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

Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I am Michael Ulz, one of the biotech analysts here and it's my pleasure to introduce Faraz Ali, CEO of Tenaya Therapeutics. Just a reminder, a 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 for those that maybe aren't familiar with your story.

Yes. Great. Well, good morning, and thanks for having us here. 7:00 a.m. is always a tough slot for the presenters and for those who are going to join in the audience. Tenaya, this is an exciting time for us, as a company. We are, obviously, clinical stage company, 3 programs in the clinic and exciting for 2 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 6 to 12 to 18 months will give us the first set of data on the 2 gene therapy programs, which people have been awaiting for a while. And so this is an exciting time for us and things are going well, and we're now here to talk about it today.

Yes, great. Thanks for the introduction, we're looking forward to the data as well. Maybe we can start with your lead program, TN-201, your gene therapy for HCM, but maybe you could just describe some key components of the construct, what's unique about it, how it works and maybe anything that you've seen in preclinical studies that sort of give you confidence in the program?

Yes, so TN-201 is an AAV gene therapy program. And so -- and 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 going to have a couple of main components. It's going to have a capsid, it's going to 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 at Rocket in their Danon program. And the safety database is incredible. 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, provide distribution and 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, been able to demonstrate that we can reverse the symptoms of the disease and prevent decline. We've shown reduction in heart mass. We've shown improvement in contractility. We've shown improvement in ejection fraction. We've shown an extension of survival. And so time and time again, within relevant doses, 3E13 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 onboard. I know we'll talk about that later and 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 yes, that's the construct. The last thing I would say, we talked about the capsid, talked about the preclinical data. So what makes this program special, 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 in 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 exclusive expression in the cardiomyocytes of the heart versus other organs. We have, at this point, 3, 4 different IP filings have been issued. And so I'd say, validated capsid novel promoter and overall design of a cassette that is innovative, that is protected by IP.

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?

Yes. Yes. It's -- unfortunately, it's a terrible disease. So hypertrophic cardiomyopathy, about 600,000 patients estimate in the United States alone. And then the MYBPC3 represents the leading genetic cause of HCM and accounts for about 19% of all patients. And so 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. So 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, downstream of that fibrosis and arrhythmia and the patient's experience maybe early on with like dizziness and fitness and lightness of breadth. 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 much more severe core. So they're typically diagnosed more than a decade earlier than people with a nongenetic version of the disease, and they typically progress faster and have worse outcomes. And then there's a lot of heterogeneity here in this disease. So we've had -- 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 a TN-201 has got a very simple thesis, use AAV9 to deliver a working copy of the MYBPC3 gene, produce some of the missing protein, prevent disease progression, restore some function and hopefully prolong the lives of these patients to improve their quality of life.

Makes sense. Maybe can you talk a little bit about the treatment landscape. You mentioned unmet need. Where is that? And how could TN-201 fit in?

Yes. So in the past, most of these patients, unfortunately, were just given the standard cocktail of 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. It's been commercialized by Bristol Myers Squibb. That has 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 is outstanding that there are some new options for these patients because 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 road map of what's going to be necessary for us to get to our own approval down the line. But there's a lot of unmet need. The response rate on CAMZYOS in their pivotal study was 40%, 20% in excess of placebo. And so there were a lot of nonresponders. And -- 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 nonobstructive patients, that's not an option. And as it turns out, patients with this MYBPC3 mutation, 70% of them have the nonobstructive form of the disease, and 30% have the obstructive form disease. So the obstructive -- patients with the obstructive form of the disease, they might benefit from a myectomy, but that's also not addressing the underlying genetic cause. Our hearts will still progress. They may benefit from a myosin inhibitor, also not addressing the underlying cause of these. On the nonobstructive 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 -- that's a large population with severe disease and a lot of unmet need and opportunity to address.

It makes sense. And is the strategy, I think, it's target nonobstructive first and then kind of maybe move into obstructive later? Is that kind of...

Yes. That's the -- from a clinical development perspective, since all of this heterogeneity that I described earlier, adults, adolescents, children, homozygotes, heterozygotes, obstructive, nonobstructive, but they all share in common is that they have the MYBPC3 mutation and they're missing the relevant protein. And so we think TN-201 is going to be relevant for all of those populations. Having said that, we have to start somewhere. And so we chose to start with the nonobstructive 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 going to 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 heterogeneity and let's focus the first couple of patients here, but from their branch to other of their patient population. So from a clinical development strategy, very much want to 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.

And if you're successful in non-obstructive, is the expectation you'd also be successful in obstructive? Are there 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 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 0 proteins, and they die within the first year of life. The heterozygous adults have anywhere from 40% to 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 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 are doing has not been done before, right? Gene therapy has been done, gene therapy and cardiomyopathies have been done, but for this specific condition, with this sarcomeric mutation, this is the first time we're doing it. So we have the humility to know that the Phase Ib 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? And what does that look like for different patient populations. It's possible that obstructives respond differently than nonobstructives. They certainly did with the myosin inhibitors, right? They saw a dramatic benefit with the obstructive population, not as much in the nonobstructive, 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 it's fair to say, well, gosh, myosin inhibitors worked in obstructive, haven't worked quite as well yet in nonobstructive. 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. 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 and it maybe that the protein levels need to be different. But that's exactly what the Phase Ib and subsequent studies are designed to address.

Yes. So a lot of questions and you'll answer those with your MyPeak study first. So maybe let's move there and just talk about the design there and kind of what are some of the endpoints?

Yes. We've just started to address some of that. The MyPeak-1 study is initially focused on nonobstructive patients. Obviously, everybody has to have the MYBPC3 mutation documented. They -- we've tried to enrich for patients who have some symptoms. So the New York Heart Class 2 or 3, they also enrich for a more severe initial population who have ICDs onboard 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 justify starting something and trying something 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 a low neutralizing antibody AAV9. We've produced data on that front from our CRO status showing that the vast majority of patients do not have neutralizing antibodies to AAV9 and would qualify for a study on that basis. So 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, you'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 will give us vector copy number, RNA and protein expression. We're capturing -- circulating plasma-based biomarkers that can be measured 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 dimension of the ventricles, the thickness of the ventricles, you get ejection fraction, you can measure the strain. We're measuring functional capacity in 2 different ways, 6-minute walk test as well as CPET. And 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. But 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 and what's moving slower, what's the relationship to dose. So our -- again, you could look at pretty much everything that -- 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 the endpoints that were agreed to with the FDA with Rocket under Danon program for the potential -- full approval as well as potential for accelerated approval. So while it's just a Phase Ib, there's a lot we will learn. And from that, things can move quickly once we determine that right relationship between dose and certain endpoints. So we're excited. It's a first step in our journey, but it's a journey that can move very quickly once we start seeing movement in some of these endpoints.

And 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, what endpoints?

Yes. So one thing we didn't mention with the design of the study is there are 2 dose cohorts: dose cohort 1 3E13 vector genomes per kilogram; dose cohort 2, 6E13 vector genomes per kilogram. And those doses were chosen deliberately. We saw near maximum efficacy with our 3E13 dose in our preclinical studies. So that's where we're very pleased the FDA allowed us to start there, and then we go to 6E13 after that. And there is sentinel dosing over there, so we dose a patient pause DSMB clearance. Dose again, pause. And after dosing 3, we get to escalation and/or expansion and same at the end of 6E13, we can get to expansion. So serial dosing to begin with and then after that, 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 going to be the first couple of patients in the dose cohort 1. And then in terms of the end points 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, NYHA cohort 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 want to make sure -- we believe it's going to be a meaningful update, but it's an early update, right? These are the first patient who was dosed in October. That means that first patient reaches their 1-year mark in October of this year. And so I use that to bookend first couple of patients from the first dose cohort and the first patient will be at a 1-year mark in October. That means everybody dosed subsequently will be before the 1-year mark. And so that starts setting boundary conditions for setting appropriate expectations that everybody -- one patient can be at 1 year and everybody else will be before the 1-year mark. But we think that, that's a meaningful horizon. Certainly, to assess safety, certainly to get early reads for the biopsies. We take 2, 1 at 8 weeks and 1 at 52 weeks. We've mentioned that in the past. And then circulating biomarkers are collected more frequently and some of the other measures are captured quarterly or biannually or annually. So that gives you a feel for. We'll have a mix of different data, some of which will be more -- there will be more of that for several patients only 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 datasets from the other endpoints as well as then subsequent doses sort of the next dose cohort up. So an exciting early update, managing expectations of how much we're going to give. The comparison we make with this initial data release is Rocket circa December 2020. They did their first data release 3 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 was -- that came in subsequent data releases. And so we've kind of modeled our initial data release after theirs. It's at an earlier time point than their initial data release, but qualitatively, it represents the same thing, the initial step in the journey. We all know the journey that Rocket went on and after that, where then they showed subsequent to that LV mass reduction, that looked better the year after that. And by 2023, with 6 or 7 patients, they were in alignment with the FDA on 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 yet know 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.

Yes. Makes sense. Maybe we can dig into a couple of those sort of updates, maybe starting with safety. Just you mentioned earlier, AAV9s were well validated and understood these days, but anything on the safety side that we should be looking for?

I mean we -- some people have asked us about that, and we generally say no news is good news. 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 elevated to the level that it would pause their program and so we're looking for -- we -- there's some signals that we expect are consistent with almost every AAV gene therapy. Elevation of liver enzymes is a point isn't whether they have them or not, it's like can they be managed with immune suppression of corticosteroids. 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 to profile that's as good as any other AAV gene therapy program. But we've designed the study to mitigate the worst things that have been seen in the field, including 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 clearance with the FDA, no clinical hold at that point. And that's important, by the way, because if you recall, when we started, that was against the backdrop of a lot of clinical [ holes ] in this field that kind of 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.

What about just cardiac biopsies? I know you're going to be measuring a couple of 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 0 protein and then show some protein expression. There's some level to begin with, so how do you -- how do we think about that?

Yes. So biopsy gives you a lot of information, and we're collecting it at 2 different time points for these patients at 8 weeks and 52 weeks. Each patient -- they're at centers of excellence where 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, single sample and that like did it. Was it in the right spot or not in the right spot, but there are actually -- these are experts who know how to take multiple samples. And so we're not going to 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 3 different things. Obviously, you want to see high vector copy numbers. That's actually the starting point really of the journey, then you want to see some expression in the RNA and protein. This is where, like you said, what is 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 is 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 dramatic 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 who's starting baseline to 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 will move the needle for them? So one thing we've learned from this study is, is there a single level that 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 the study a bit unique compared to others. Most other gene therapy studies and [indiscernible] indications, they're 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. And so 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 ability to know that, that is exactly what we're going to 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, 0. 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, they're patients with a mutation and they don't have symptoms. But we don't know what their protein levels are because there is no justifiable reason to take a biopsy from asymptomatic patients. So we know that there are threshold effects. We've hypothesized that if the average patient is 60% to 70% wild-type protein and in the animals, we see that 80%, 85% and below, 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 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've got to prove this via clinical development. And we will not answer all of 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.

Yes. Maybe just a quick follow-up. Will patients have baseline biopsies or just the 8-week and 52 weeks?

The initial patients don't have a baseline biopsy. They have 8 week and 52 weeks. Part of the rationale there is 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. In 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 -- anybody has 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 of time. So this will -- this space will change and it will change deliberately because we're going to be actively exploring and trying to understand that expression kinetics curve. But for the first couple of patients, you can't tell them that you're going to take a baseline and 2 months and 4 months and 6 months and 8 months. Like we pretty much not have -- no patients will sign up for that, especially patients who already have pretty compromised hearts and no expert will sign up for that. So you kind of have to be patient and do that over time.

Maybe we can move to just biomarkers quickly. What's a positive result on those? Is it just directionally the way they move? Is that the way to think about it?

Biomarkers -- circulating biomarkers are informative, and we're overall looking at the study for directional improvement and consistency across multiple parameters. And so that will be true for echo, circulating biomarkers and 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 for -- in the case of mavacamten, CMIs in obstructive, those came down dramatically. Like within 2 weeks, you saw a dramatic reduction in NT-proBNP, for example. And that was because of the unique mechanism of that product that provided immediately relief. Immediate relief in those patients, less pressure, less strain. And so that brought NT-proBNP. But in Rocket Danon, it took time. It took more like -- it was more on the rise than a 12 to 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 is a quite 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 within 14 days, we're seeing a dramatic benefit. So that's some of the expectations setting there.

Maybe just in the last minute, just the echo parameters and LV mass. Maybe just talk about if we get that, for example, like what's a good result there?

Reduction is good, how much reduction is -- and more reduction is better. Again, we're going to be cautious. We haven't committed to providing echo data as 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 got to be careful. There's a lot of -- we've tried to control for some of that noise by having central labs, but there's -- 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. And going back to the Rocket example, they showed that, that LV mass data initially was promising, and it just got better, better, 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. So 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 sending 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.

Okay. Great. Looks like we're out of time. Thanks so much. Appreciate your time and we're looking forward to the data.

Yes. We didn't get to talk. We ran out of time, but 401 is another exciting program, and we'll have -- maybe next time, we'll spend more time on that, but we are on track to dosing patients there. And I think what's exciting about 2025 is that we'll have -- we start to have more data on 201, but also begin to have data on 401. We haven't provided guidance on that front, but it's part of that exciting journey that we're on that multiple programs and multiple data points and multiple data releases we can look forward to in the coming 6 to 12 to 18 months.

Sounds great. Thank you.

Thank you.