep.
You know, thanks so much. Appreciate your time, and-
No question
We look forward to the data.
Yep, yeah. We didn't get to talk. We ran out of time- But TN-401 is another exciting program, and we'll have... Maybe next time we'll spend more time on that.
But we're on track to dosing patients there, and I think what's exciting about twenty twenty-five is that we start to have-
Mm-hmm
more data on TN-201, but also
Yeah
begin to have data on 401.
Yeah.
We haven't provided guidance on that front, but it's part of that exciting journey that we're on, that, you know, multiple programs and multiple data points, and multiple data releases we can look forward to in the coming six to twelve to eighteen months.
Yeah. Sounds great.
Thank you.
Thank you.