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

All right. So thank you, Leone, for being with us this morning. We look forward to guiding to the Tenaya story. So maybe for the people that may not be really familiar with the story, would you mind giving us an overview of the company, it's history.

Yes. No, happy to do that and super excited to be here. Thank you for inviting Tenaya. So Tenaya was a company that was founded over 5 years ago, and it was on the singular focus on the heart. It's one of the most common causes of death worldwide, which is from heart failure. And so we had -- the founders were really clear that we had this singular focus because -- and it was at a time actually when cardiovascular was not in favor and people were not really pursuing this area. You look today compared to 5 years ago, and there are a number of companies that are specializing now in cardiovascular. But we have started that and innovation is amazing at Tenaya. And so we are a company that has built out capabilities with that focus on the heart. We have a very strong research organization. All our programs are homegrown. We have a development team that's focused with cardiovascular expertise. And then we've also built out our own manufacturing. We have our own GMP manufacturing that's really for our gene therapy programs, which we can talk about. But basically, with manufacturing for gene therapy, the process is the product. And so owning the product, the process is really important. And so we are now 5 years later, a clinical stage company with 3 programs in the clinic. We have 2 that are gene therapy programs and one small molecule, and those 2 gene therapy programs are TN-201, which is for gene therapy for MYBPC3 associated with HCM. And we also have a second gene therapy program for PKP2 mutation associated with ARVC. So those 2 gene therapy programs, super exciting. He's got a lot of people really into the Tenaya story. And we also have a small molecule program for TN-301 for HFpEF. And building up those capabilities has been essential for us as we start navigating what's really going in terms of the science following the science. And as you can see from the pipeline, we are modality agnostic. And we think that's really important to enable us to follow the science and find the best science that actually will help treat patients. And lastly, from a cash perspective, we raised money in February. Successful raise. We raised $50 million, and that was with new and existing shareholders. And we believe that will help move our cash runway out to actually extend it into the second half of 2025, which will be essential given that we plan to have data on the TN-201 in the second half of this year.

All right. Thank you for the overview. So again, diving directly into the gene therapy program. So with the first gene therapy program in hypertrophic cardiomyopathy. So hypertrophic cardiomyopathy. When we think about the standard of care, oftentimes, gene therapy is new to that space like you mentioned cardiac gene therapy is really [indiscernible]. How should we think about genetic testing and identifying those patients?

Yes, that's really important, especially with the genetic mutation. And actually, we don't know exactly how much this is really -- has generated. But basically, we believe it's on the rise. And what gives us an idea is that organizations such as American Heart Association, ACC and ESC are actually -- have genetic testing and the recommended guidelines. Now -- and also some of the largest centers are also testing as well. And obviously, being such an inherited cardiomyopathies is one of the most common forms, right? And so we think that, that's important for families because it obviously runs through families and having that there is motivating and it will allow us. And I think also with the awareness that will come once you have a cure or a program like Tenaya's that will lead to more awareness and genetic testing will come even more from where it is today.

And do you see an increase in kind of like interest in genetic testing within those families just because of the...

Yes. I mean, we've had some amazing patient experience days at Tenaya. And while not every patient will qualify for our TN-201 program, have the MYBPC3 mutation, families that we get to learn about and have a part of the Tenaya story now, it really is -- they see that as it's so emotional. And it's so emotional to see that there is a way of maybe diagnosing what they have. And people will have these realizations well uncle, Fred, and grandfather, John passed away early and now it's becoming more real about why that happened and through the genetic testing that's allowed them to be motivated to get genetic testing.

So thinking about the HCM patient population, where do you see the greatest unmet need?

Well, it's interesting. We obviously focus on MYBPC3, and we see that there's nonobstructive patients and obstructive patients. And the way it works out is that they're about 70% of patients have nonobstructive and 30% have obstructive. And obviously, in the overall hypertrophic cardiomyopathy population, that can be a different story, right? So if you think about the programs, products that are out there, so we actually see for us, following this precision medicine approach, knowing the nonobstructive as the most common form in MYBPC3 patients that, that is the best place for us to start. But we -- and that's what we'll go through -- we can go through our clinical trial design, but that's where we see the most initial value. And then we can move to obstructive. We think there is room for us to move into the obstructive population because of the precision medicine approach and because it's a onetime -- potential onetime cure.

And thinking about the nonobstructive patient population. So the Phase I study started with the patient population with the first patient being dosed late last year. Maybe can you give us a reminder of the study design and also how enrollment is [indiscernible].

Yes. Yes. So super exciting for Tenaya. First -- actually, first patient, we [indiscernible] dosed with the gene therapy approach for MYBPC3 in the world. So that was a huge milestone for Tenaya and also the MYBPC3 population. And so that study started. It's a Phase Ib open-label dose-ascending study, and we'll dose patients at 2 doses, 3e13 and 6e13. And just to be aware that at 3e13, we actually had maximal efficacy in the preclinical model. So that tells us that's a good place to start. And that will be centers. We've got 4 sites open, and we continue to activate sites. We believe that given the size of the population, we not only want to be prepared for today but also for the future. Getting through the study objectives. So it's, first and foremost, obviously, safety. It's a first-in-human study, safety and tolerability, but we're also looking at PK such as doing biopsies at 8 weeks and 52 weeks. And we'll also be looking at other, obviously, clinical outcomes as well, exercise as well as plasma biomarkers. And look, it's a really rich study for data that we think will give us some indication of really how Tenaya's TN-201 program is working. But the trajectory or the time period over what -- when we might see certain outcomes, is going to be interesting. Obviously, there's the cardiac myosin inhibitors where we can see that trajectory for those studies and when did it actually start working. And then you have gene therapy programs like Danon Rocket's program, where you saw some of the clinical outcomes some of them came later. So for us, it's sort of we're sort of in between. We're both obviously going after HCM patients as well as the gene therapy program. So I think for us, seeing how that might -- the outcomes that might come over time. And just to be clear with our data in the second half of this year is interim results because this is a 12-month study. And so to that point, what we might see over that time period will be interesting. And obviously, the eligibility is MYBPC3 mutation, it's an adult study, and I love to talk about where we might go beyond adults. And also, we obviously -- AAV9 capsid that we're using. So we've bought just 2 neutralizing antibodies to AAV9 and the patients have to have ICDs and they obviously have to be symptomatic in MYBPC3. And so it's super exciting to have the study started later in the second half of this year. And with the certain outcomes of seeing when things might show up, we certainly will know that we'll have biopsies, right, because we do those at 8 weeks in the safety and tolerability and maybe some other initial endpoints will start showing up. But hard to know what those might be at this point.

Yes. So speaking about this upcoming read-out later this year. In terms of -- so given the pace of enrollment, what number of patients should we anticipate? Should we anticipate enough patients to have a sense in terms of the PK parameters that you had mentioned, the biopsies? Or would that still be a little early in terms of the end number to try and have a sense of the...

Yes. No, it's a good question. And the enrollment is on track, by the way. But what we have said previously is that we -- we're not going to dribble out patient-by-patient data. We want to make sure we have the totality of the data to look at. And so we believe a 6 months period of time thereabouts for the first 3 patients at the low dose will make the most sense in terms of having some sense of -- as I was talking about the outcomes and the sort of the time line of when we actually might see [ things ]. So 3 patients, we expect to have 3 patients early -- obviously, safety and tolerability is really key, 8-week biopsies and then maybe some of the other biomarkers that we might see as well.

Great. And so separating maybe a little more obstructive HCM and nonobstructive HCM. So thinking of nonobstructive HCM, where there are no specific kind of treatment. How should we think about the regulatory path and potential pivotal study design, end points?

Yes. No, that's super exciting to think about that, right, that going into pivotal and obviously watching Rocket with the Danon program being in Pivotal, it's sort of an adjacent thing for us to look at. And what's more interesting for us because it's HCM, we have other reference points to look at. So from a regulator's perspective, we still think, feel and function will be the key and seeing clear clinical benefit from feel and function will still be really important, and that's looking at your traditional clinical outcomes and the cardiac myocyte inhibitors, that myocyte inhibitors provided that path to see how the regulators might think about it. But the thing that's interesting for us is that with the FDA CBER that we would also be looking at the interacting with because it's gene therapy. So when you look at that and you think the comments, Peter Marks, who's out there talking about gene therapy, there's a lot of leaning in on how to use other potential outcomes to determine whether there's efficacy. So if you could have a surrogate endpoint that could demonstrate efficacy and obviously, we've all been looking very closely how Rocket's moving forward with their Danon program given the relative indication. That's interesting for us to see one, the size of the study, much smaller than I think people anticipated because I think -- because it's gene therapy and that one, obviously it's rare similar to ours. But two, the surrogate endpoints and how it's interesting to see how really looking at protein expression and LV mass, which is interesting that they are seeing that as another way to a path forward. So running a pivotal study with a small number of patients is potentially possible and also potentially surrogate endpoints, if you can demonstrate efficacy and the sort of the translation into clinical outcomes from that, I think that really lends itself to really exciting pivotal path for us.

Yes. And thinking about demonstrating efficacy. How should we think about the bar for success in the indication, right? Because this is -- like you say we had a reference in HCM, and HCM is a nonobstructive, a little bit of a difference set up there. So what should we see as kind of the bar for success in terms of should we look at the cardiac structure and kind of have a delta of difference that we want to see there, a delta of improvement? Or do you think it's more kind of more general, we should see just everything trending in the right direction?

I think it's going to be more the latter, but we are all hopeful that structural changes, other -- like as I said, surrogate endpoints such as demonstrating through protein expression transgene and our messenger RNA that you're actually and then watching the sort of the study, how it moves on that actually has led to an early indicator of clinical outcomes, which is the feel and function, which, as we all know, are very -- I mean the 6-minute walk test, there's the CPET test, which is the exercise requirements. And then there's New York Heart Association class measure, which is quite subjective. And I think the patient community and the doctors are starting to move towards KCCQ as being potentially which is the questionnaire that allows for maybe more accurate measurement of really how the patient is really doing. So we'll see. And I think those are all potential ways for Tenaya to proceed and see success in nonobstructive patients to begin with, but we can get to this, but I think there's room for us. We're doing this in obstructive as well.

Thinking about the development in obstructive.

Yes. So as I mentioned, the patient population for MYBPC3, 70% of the patients present with nonobstructive, but there are those 30% are obstructive. And we started there because that's the largest piece of the patient population for us. And we think, as I was mentioning earlier, a precision medicine approach, we are a potential onetime cure, there is room -- I mean, this is a fairly large population, too, right? But when you have a cure rather than having to take an ongoing treatment that has -- obviously, we know about the REMS for CAMZYOS. But I think there's room for a gene therapy approach for sure, for nonobstructive and for obstructive. And when we think about where we might go with our program, that we feel very fortunate we're starting in adults, but we know that there are adjacent populations, as we just mentioned, nonobstructive to obstructive, but also patients in pediatric patient population. There's a really high unmet need there. Most patients present with MYBPC3 in early 40s. However, there are babies and children that also have MYBPC3 and a lot of them don't make it because they have little to no MYBPC3 protein. And most adults have about 60% that present with it. So the earlier pediatric population is one we see as an accelerated development path. And we have been running a noninterventional study called MyClimb to look at the natural history of the pediatric population. And we believe that will give us really good indication of the progression of the disease and how we may actually be best suited to treat the pediatric patient population. And if you go down that path, you could end up with a combined Phase I, II, III, right, because it's an unmet need, small patient population, and you're really treating children potentially that are going to die. And we have on our website and in our presentation, a boy named Gabe, who has got MYBPC3. He is not able to be part of the Tenaya program right now, but he just puts a face to that population that we believe could really benefit from a gene therapy approach, whether they have obstructive or nonobstructive.

So clear that there is an unmet need in the pediatric population. So what would it take to include those patients in the clinical development? And do you think that we need to have more clinical proof-of-concept data with the adult population first? Or is there a path for further development?

Yes. No, that's a really good question. And so we wanted to start in pediatric population because of this unmet need. But certainly, as I mentioned earlier, being the first in-human study with MYBPC3 for MYBPC3 patients for TN-201, the FDA, we're very clear -- and we agree that from a safety profile perspective, you want to start with adults. And so once we do that and once we see some early proof of concept in the TN-201 study that we're running right now for adults, that we could move into -- very quickly move into pediatric population. And really hope that we can do that, as I mentioned, because I think it would really benefit patients. And so we are going to -- we started with adults. We're running the Phase Ib. Obviously, if that's successful, you can move into a pivotal for adults, but you could also at the same time in parallel, run a development plan for the pediatric population, which could be based on the unmet need and rare indication, a Phase I/II/III. So you could be running that in parallel where you're still running your adult Phase III study, a pivotal study.

Great. Well, we look forward to the upcoming readout.

Yes. No, it's super exciting times for us. And -- we definitely have a lot of discussions around it. We've -- I've been with the company since 2021. So seeing this now come to this point of actually dosing patients, especially since we've had these patient experiences come into Tenaya, it really brings it home of there needs to be something found for these patients. They really, really -- and the patient population is leaning in, along with the investigators because they see how this could really serve that patient population.

So moving on to your second gene therapy program for PKP2 arrhythmogenic cardiomyopathy. So maybe you could give us an overview of the disease and the current standard of care and where you see maybe the greatest unmet need?

Yes. No, I think this is our second gene therapy program following on the heels of TN-201. This is another area of high unmet need. Patients who present with PKP2 associated with ARVC, it's -- how would I put it? So they -- basically patients when they get diagnosed, they're given ICDs and basically, that enables the patient to be monitored for arrhythmias, right? So they've been diagnosed arrhythmias, so they have the ICD implanted. But it is really not a great way to live. It's the quality of life. They can't exercise. Generally, it presents earlier than 40, like this is a younger patient population. And a number of times of high proportion of patients, I think it's like 1 in 4, first time it presents as sudden cardiac death. So they have heart failure. And so there's no signal and then all of a sudden, they have a cardiac experience. So for us to be able to find, again, a onetime treatment, such as TN-401 could really benefit these patients who have ICDs who live day-to-day. And the other thing that's interesting about the disease -- on the total ARVC population, 40% have PKP2 mutation, right? So just to set that stage, and it's a fairly large patient population. We believe there are 70,000 patients just in the U.S. alone. But when these patients have these shocks or ICD goes off, there's no correlation to what they might have done that day. So there's no like, oh, I shouldn't go walk to the store or I shouldn't. So there's nothing that, that they can say. So then they shrink in terms of what they think they can do in their [indiscernible]. And while it may say more, it's just quality of life, well, it's a really, really hard way to live when you don't know what's going to trigger the ICD going off, right? So the arhythmias happen, sudden cardiac death is looming, right? So patients -- and this -- this beta blockers. But look, really nothing is treating the underlying cause of the disease. And so just to simplify it for people, what TN-401 is, it's an AAV9 capsid and it's delivering, obviously, with the protein, it's enabling the patients to produce the protein themselves rather than having some sort of monitoring measurement like an ICD or a beta blocker, but there's just no real cure. And so when you think about the patient population, they are highly motivated. We have had a number of interactions, we believe in rare disease. Patient foundations are absolutely key, and you want to -- we want to serve them and make sure we're listening to their needs. And they are super motivated similar to TN-201, this patient population is very motivated and wanting to find a way to treat the underlying course of the disease as opposed to monitoring through ICD and limiting what they can do on a daily basis. And same with the investigators, a significant amount of excitement because of what they hear from their patients and having a onetime cure for them is just an amazing possibility.

And the IND was cleared late last year for the initiation of the clinical development for the program. So how is the Phase I preparation advanced? And when should we be expecting the first set of patients to be treated?

Yes. So again, second program on the heels of TN-201. IND open. By the way, both INDs with the FDA and this is no small feat, was a simple 30-day period. You submit the IND, you wait for 30 days to hear from the FDA. You might get some questions. We literally had 30 days pretty much and we were cleared. And that speaks to the preparation that the company had, especially on our manufacturing process, a number of gene therapy companies have gone on clinical hold as a result of their manufacturing process, but in both cases, really limited a number of questions and comments around manufacturing. But getting back to the clinical trials. So we have -- going to enroll patients in the second half of this year. Our goal is to start enrolling patients. But sites are coming up. We're up on clintrials.gov, you can check out the study design and again, getting the protocol reviewed at IRB. All those things are happening. So again, because of the investigator interest, that's going really well. And we feel -- we're really excited about the study starting in the second half of this year.

And so given the study design and potential enrollment pace, how soon after the initiation of first patient, should we expect biopsy data?

That's a good question. So when you look at the study design, we -- it's very similar to the TN-201 Phase I study. So we have similar design, 2 doses, 3 cohorts -- sorry, 3 patients in each cohort, 3e13, 6e13. But the difference between TN-201 and 401 is that we're doing baseline biopsies, 8 weeks and 52 weeks, similar 12 months ultimate endpoint, safety, tolerability, we're measuring. And the other thing that's interesting here is we're measuring the number of ICD shocks, right? So that's a really quantitative measure, easy for us to measure, I would say, not obviously easy on the patient, but easy for us to measure. We'll obviously be doing the biopsies and measuring for transgene and messenger RNA, but that -- be able to see how many shocks and arrhythmias, I think will be a really interesting measure for us to see how successful is the program. And similar to TN-201, the time period over what we might see outcomes is still to be -- to see, but same doing plasma imaging biomarkers as well. So we'll see that over time. If we dose the patient in the first half -- sorry, in the second half of 2024, we probably wouldn't see data until 2025, right? So that's sort of the time frame based -- similar to TN-201, where we dosed this patient and having that in the second half of this year. So -- but there's a lot of excitement I think that the measures are slightly different, which I think makes it interesting as well. And we have a lot of excitement for both programs.

So -- and for this particular indication, so the PKP2-driven arrhythmogenic cardiomyopathy, so there are several gene therapy approaches that are being developed using different vectors. So I know it's early, so but how should we think about those different approaches and then potential differentiation?

Yes. No. look, for the PKP2 population, the fact that it's gained as much attention, I think is fantastic for the patient population. Yes. So we're using AAV9, and AAV9 has now, from a safety profile perspective, has dosed over 3,000 patients in 50 countries and people will go, well, you just said you haven't started the study. Well, that's because AAV9 has been used in a number of other companies, including, obviously, a very well-known product approved Zolgensma that Novartis has. And so there's a safety profile that none of the other vectors have, right? So it's -- and also from an efficacy perspective and durability, those patients -- the reason why Zolgensma got approved was because of the patient outcomes. So when you think about that and also, I guess, the other adjacent is that Danon disease for Rocket is using AAV9 as well, which is the cardiovascular outcomes. And so we're using AAV9. And so you could see the bridge and the walk over to how you could see potentially the vector performing in the clinic in cardiovascular with the measurements from protein expression and messenger RNA. So we believe that from our preclinical data, we have shown really good efficacy and safety profile. And all of those things point towards a really likelihood of success. But at the end of the day, clinical outcomes wins a day, right? So we'll see how that goes. And -- but we're excited about our enrollment time line, the patient engagement as well as investigators. So we're very excited about that.

Great. Thank you. So we are up on time. But maybe in the last few seconds we have, so -- maybe you can give us kind of an overview of where things are at for your HDAC6 small molecule program.

Sure. Yes, let me try and [indiscernible]. So TN-301, we -- it's an HDAC6 program, small molecule program. We have completed the Phase I study, it was well tolerated at a variety of doses we tested. We saw target engagements as well. And this program is ready for the next stage of development. We expect to do that with a partner because it's a very large indication. There's 3 million patients. The development pathway is extensive. So we are excited about the program, and we believe it will be best done with a partner.

Well, this is all the time we have for today. I'd love to discuss, maybe year ahead for you, and thank you so much for your time today.

Thank you. Thank you, everyone.