All right. So, thank you, Leone, for being with us this morning. We look forward to diving into 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 and history?
Yeah, 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 five 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 five years ago, and there are a number of companies that are specializing now in cardiovascular. But we have started that, and the 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, five years later, a clinical-stage company with three programs in the clinic. We have two that are gene therapy programs and one small molecule, and those two gene therapy programs are TN-201, which is for gene therapy for MYBPC3 associated with HCM. We also have a second gene therapy program for PKP2 mutation associated with ARVC.
So those two gene therapy programs, super exciting, has got a lot of people really interested in the Tenaya story. And we also have a small molecule program for TN-301, called TN-301 for HFpEF. And building out those capabilities has been essential for us as we start navigating what's really going to, you know, 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, a successful raise. We raised $50 million, and that was with new and existing shareholders.
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, you know, the gene therapy is new to that space. Like you mentioned, cardiac gene therapy is really new term. How should we think about genetic testing and identifying those patients?
Yeah, that's really important, especially with a genetic mutation, and actually, we don't know exactly how much this has generated, but basically, we believe it's on the rise. And what gives us the idea is that, you know, organizations such as American Heart Association, ACC, and ESC are actually have genetic testing in their recommended guidelines now. And also, some of the larger centers are also testing as well. And obviously, you know, being such an inherited cardiomyopathies is one of the most common forms, right?
And so we think that that's important for families because this 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.
Do you see even increase in kind of, like, interest in genetic testing within those families just because of, you know, the, the-
Yes.
Available of those?
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, they 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.
It's so emotional to see that there is a way of maybe diagnosing what they have, and people have these realizations, well, Uncle Fred and Grandfather, you know, John, passed away early, and now it's becoming, you know, more real about why that happened and through the genetic testing. That's allowed them to have been motivated to get the genetic testing.
Thinking about the HCM patient population, where do you see the greatest unmet need?
Well, you know, it's interesting. We obviously focus on MYBPC3, and we see that there's non-obstructive patients and obstructive patients. And the way it, you know, sort of works out is that there are about 70% of patients have non-obstructive and 30% have obstructive. And obviously, in the overall hypertrophic cardiomyopathy population, you know, that can be a different story, right? So if you think about the programs that are products that are out there. So we actually see, for us, following this precision medicine approach, knowing that non-obstructive is the most common form in MYBPC3 patients, that that is the best place for us to start. But that's what our, w e can go through our clinical trial design, but that's where we see the most initial value, and then we can move to obstructive.
You know, we think there is room for us to move into the obstructive population because of the precision medicine approach and because it's a one-time, a potential one-time cure.
So thinking about the non-obstructive patient population, the phase I study started with that patient population, with the first patient being dosed late last year. Can you maybe give us a reminder of the study design and also how enrollment is anything?
Yes. Yeah. So super exciting for Tenaya. First, actually, first patient we believe dosed with a 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 two 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 four 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, you know, 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 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.
Then you have gene therapy programs like Danon and 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, it's 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 love to talk about where we might go beyond adults.
And also, it's an AAV9 capsid that we're using, so we've got to test for 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, data 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'll be doing those at eight 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.
Yeah. So thinking about this upcoming readout later this year. In terms of, s o given the pace of enrollment, what number of patients should we anticipate? Should we anticipate, you know, 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-
Yeah, no, it's a good question. You know, as the enrollment, you know, enrollment's on track, by the way. But what we have said previously is that 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-month period of time thereabout for, for the first three 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 timeline of when we actually might see things. So three 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 non-obstructive HCM. So thinking of non-obstructive HCM, where there are no, you know, specific kind of treatment- How should we think about the regulatory path and potential, you know, pivotal study design, endpoints?
Yeah, no, that's super exciting to think about that, right? That going into pivotal and obviously watching Rocket with their Danon program being in pivotal, it's a 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 in 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 myosin inhibitors, that myosin inhibitors, provided that, you know-...
But the thing that's interesting for us is that with the FDA, it's CBER, that we would also be looking at, at the interacting with, because it's gene therapy. So when you look at that and you think the comments, you know, Peter Marks, you know, 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 all been looking very closely at 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, 'cause it's gene therapy, and that one, obviously is, it's rare, similar to ours.
But two, the surrogate endpoints and how it was 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.
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 a really exciting, pivotal path for us.
Yeah, and thinking about demonstrating efficacy, how should we think about the bar for success in the indication? Because this is, like you, like you say, we have a reference in HCM, and HCM is a non-obstructive, a little bit of a different set up there. So what should we see as kind of the bar for success in terms of, you know, 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 a more general, we should see just everything trending in the right direction?
I think it's gonna 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 six-minute walk test, there's the CPET test, which is the exercise requirements, and then there's New York Heart Association class measurement, 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, you know, to proceed and see success, in non-obstructive patients to begin with. But I... You know, we can get to this, but I think there's room for us for doing this in obstructive as well.
Yeah, great.
Let's go there.
Thinking about development in obstructive.
Yes. So, as I mentioned, the patient population for MYBPC3, 70% of the patients present with non-obstructive, 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, where you're a potential one-time cure, there is room. I mean, this is a fairly large population, too, right? But when you have a cure rather than, you know, having to take an ongoing treatment that has, you know, obviously we know about the REMS for Camzyos. But, you know, I think there's room for a gene therapy approach, for sure, for non-obstructive 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, non-obstructive to obstructive, but also, patients in the pediatric patient population.
Yeah.
There are, you know, there's a really high unmet need there. Most patients present with MYBPC3, in, you know, early forties. However, there are, you know, 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, you know, about 60% that present with it. So the earlier pediatric population is one we see as a accelerated development path, and we have been running a non-interventional 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 know, you could end up with a combined phase I, II, III, right? Because it's an unmet need, smaller 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, you know, 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 non-obstructive.
It appears that there is an unmet need in the pediatric population?
Yes.
So what would it take to, you know, 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 parallel development?
Yeah, no, that's a really good question. 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 were 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 of phase I, II, III . So you could be running that in parallel while you're still running your adult phase III study, a pivotal study.
Great. Well, we look forward to the upcoming read out.
Yeah. No, it's super exciting times for us, and we definitely have a lot of discussions around it. 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 in to 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.
Yeah, no, I think this is our second gene therapy program, following on the heels of TN-201. This is another area of a high unmet need. Patients who present with PKP2-associated ARVC, it's a... 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, have 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 one in four, first time it presents is sudden cardiac death.
You know, so they have heart failure, and so there's no signal, and then all of a sudden they, they have a cardiac experience. So for us to be able to find, again, a one-time 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, of 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's 70,000 patients just in the U.S. alone. But when these patients have these shocks or, you know, the 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..." You know, so there's nothing that, that they can say. So then they shrink in terms of what they think they can do in their day. And it's... And while it may seem, oh, it's just quality of life, well, it's an, really, really, hard way to live when you don't know what's going to trigger-
Trigger, yeah
... the ICD going off, right? So the arrhythmias happen, sudden cardiac death is looming, right? So patients... And there's, you know, there's beta blockers, but, like, 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, you know, having some sort of monitoring measurement like an ICD or a beta blockers. 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, you know, we, 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 cause of the disease, as opposed to monitoring through ICD and limiting what they can do on a daily basis. And same with the investigators. Significant amount of excitement because of what they hear from their patients, and having a one-time cure for them is just an amazing possibility.
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 expect, you know, 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—it was a simple 30-day period. You know, 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 around 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 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 are up on ClinicalTrials.gov. You can check out the study design, and again, getting the protocol reviewed at IRB, you know, 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, you know, potential enrollment pace, how soon after the initiation of, you know, 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 MyClimb... Sorry, 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 TN-401 is that we're doing baseline biopsies, 8 weeks and 52 weeks. Similar 12 months, you know, 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're obviously doing the biopsies and measuring for transgene and messenger RNA, but that be able to see the 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 of over what we might see outcomes is still to be, to be to see, but same, you know, doing plasma imaging biomarkers as well. So we'll see that over time. You know, if we dose a patient in the first half, sorry, the second half of 2024, you know, we probably wouldn't see data till 2025, right? So that's sort of the time frame based on... Similar to TN-201, you know, where we dosed this patient, and having data 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, for both programs.
You know, for this particular indication, so the PKP2-driven arrhythmogenic cardiomyopathy, so there are several, you know, gene therapy approaches that are being developed, you know, using different vectors. So I know it's, you know, it's early, so, but how should we think about those different approaches and then potential differentiations?
Yeah, I know, and I... Look, for the PKP2 population, the fact that it's getting this 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, but you just said you haven't started the study." Well, that's because AAV9 has been used in a number of, 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 Duchenne disease for Rocket is using AAV9 as well, which is the cardiovascular outcomes.
And so we're using AAV9, and so, you know, 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, you know, protein expression and measured 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 the day, right? So we'll see how that goes, and... But we're excited about our enrollment timeline, the patient, engagement, as well as the 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.
Yeah.
Yeah. Let me try and finish that in 2 seconds. So TN-301, we are... It's an HDAC6 program, small molecule program. We have completed a phase I study. It was well tolerated at a variety of doses we tested. We saw target engagement, 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, so...
Well, this is all the time we have for today. A lot to discuss. A busy year ahead for you and, thank you so much for your time today.
Thank you.
Thank you, everyone.