Good morning, I think still, everyone, and thank you for joining us. I am Whitney Ijem, one of the biotech analysts here at Canaccord, and it is my pleasure to be joined by Tenaya Therapeutics this morning. Speaking with me from Tenaya this morning is Faraz Ali, CEO. Thank you so much for joining us.
Thanks for having me.
To start off, for anybody in the room and listening on the webcast who's not familiar, can you briefly introduce the company, the founding goals, and how that led you to your pipeline and platform?
Yeah, great. Tenaya was founded in 2016 with a bold vision and mission, which is to go after the leading cause of death in the world. We aim to advance in a modality-agnostic way, different therapies against different forms of heart disease, both rare genetic forms as well as prevalent forms of heart disease. We're clinical stage, obviously publicly traded. Right now, we have three clinical stage assets, which we will be talking about today. Early pipeline includes gene therapies for leading genetic causes of cardiomyopathy, as well as a small molecule originally intended to go after HFpEF, which is a non-genetic but very prevalent form of heart disease. We've made very important efforts to internalize capabilities from research, manufacturing, and now clinical development. Right now, we have more than 40 clinical sites active in seven countries, actively recruiting patients for both dosing our gene therapies, but also for natural history studies for our two lead gene therapy programs. A lot going on under one roof: gene therapy, gene editing, small molecule, cardiac regeneration, but with a very, very intense focus right now on our two lead gene therapy programs, TN-201 and 401, which is, I know, we'll be talking about today.
That we will, yes. Perfect. On that note, before we get into the program specifically, both use AAV9, which is a particular viral vector as the delivery modality. Can you talk about the pluses and minuses of AAV9 as the modality, and I guess in particular relative to some recent news or updates in the space with other AAV9 programs?
Yeah, I can, the short answer is I can only speak to pluses and no minuses because we selected AAV9 for a reason. It is the single most validated capsid in the world. There is no other program, no other capsid that has been used in as many patients as AAV9. Zolgensma, which was approved by Novartis globally many years ago, that one product alone, which is used as IV AAV9 at the 1E14 dose, has been dosed in more than 4,000 kids in more than 50 countries. It's got the single largest safety database in the world. It also happens to be the best capsid of choice for cardiac applications. Compared to other capsids, it's the one that has the most validation for its ability to transduce and express in the heart. That includes our friends from Rocket Pharmaceuticals who are using AAV9 in their Danon disease program. Safety database established, ability to penetrate the heart established. There have been unfortunate things that have happened. Unfortunately, there have been some deaths. You mentioned Rocket, but what's been in the news the most was Sarepta, and Sarepta is using a different capsid. It's AAVrh74. When you actually take a step back and look at the safety of the capsid, first of all, more than 4,000, actually more than 5,000 patients have been treated just on commercial AAV. There have been some unfortunate cases of death, but that actually total adds up to less than 15 patients. The rate is less than 0.3%. There's no propensity for any one capsid. AAV9, AAV8, AAVrh74, many different capsids have been involved. It's not an AAV9 problem. I think we have learning and with the sophistication of the field that things like manufacturing, things like your immune suppression regimen, which is really the primary culprit in the Rocket death was their use of a particular immune suppression regimen. This was a rare side effect of that immune suppression regimen. In the case of Sarepta, they weren't using enough immune suppression regimen. The FDA asked them to add sirolimus. Companies like ours have been using sirolimus from the beginning. When we talk about safety, need to put in perspective, it is a very, very, very small fraction of patients that have these worst outcomes balanced against thousands who are benefiting from the cures. It's not just the capsid. It's capsid, manufacturing, immune suppression, and all of it together that has an overall effect on safety. We're very pleased with all that we have done with world-class advisors to put safety in place for our patients.
Perfect. Okay. We will get into the specifics of each program, but you have not seen any safety issues of note to date in the vein of what we've seen?
When we talk about, you know, we have, if you take across our two gene therapy programs, now granted we're still early in our dosing, but we've dosed a total of nine patients. We just recently announced DSMB clearance for both of our programs to go to the next level. We have not had any safety-related issues that have blocked our forward progress of dose escalating and dosing patients. Our programs have been well tolerated, and any adverse events that have been seen have been consistent with other gene therapies and/or unrelated to the product altogether.
Okay, perfect. Yes, diving into TN-201 specifically for MYBPC3-positive hypertrophic cardiomyopathy.
That's a mouthful.
Mouthful, yes. Can you briefly describe the disease again for those who might not be familiar, current treatment, and outcomes?
Yeah, so TN-201 is going after the leading genetic cause of hypertrophic cardiomyopathy, and that is due to the MYBPC3 mutation. It accounts for about 20% of all hypertrophic cardiomyopathy, which translates to about 120,000 patients in the U.S. alone. It's an orphan disease, but a quite prevalent orphan disease by orphan standards. This is a disease of the sarcomere. Every cardiomyocyte in the heart has a sarcomere; it's part of that contractile apparatus. MYBPC3 is a very, very important regulatory protein that supports the overall contraction of the heart, the healthy normal contraction of the heart. As a result of mutations of that gene, there's a deficiency of that protein, and that causes the contractions to not be normal anymore. They go through a period of hypercontractility, which causes the heart to thicken and enlarge. That's why it's called hypertrophic cardiomyopathy. There's fibrosis, there's arrhythmia, there's risk of heart failure, sudden cardiac arrest, and sudden cardiac death. The typical patient presents in their 40s with severe symptoms, which might start with dizziness and palpitations and difficulty breathing, but eventually progresses to much more severe disease, including loss of heart function and eventually heart failure, and as I mentioned already, the risk of sudden cardiac arrest and death.
Okay, perfect. Maybe on that note, at the risk of being a little bit redundant, you'll be presenting natural history data here in a couple of weeks. What should we expect to see or what should be the focus? Are there key, particularly as we think about kind of the trial design for your program, what should we be focused on in that update?
Yeah, so everything I just described, I mean, HCM is pretty well now understood, partly because of the good work done by Myocardia and now BMS in the category, and now Cytokinetics and others. The genetic form of the disease is still being understood. We presented actually at ACC earlier this year data in adults just showing how patients with the mutation have more severe presentation, earlier presentation compared to patients without the genetic mutation. What you're referring to, we just announced in our latest earnings that we'll be presenting pediatric natural history data at the upcoming European Society of Cardiology. We have a natural history study called the MyClimb Natural History Study. It is the largest natural history study in the world for kids with this mutation. We have more than 220 kids enrolled from multiple countries. Why would we do this? One is to just better characterize the progression of the disease in children and the burden of the disease. It shows how severe these kids are, where some of them are presenting with symptoms certainly before their teenage years, but some of them as early as the first few days, weeks, and months of life. Very underdiagnosed, as you'd imagine. We're really shining a light on the severity in these kids and the progression of the disease. We think that this is actually an important and exciting opportunity as we advance TN-201 currently in adults. There may be an opportunity at the right moment with a sufficient number of adults treated, efficacy, and safety to go into a pivotal study in children that could lead to an approval with an accelerated approval of surrogate biomarker, much like what our peers at Lexeo for Friedreich's Ataxia and Rocket with Danon disease have achieved. That is why the natural history study work that we put in motion years ago is so important. It gives us a body of patients who are around the world who are being prospectively followed. It gives us the natural histories that would serve as a control arm in a potential pivotal study. Exciting data that we'll be presenting to really shine a light on this very severe pediatric form of this disease.
Perfect. Okay. As far as the ongoing Phase Ib study you mentioned in adults, can you just briefly talk about the design of that study and what you've shown so far?
Yeah, we were excited to recently complete the dosing of the high-dose cohort. Now we've dosed three patients in the low-dose cohort and three patients in the high-dose cohort. I mentioned that the DSMB has cleared us to continue to dose patients at either cohort. We're outside of the sentinel phase. We can dose as many as 20 or 24 patients in that study. We can continue dosing more patients if we'd like to dose adults, or we can pivot towards children. We presented exciting data on this program. First, the release was end of last year, but a more recent date was at the American College of Cardiology. All three patients who had symptomatic disease at baseline have gone from New York Heart Class II or III to New York Heart Class I. Two out of three of them have had improvements in one or more measures of hypertrophy, improvements in circulating biomarkers. The biopsy data confirms that this is not random. The biopsy data shows that TN-201 is reaching the cells, it is transducing the cells, the RNA is expressing, and the protein is measurable. We have the evidence of TN-201 activity in the biopsy, and we have evidence of clinical benefit even from the first couple of patients, not all of them were at their mark. I think that was a very exciting first update at ACC. In the second half of the year, we've committed to doing another update where we will show more information from the first-dose cohort and initial data from the high-dose cohort.
Perfect. Okay. Looking to that update from cohort one, is there a specific amount of follow-up that every patient will have, or can you talk a little bit more about what we'll get from cohort one, and then same question for cohort two?
Yeah, so for cohort one now, by now all three patients would have reached their 52, so the one-year mark. Full cohort data at the one-year mark is sort of an important milestone. We'll be providing an incremental update from where we were at ACC, where every patient was not at the one-year mark. We'll be able to show where every patient is. Importantly, in cohort one, the first two patients did not have the benefit of a baseline biopsy. While we were able to show RNA increase and protein increase, for the protein in particular, we did not have a baseline biopsy. Starting patient three, the third patient in the first-dose cohort, we have baseline biopsies. That'll be an expectation that we can deliver on that we'll finally be able to show definitively the comparison of protein expression with the baseline biopsy. With the high-dose cohort, these patients are still early in their journey. There'll be biopsy data to tell us about, you know, vector copy number, protein, and RNA for a certain number of patients. We're not making any commitments for clinical data on the high-dose cohort because most patients will, or at least anything that we would be a bonus. The expectation setting for the high-dose cohort is safety, which is all important, especially given your first question and where the field has been recently. The biopsy would be for comparing that biopsy data to the first-dose cohort. Certainly we'd be hoping for higher overall expression and kinetics of expression that would be then predictive of clinical benefit.
Okay. Can you remind us on the timelines of the biopsies? Baseline, everybody got a baseline biopsy in cohort two?
In cohort two, every single patient has a baseline biopsy, and then we do one near-term biopsy. We have a lot of flexibility of when that could be. It could be eight weeks, 12 weeks, 24 weeks, but we have flexibility. Then another one is around the 52-week mark. These initial biopsies would not be at the 52-week mark because they're too early in that course. It would be the baseline and the early biopsy, post-dose biopsy sample. We think that'll be informative because it'll allow us to compare that data to the data we now have from the first-dose cohort and have meaningful things that we'll be able to say with that.
Right. Okay. Headed into that, what is good, as you said, can you talk a little bit about what is known or not known about the level of protein that's needed and what your preclinical data is guiding you to expect for cohort?
Yeah, that's a great question. When you're pioneering in a new area, sometimes that's exactly the stuff that you have to elucidate. Going into this, we knew that, and we know this, there's quite a wide range of protein levels in the disease population. There's also quite a wide range in the healthy normal population. In fact, there's even a tiny bit of overlap between the protein levels in the disease and the normal population. You could have, you know, you could have 78% of the average protein and have severe disease. You can have 78% and have normal presentation. What that tells us is that each patient reacts to their own level of protein differently. The goal is not to get to some magical threshold, but to increase the level of protein for every single patient. That's been consistent with the other gene therapies as well. What the FDA has asked for from the other gene therapies is not to get to a 100% normal level, not to get to some magical threshold, but to deliver more of the missing protein to each patient. If we give them more than what they have, then that should lead to some benefit. Now, what exactly, how much protein results and how much benefit? These are, in a rare disease, it's probably going to be impossible to draw straight lines in that. Our belief from our work and the work of others is a little can go a very long way and that the FDA seems to agree with that hypothesis as well.
Okay, perfect. After you have that data or the data that we'll see later this year, is the expectation that you'll be able to choose a dose and, as you mentioned, either move forward and dose more patients or younger patients? How should we think about next?
We always wanted to explore both doses and see, and we're very pleased that even with the first-dose cohort that we're already seeing benefit, as I described at ACC, and we'll provide more of an update in the second half this year. In fact, we narrowed our guidance to, by the way, to Q4. Q4 is when we'll be doing the data release on TN-201 this year. Even the first-dose cohort is doing well. The second-dose cohort will tell us how much more benefit we're getting, both measured by the biopsy as well as by the clinical data, and how is the safety looking for the second-dose cohort compared to first. That will allow us to pick a dose for pivotal studies in both adults and in children. We have not declared yet which dose we are going to pick for pivotal studies because we're still actively dosing patients in the high-dose cohort, and we're still analyzing that data and accumulating that data. Very similar to our peers, you dose a few patients, wait a little bit of time to accumulate enough information to make a determination of what dose you want for pivotal studies.
Okay. Just a quick follow-up on the pediatric population. Will you need to dose, or do you want to dose some patients in the phase Ib, pediatric patients, before moving to a pivotal?
We would actually probably not convert the phase Ib into a pivotal because the children are distinct enough that they would actually have some different measures, frankly, than what we would be measuring in adults. That is probably a deeper conversation for a future time, but it would be more likely that we would launch a separate study specifically for the children. There are so many points, for example, the children present with a lot of variability. Some of them present with a much higher burden of arrhythmia, which leads to the sudden cardiac arrest and death. Some of them, the homozygous infants, die within, you know, the first year of life. Over there, you would be talking about a survival endpoint, which we don't really think about using a survival endpoint in the adults. Not that they don't have premature mortality, but that's not the clinical endpoint. There are enough differences in the clinical endpoints for the children that it would be a standalone pivotal study and not just converting the phase 1b into a pivotal. In that case, that could be different for 401, which I know we'll transition to.
Yes, yes, perfect. TN-401, second AAV program, also using AAV9 for PKP2 ARVC, another rare genetic cardiovascular disease. Data expected in the fourth quarter of this year. Can you review the disease briefly, burden, current treatment, and outcomes here as well?
Yeah, sure. In this case, we're talking about arrhythmogenic right ventricular cardiomyopathy. It is a different form of heart disease where the hallmark of the disease is the arrhythmia. The PKP2 accounts for the, it's the leading genetic cause of this condition or accounts for about 40% of all disease, and that translates to roughly about 70,000 patients in the U.S. alone. While it's rare, similar to MYBPC3, these are large orphan conditions, so tens of thousands and more in the U.S. alone. Attractive opportunities, very severe disease, typically presents in 30s and 40s. Unfortunately, one gruesome statistic for this disease is about a quarter of all patients, their first presentation is sudden cardiac arrest and death. The first time you find out that you have this mutation is because you're dead in about a quarter of the patients because they present with such severe symptoms. This is a disease of the desmosome, which is a structure that connects the cardiomyocytes and the heart to each other. As a result of the mutation, they're not producing enough of the protein that causes structural damage to these desmosomes, which means there's not proper mechanical and electrical conduction that the heart needs. Over time, that causes fibrosis, fibrofatty replacement, heart failure, but along the way, these very, very severe arrhythmia. The point with TN-401 is to add a copy of the human gene to produce the missing protein to reform these desmosomes and get the heart functioning properly again and hopefully measure the decrease in the arrhythmia burden in these patients.
Okay, perfect. Is there a better understanding of a level of, or is there a threshold level of protein in this disease that's more?
This is something that we'll be sharing more information as we get into the second half this year. Similar to MYBPC3, there is a wide range of normal. There's less known about the protein levels for PKP2 in both the disease and normal population than there was for MYBPC3. We've done some important work, some of which we'll be sharing in the second half this year about what we consider to be the range of the protein in the normal population, which is quite heterogeneous.
Okay, got it.
There is no magical threshold. Long story short, it's too early to state one.
Okay, so without a magical threshold, what is good data as we expect to see biopsy data?
Yeah, so the second half of the year or Q4, we'll be presenting the data on this program for the first time, the first three patients in the first-dose cohort. We've committed to biopsy data. Obviously, safety is always important, but biopsy data, all patients have a baseline biopsy. We'll have the baseline and the first post-dose biopsy, and vector copy number, RNA, and protein for these patients. That's a commitment. It's very similar to our first data release last year for TN-201. We haven't guided to any clinical data, like measures of arrhythmia. Having said that, some of our peers who are also working on this mutation and gene therapies for this mutation did present data earlier this year where they showed protein and biopsy data, but also showed some early arrhythmia data. There's probably some expectation out there that we will do something similar, but we haven't formally guided to what we would be sharing.
Okay, got it, got it. Focusing on the biopsy data in particular, what are you expecting or how would you set expectations into what you're hoping to show? Is it just increase from baseline and that's good enough?
I think for now that that would actually be quite good. That's, I think, to varying degrees, what our peers have shown to date. We're very thorough in our methods. In fact, we have an upcoming webinar as early as next week, on Monday or Tuesday of next week, Tuesday of next week, where we're actually going to have some of our experts who've been helping us with protein analysis conducting a webinar to help put protein—how do you measure protein expression in both of these conditions—very, very differently than other gene therapy programs where often you're starting with zero and then you're showing a little bit. In both of these conditions, they're heterozygous, so they have a lot of background protein, right? Now you're trying to show the increment on top of that and show that over time. How do you do that? We have methods that we really stand by and believe in, and we'll be presenting more about that. We're going to actually do a webinar next Tuesday for those of you listening and interested in learning more. That will help set up our data release later this year. Yes, we will be measuring changes from baseline for protein. We'll also be showing RNA data, which often captures things that protein doesn't, and of course, vector copy number, which is just the measurement of transduction. Obviously, some people will be able to compare results, perhaps imperfectly, between our data and our other two peers.
Okay, some people.
Some people, yeah.
Okay. In the last 10 seconds, any updates on TN-301, your small molecule program?
Yeah, so TN-301, we love that molecule. We completed a first-in-human healthy volunteer study back in late 2023, presented that data. 72 patients, well-tolerated, no dose-limiting toxicities, target engagement, which you often don't get in a first-in-human healthy volunteer study, but we were able to demonstrate target engagement. That molecule was originally developed with the idea of going after HFpEF, which is a very prevalent indication. We're actively exploring opportunities for moving this forward either with partners, and if not with partners, then on our own. We have our ideas of what would be very attractive indications to move this forward as long as we have the capital to do it. Right now, in a capital-constrained environment, we have focused our capital in TN-201 and TN-401, but under the right circumstances, we'd love to find a way to move 301 forward, either with a partner going after larger indications or on our own going after very severe, rare diseases where we think 301 could really sink. That's, I guess, all we can say about that for now.
Okay, perfect. Thank you so much.
Thanks, thanks for having us.