Hi, everyone. Good morning. Thanks for joining us again for the Tenaya Therapeutics Fireside Chat here at the TD Cowen Genetic Medicine Summit. Thank you so much for joining us. I'm covering analyst Ritu Baral. Joining us from Tenaya, we have CEO Faraz Ali. Faraz, thank you so much for joining us today.
Thanks.
And like I mentioned, happy Biomarker Accelerated Approval Day. We are going to, not for you, but hopefully soon, we're going to address this whole Biomarker Accelerated Approval issue pretty shortly as far as your program. Let's start on 201. You've got an important data catalyst coming in the second half of the year. This is the initial phase 1B data from your MYBPC3 mutation, hypertrophic, I'm sorry, MYBPC3, hypertrophic cardiomyopathy gene therapy. Maybe to start at a high level, I get a lot of questions about patient numbers. As you understand HCM and those patients with MYBPC3, how do you see the diagnosed patient numbers? And are they sitting genotyped right now?
Yeah. So thanks for having us, Ritu. Good place to start. As you know, and maybe for the benefit of your audience, HCM is the most common inherited cardiomyopathy. Within that, the MYBPC3 mutation is the leading genetic cause of hypertrophic cardiomyopathy. It accounts for about 20% by most estimates of the population. And that's how we come up with our number of more than 120,000 or more than 115,000 or approximately 120,000 patients in the U.S. alone, which in terms of a market opportunity, it's on the larger side of orphan therapies and one of the larger programs or market opportunities for any AAV gene therapy program out there today focusing on genetic disease. So now, are all of those patients, are there 120,000 patients diagnosed out there? No.
That's the estimate based on, and which is very common in genetic diseases, is that some academics usually have performed some point prevalence studies in a particular geography. Then we triangulate across those studies to come up with an epidemiological assessment. Often, quite frankly, those end up being underestimates because when you finally have an option in clinical development or commercially approved, then you have a lot more drive for genetic diagnosis. Having said that, genetic diagnosis is happening at an ever-increasing rate for HCM in general, partly stimulated by the activity of others in this space, whether it's Mavacamten and Aficamten.
Even though they don't need genotyping.
Even though they don't need genotyping. I think there's an overall, and that has come all the way from the top, from the medical congresses and the societies, both in the U.S. and Europe, pushing for genotyping for HCM, partly because there is information that tells you, there's important information that comes from having a genotypic analysis. One is, of course, family trees. So you identify others who are at risk in the population in many of these diseases. The first presentation is sudden cardiac arrest and death because of arrhythmia. That is also true for children with this mutation. So it's also true for PKP2, our other program that we'll talk about later. So there's a drive because you can do something, you can do family testing, and then more closely monitor them.
Also, in a world where there are clinical studies like ours and our peers working on different forms of genetic cardiomyopathy, there's more you can do with it. Also, really importantly, genetic testing tells you that these patients are more severe and more likely to progress to bad outcomes. There's a lot of literature showing that patients with these sarcomeric mutations like MYBPC3 mutation, that they present earlier with more severe symptoms at a rate faster and higher and worse than people without these mutations. Knowing that information helps physicians do, it affects the way they manage these patients. I say all that because actually that's a great tailwind. The genetic testing happening, certainly in the US and EU-5 and really increasing around the world, provides an excellent tailwind for us.
We're not fighting an uphill battle to get genetic testing, but the medical establishment themselves are pushing for it because there's something that you can do about a genetic diagnosis now. There's more information that comes from it that is important for patients and families.
Got it. And as you see Mavacamten being taken up and used in this population, what do you see as the remaining unmet need for medical management, clinical benefit in the MYBPC3 patients?
Well, first, I would just say we're grateful.
Does it not work as well? What do you see?
Well, what I see is first, a wonderful thing that happened for the HCM community. The approval of Camzyos was great. It was great for the patients, and it was great for the field, including for us, because it established the path for an approval for a small molecule. Now, is there unmet need? Of course. There's tremendous unmet need. As a reminder, Camzyos has only been approved for obstructive patients. The majority of patients with MYBPC3 mutations actually are non-obstructive. So 70% of the patients that we're trying to address have non-obstructive form of disease. And so forth, not only is there not an approval for a CMI in the non-obstructive population, but frankly, the data package looks very different, not only for Camzyos, but also aficamten, the other CMI.
And so there seems to be an earlier, more dramatic improvement possible for patients with obstructive disease, but it seems to take longer and still to be proven what will happen in non-obstructive. And of course, the response rate.
Yeah.
The response rate in even the obstructive population was 40%, 20% in non-obstructive HCM. So overall, unambiguously, there's unmet need. And importantly, what we're trying to do is simply different. We're trying to address the underlying genetic cause of the disease. And so within the population of patients who have HCM, whether obstructive or non-obstructive, we know that, and whether they're children or adults, we're addressing patients who have this specific mutation with an addition of a working copy of the gene. We expect the, because this is such a more precise and targeted approach, we are hoping to over time demonstrate that the magnitude of the effect is simply different than it would be with a small molecule indirect approach.
And the durability, certainly, of the effect, because we're producing the missing protein continuously, that the magnitude and the durability of the effect will be fundamentally different for TN-201 in patients with this mutation compared to a small molecule approach that is indirect. And so there's a lot of unmet need, and there's a lot of hope for an approach like TN-201. And frankly, one measure of that interest and opportunity is the fact that at this point, we have nine active sites for our TN-201 study. And most of that, all of these sites are also sites that have been involved with the development of myosin inhibitors. So the experts are speaking, they're voting with their feet and saying, we think there is another swim lane where we need a genetic approach for genetic disease. And so we think there's a lot of opportunity.
It's probably an overlapping Venn diagram where it's great for patients to have choices. Some will be appropriate for small molecule. Some will be appropriate for gene therapy. Some may be in a position to consider both. That's good for the field, and that's good for the community.
Got it. So that first data that's coming, the phase 1b, what data is that going to include? How many patients, how much follow-up? And you're taking biopsies. And could you spend 10 seconds to just go through how you talk me down from the trees on this concept of heart biopsies? I was so freaked out. And then it turns out it's actually the easiest biopsy to take. But what those biopsies will generate.
Yeah. No, thanks, Ritu. And we get that. As you can imagine, it's a big year for us. This is obviously one of the most significant catalysts for the company. We've committed to and are on track to deliver data in the second half of this year. What we have consistently committed, even going back to last year before we provided guidance, formal guidance, is we've been saying that, look, this is a data-rich study. We are measuring a whole lot of things on these patients. And so there's a lot that we're going to learn about every single patient we treat over time. But the early data we've committed to in the second half of this year will be from the first dose cohort, the 3E13 vector genomes per kilogram dose cohort. And safety, biopsy, which we'll double-click on in a second, and some other biomarkers.
That is the extent to what we've committed to in this initial data release. Just to put that in perspective, that's not terribly different than what Rocket did when their first data release in their Danon program back in December 2020. We often guide to and make that comparison with the initial release of Rocket. It was their first three patients. It'll all come from the initial dose cohort. That's what we're going to offer. Safety is really important here. I don't want to just underestimate how important that is. If you recall, several years ago when we were moving and transitioning to clinic, the field was plagued with debates about safety and clinical holds.
We haven't heard a lot about it for a while because as a field, we've learned a lot about how to design these studies, immune suppression regimens, prophylactic or reactive approaches to complement activation, hospital monitoring, just we're employing cardiomyocyte-specific promoters to ensure expression only in the heart. Safety is really important. So that's one of the things we'll reveal. Now, biopsy. What does biopsy tell us? Biopsy tells us a lot. And yes, I'm glad that you appreciate that biopsies have an important role to play. It is something that's done routinely in care of patients with severe disease, including patients who are, for example, going to heart transplant. So the system and the centers where we're operating know how to do biopsies, and we're not teaching them something that is not normal to them. But a lot of information can be gathered from a biopsy.
One and frankly, most importantly, is superior capsid getting into the heart. That's a vector copy number measure that you get from a biopsy. Two, is that capsid then successfully expressing RNA? That's the second stage. Three, does that RNA translate to protein? So those are three distinct things that you get from a single biopsy. We'll be taking multiple biopsies from these patients over time. So there'll be a lot of information that we'll get. Again, this is very similar to what Rocket has done over time, that you have biopsies at different data points. That over time produces a real clear picture of what's the level of expression you're getting. What is the level of vector copy number? What's the level of expression? Do you get more with higher doses? Does it get more with time?
What is the relationship between that expression and the clinical efficacy? Rocket has done that in spades. In fact, as we talk about accelerated approval, it was because of that data package over time that allowed the FDA to say, yes, there is a world in which you could get accelerated approval if you demonstrate protein expression as a surrogate marker as well as reduction in LV mass as surrogate markers for clinical benefit. So biopsies are important being able to demonstrate those three things. Then circulating biomarkers are there are things in the blood that you can measure, NT-proBNP, cardiac troponin I. Again, Rocket has done some of that. Mavacamten in their pivotal studies also had demonstrated reduction in those circulating biomarkers, which tell you different information. Is there less strain in the heart? Is there less necrosis of the cells?
And so that's a lot of information right there before you ever even get to the world of echo-based parameters, like size of heart, thickness of ventricles, peak VO2, and other things that you might get. We're also measuring 6-minute walk tests, quality of life throughout. We expect biopsy and some of these early data release to be early harbingers of other things that will come later. Again, not unlike what Rocket had over time.
Faraz, as you think about HCM, specifically obstructive or not, in this case for MYBPC3, non-obstructive, what correlation data might you have to generate either between protein expression and maybe a serum biomarker, maybe it's troponin, maybe it's BNP, or something else, something echo? What correlation data do you think you may have to generate or do you want to generate to put your best foot forward for accelerated approval for this path? I'm sorry, for this indication.
For this indication. I mean, look, what we're doing, you'll find us often referring to either the myosin inhibitors or Rocket because those are the two most people would agree that those are probably two of the most relevant comps. But we also have to remind ourselves that what we're doing here has never been done before. What we're doing here is being tried for the first time. So in some ways, my first short answer is we don't know. We have to go through this, have the humility to know that what we're doing before, first time anybody has ever tried gene therapy for this specific mutation. So the expression kinetics, the magnitude, the speed, and the relationship to efficacy is yet to be determined. That is exactly what Rocket was able to do with time.
Even with six patients, they were able to paint a story that said, hey, we're getting a certain amount of expression, not the same amount that we were getting in our preclinical studies. And that's often the case in gene therapy. But we're getting enough. And over time, that seems to lead to better and better efficacy as measured by heart reduction. So initial data release, no mention of heart reduction. But over time, 2021, 2022, and then eventually 2023, more and more improvement seen. And so that package ended up, even with six patients being enough to convince the FDA, that even with this level of expression, which wasn't wild type levels, you're seeing an improvement over time. So there is a link between expression and heart size reduction.
Then what Rocket then did, which I think was very smart, I have a lot of respect for that team, then they showed that in other studies where you show an improvement in heart size or LV mass, that leads to good outcomes. And that was enough stitching together protein expression, improvement in reduction in heart size or LVMI, and then connecting the dots with the field. And what we've learned from the entire field of hypertrophic cardiomyopathy across different indications, it's all in the public domain. That was enough to convince the FDA there's a shot here at an accelerated approval, not a guarantee. And from our, I would say, informal discussions with the relevant members of the FDA, we have reason to believe that that isn't unique to Rocket and Dana, that that logic could apply to us as well.
And that makes sense, but you never know. And so that's what we had hoped to do, Ritu, is over time. Look, we have 15 patients that we have permission to dose in this phase 1, 2, 9 sites active. Our goal is to accumulate as rapidly as possible a body of evidence so that we're not relying on maybe a handful of patients over time. But the more patients you have in there, then the more information you have about expression and clinical benefit. And then the faster, hopefully, you can make that argument to the FDA. We're not guaranteed, but the things are the signs are good based on what they've been willing to do both for Rocket as well as, of course, as you know, Sarepta.
Do you think that that sort of time element or the time axis that Rocket needed to basically prove that follow the bouncing ball there, you guys will need a similar amount of time or a similar amount of follow-up?
I know where you're going with this, Ritu, and support the question. We will need time. I mean, similar to Rocket, certainly. We have been trying to set these expectations for a while now, even before we dosed the first patient that, look, our Rocket initial data release, expression below wild type levels, but over time, it got better and better. If you look at mavacamten, a dramatic improvement in the obstructive population, but most people now widely believe it's going to take more time for the non-obstructive population to respond. It's not going to respond as quickly as the obstructive population. So for a lot of different reasons, we've been trying to set expectations that, look, entry states, we're safe. The vector is in there, and it's expressing. And there's some early markers that are positive. And with time, that data set will mature.
Will it be one year, two years, three? We don't know. Obviously, we hope for less shorter time, but we just simply don't know. The other factor in the equation isn't time. It's also N, like the number of patients. So I think the combination of the more patients you have, then the tighter your assessment of the different measures, and that might make up for some time. You have maybe a higher reason to believe that I'm seeing enough patients in the first 12 months responding this way. That gives me some hope that what I'm seeing with a couple of patients at the two-year mark will unfold in the same way. So the more patients we treat, the better our assessment and the better the argument we can make. I will also say one more thing since you're on the top of accelerated approvals.
Look, we have to be prepared for a full approval with clinical benefit and run a study like that. I think that's one of the lessons from Sarepta that you need to be running a study that can support a full approval and in parallel hope that you get signals for an accelerated approval. That's what Sarepta did. That is what Rocket, I believe, is trying to do. In our context, that's the approach we would take. I would also point out that there may be differences in how the FDA views the adult population versus the pediatric population. As we've mentioned many times in different forms, and we have a slide in our deck about that, there's a very, very severe pediatric population. They progress to life-threatening symptoms in the first months, years, weeks, months, and years of life, depending on their mutation status.
For those patients, there's really no hope. There's been nothing demonstrated that the small molecules for really, really severe patients. And it could be for those patients, gene therapy might be the only option that they will ever have that will actually make a dent in their disease. And so you can imagine that the FDA may take a more. That's probably a closer analog for what's going on at Rocket. So it could be that the accelerated approval could be more of an instrument for the ultra-severe pediatric population and then also have some relevance in the adult population. Time will tell, data will tell. But as you can tell, we are thinking about all of this, and we're preparing accordingly. We launched the MyClimb Natural History Study so that we can study the children and characterize them.
I think you can count on there being some data that we will share to better cast more light on the pediatric patients and the opportunity there in the not-too-distant future. And so more to come on the pediatric population, but overall, an exciting time for HCM against the backdrop of accelerated approval moves or signals from the FDA for both Rocket as well as for Sarepta.
So before we move to 401, I do want to ask one last question, and maybe this extends. As we think about echo, you mentioned LV mass. Reduction of LV mass is a key echo parameter. Any other echo parameters? There were a whole lot of.
There's a lot that you get from echo, Ritu.
Yeah.
There's a lot that you get from echo. You get measures of, of course, function, like ejection function. You get measures of LV size, LV mass, LV thickness, the diameters, sorry, the overall dimensions of the heart, the different chambers and whatnot. You also get measures of, of course, diastolic function or dysfunction. Some of these patients have diastolic dysfunction, which because of the stiffness of the ventricles. So echo is a very rich milieu in which you get a lot of information. Now, echo is also noisy. There's no secret here that echo can be very, very noisy. So I want to sort of caution here. On one hand, there's a lot of hope that across different parameters, we might show some things that are internally consistent across multiple parameters in the echo. But on the other hand, caution because echo is super noisy.
And so you can see we've tried to control in our study for some aspects of that by centralizing echo reads, for example, but it still doesn't change the fact that echo can be noisy. You may need to generate a certain amount of N to have some information. That's why we also have been careful about not promising early echo data because it's just for a handful of patients. I can show you paper after paper where if you pick those three echo points on the graph, you think your product is working beyond your wildest imaginations. If you pick the next three dots, you'd be like, "Oh, it's not working at all." We've seen this even with Mavacamten and some of their echo data.
So echo is something, and we are going to do more with your health to educate the investor community about the data-rich study that we have and what can move and what are the benchmarks and how do we think about it. But Rocket, again, to use the Rocket example, I think they've really focused on LV mass reduction. There's not as much discussion about all the other echo parameters. In their first data release, cardiac stroke output was one of the things they reported on, never to be heard of from again. So to some degree, we're all looking for what is the signal in the noise that I can tell a coherent story about. And we're just at the beginning of that journey of what will be the things. Will it be LV mass? Will it be thickness of the ventricle? Will it be diastolic function or dysfunction?
Will it be something else that will emerge that is consistent with our hypothesis of the biology of the disease and the way in which the product works?
Got it. All right. Let's move now to 401, which is your AAV9 for PKP2 arrhythmogenic cardiomyopathy. So as of May of last year, you got your first two clinical sites for your RIDGE-1 trial open, and it started dosing. Well, you're going to start dosing.
We started screening. Now that we have active sites, we're super excited. I think we now have three sites that are active in their screening. And so then we'll, of course, announce once we've dosed the first subject there. And we're on track for our publicly stated guidance, which is to dose and announce dosing in the second half of this year.
Can you walk us through the patient numbers here for PKP2 and timelines to data, essentially?
So simple, what we've said pretty consistently, and it's in our deck, is that we estimate over here about 70,000 patients in the U.S. alone. Now, similar to HCM, you've got, all this is based on point prevalence estimates from different studies. And then you try to do your own math. And the math ends up in some ways possibly overestimating and other ways probably underestimating. And so 70,000 is a number we've picked. There's probably a range around it. Some of our colleagues also working on PKP2 have put out different numbers. But the bottom line is what they all have in common is that this is another large orphan opportunity. This is not ultra rare, which is where the gene therapy has mostly been. As you know, Ritu, there's been 5,000-10,000 patients in the U.S., ultra orphan type gene therapies.
But with both TN-401 and TN-201, we're dealing with large market opportunities, large areas of unmet need. So that's an answer on the epidemiology side. And similar to TN-201 and MYBPC3 mutations for HCM, in the ARVC space and the arrhythmogenic ventricular cardiomyopathy space, there is also similarly a drive for genetic testing. So we also have a tailwind here. So it's not that those 70,000 patients or 50,000 patients or 100,000 patients, however many of these, it's not like they're sitting there diagnosed somewhere, but that the genetic testing is progressing. And similar logic, that there's something you can do. When you know that you have this mutation, you're more likely to experience, unfortunately, in this case, sudden cardiac death. I think the initial presenting symptoms for about a quarter of patients with this mutation is sudden cardiac death. So that's a wake-up call.
We need to know that people have this mutation because you might then take measures like a prophylactic ICD to prevent the, so that's the numbers question. In terms of data, we haven't yet, Ritu, on this one, given guidance on when we're going to present data. It stands to reason that if we're dosing in the second half of this year, that there's more ways than not that the initial data presented will be in the following year. But of course, we're just not giving clear, simple, straightforward guidance. Very consistent with what we did with TN-201. We just didn't give guidance on data availability too far in advance. We'd rather be sort of conservative and give more later.
Is there any gating factor to dosing that first patient or now that screening's begun?
Screening has begun. So I would say that there's no, nothing gating. Just to be clear, on both of our programs, we have more than enough drugs. Both programs are open to dose up to 15 patients, both 201 and 401 in our phase 1b. And for both programs, we have produced, it's in the bag, all the material we need from a GMP perspective. So the manufacturing execution is not gating at all. We've got the drug that we need. We think we have a best-in-class product here based on capsid comparisons we've done and presented at ASGCT in the last couple of months, comparing AAV9 to AAVrh74, AAVrh10. So we think we and look, we haven't heard of announcements of dosing from somebody else or anybody else yet.
So it feels like this is maybe the year that all three companies that are involved in this will announce that they've dosed patients. And then the clinical data over time will show which product is working or to what degree they're working at different doses. The preclinical data would favor the TN-401 approach just by virtue of the performance of the capsid. And specifically, what we've demonstrated is expression in the cardiomyocytes.
Got it. I'm glad you mentioned that poster at ASGCT because I went to try and catch it, and there were a cluster of people around it that rapidly scattered when I approached. So can you I think I even emailed Michelle about it.
It's on our website, by the way. We put everything in the public domain because we stand by our science. We're pretty rigorous. Right now, you will find if you go to Tenaya, there's 50 posters online, including that one. And any investor who listens to this can look at that poster. We haven't yet updated our corporate deck with the data that we presented there, but the poster is there on the website and rigorously shows head-to-head comparisons of the three capsids in mice, then in NHPs, and then in the disease model, efficacy comparisons in a severe disease model. And what we get is a consistent story. AAV9 consistently expresses higher than the other two, significantly higher in the cardiomyocytes, which is what you care about.
You might have similar transduction, which is a measure of the infection in the heart, but what you care about is expression in cardiomyocytes. Consistently high expression for AAV9 versus the other two in the cardiomyocytes of both the mouse and NHP heart. And then you also see in the efficacy model, AAV9 outperforming the other two in an efficacy model. And that has also been. I'll just say, at ASGCT and in other publications. People have shown the same data that we're presenting, that AAV9 outperforms AAVrh74 and AAVrh10. In fact, at ASGCT, there was another poster by another company that showed very, very similar data to ours. And so I think there's some internal consistency to all of that.
Got it. Well, Faraz, thank you so much. We're at time. Thank you for the review of the programs. We're really looking forward to the first data from 201 later this year and the first data from 401 as that trial matures.
We look forward to continued discussion, debate, and intrigue about accelerated approvals for these severe genetic diseases for which now there is new hope on the horizon, including TN-201 and TN-401. We look forward to more discussions with you. Maybe we can write about it in a future note, Ritu. I think there's enough here to not put work on you. I think there's enough here to talk about. It's one of the things that get us excited about TN-201 in particular.
Great. Thanks again, Faraz.
Take care. Bye.