Okay. Hi, everybody. Welcome to our next session for H.C. Wainwright's Global Growth Conference. Happy to have with us, Faraz Ali, the Chief Executive Officer of Tenaya Therapeutics. Looking forward to a productive fireside chat here, especially after the company has been very busy over the last several months with a growing positive data set from their lead two assets. With that, I would love to just jump right in because we have a lot to cover, and thank you for being here, Faraz.
Thanks, Joe, to you, and to the HCW team for inviting us.
You bet. First, let's go back to your lead asset, even though your second asset, TN-401, has been really increasing in visibility. With regard to TN-201.
Yep.
I'm going to jump right into the data, but if you'd like to-
Yeah.
introduce the population, that would be great.
Yeah.
You have data on six evaluable patients.
Yes.
How consistent is the relationship between the structural remodeling you're seeing in the heart and the functional/symptomatic readouts?
Yeah. So we're really excited. The update that we did recently was actually a meaningful update from what we did at AHA last year, and we were already pretty pleased with what we had at AHA last year. Now with the benefit of more time, we now have data from six patients, seven patients worth of safety, six patients worth of efficacy data. And the good news is that all patients are seeing meaningful improvements in one or more measures of all the domains that we're looking at right now. So we're looking at circulating biomarkers. We're looking at hypertrophy, so that's that remodeling you talked about. Feel and function measured two different ways, New York Heart Class, KCCQ, and for feel and function, six-minute walk test and peak VO2.
Now we don't have all of that information in hand for all patients at one or two-year time points, but we have quite a bit. Overall, the totality of the data shows that patients are doing well on multiple measures. There's quite a bit of internal consistency. Any one measure might be strong here and weak there, but overall, it is unambiguous that there's a clinical effect that is happening, and it's because of TN-201. The levels of hypertrophy that we're seeing, the reductions, multiple measures of wall thickness and LVMI. Four out of six patients had double-digit decreases in hypertrophy, and these are very sick patients, and that's being achieved on top of standard of care. Four out of six patients also have improvements in KCCQ. That was the first time we reported that. Five out of six have improvements in New York Heart Association Class.
Two out of three patients with a high dose cord have improvements in six-minute walk tests that are above what would be considered clinically meaningful. For the very first patient evaluable at the high dose for whom we have peak VO2, they also had an improvement in peak VO2 that is above what would be considered clinically meaningful. Small N, early days, but overall, circulating biomarkers, hypertrophy, feel, and function all moving in the right direction for the majority of the patients.
I'm very happy that you mentioned all those endpoints that have certainly been pointing in the right direction. You're going to have a lot more discussions with regulatory authorities going forward.
Yeah.
With so many endpoints that you just mentioned.
Yeah.
How do you look to interpret them as to what the leading indicator of clinical benefit might be as you design later studies?
Yeah. It's a good question, and let's just as a reminder, taking a step back. We're talking about the MYBPC3 mutation. It's the leading genetic cause of hypertrophic cardiomyopathy. This accounts for 20% of all mutations. That's about 120,000 patients in the U.S. alone. This is a large indication, and that makes it interesting, I think, both for investors as well as for potential partners in the biopharma space. One thing that's also interesting is there's a lot of phenotypic heterogeneity. I mean that at the level of you have adults, adolescents, even neonatal infants. You have heterozygotes. You have homozygotes. You have patients with the obstructive form of the disease and the non-obstructive form of the disease. That leads to a lot of variability in terms of how these patients are presenting, different standard of care. Some have myectomies.
Some have some kind of medications or the others. You expect there's going to be a certain amount of variability, and I'm glad that across all that variability, right now, most of our data has been generated in fact, all of our data has been generated in non-obstructive adults. TN-201, we think, is going to be important for all forms of the disease. This is a data-rich study where we're finding the signals to figure out where does TN-201 work the best. Right now, all of our data is in non-obstructive adults, and we're glad to see that even within that segment, there's a lot of heterogeneity and all these patients seem to be doing well.
In terms of we think about regulatory alignment and future approvals, one thing that we'll just have to be mindful of is that the alignment that we may achieve may be different at different times for different subpopulations. What do I mean by that? How you measure an obstructive adult versus a non-obstructive adult would be different. Majority of the patients are non-obstructive, but it would be different. Similarly, how you would measure a child who is dying of their disease within the first days, weeks, or months of life, these are the homozygous neonatal infants, very rare, very severe. That would be a different endpoint. Those would be different.
When we think about the data we're generating, all of this is giving confidence in the activity of TN-201, and we're still early in our journey to figure out where does TN-201 really work the best, in which population, and where do we want to go into pivotal studies first, second, third given the heterogeneity of the disease. Hopefully, the totality of data gives us some confidence, but mapping out which specific endpoint for which specific population, that's a work in progress. Then which population to go after first, second, third. There's a lot of energy and interest in pediatrics. We'll talk more about that. But that's the work that we're doing, and we look forward to providing an update in the second half of the year.
That is good. Yeah, definitely looking to the second half. We knew that were coming, so I'll just sort of hold off on my question.
Yeah.
What's your current wish list? Because that could change momentarily.
It will change by population, where it's like maybe this population would love to get an accelerated approval. Maybe the pediatric population we like that we were invited to participate in this Rare Disease Evidence Principles group where CBER and CDER and others come together in these areas of very high unmet need, very severe infantile populations. That's perfect. Now, what is possible in that population with that group, we'll learn. That may be different than what is possible for adults with the obstructive form of the disease, where there are some existing therapies that have been approved, versus adults with a non-obstructive form of disease where there's not yet an approved therapy. I think the engagement will vary depending on which population we're talking about. My wish list is long, depending on what we talk about, which population we're talking about. More to come, right?
But we're excited about where we are.
No, absolutely. And of course, the pediatric population would be very, very important.
Yep.
So my next question, and you and I have discussed this in the past, and I love to pontificate about it—
Yeah.
based on my very long-term coverage of Cytokinetics.
Yes.
From a competitive landscape standpoint, the CMIs, or cardiac myosin inhibitors, aficamten, mavacamten, are chronic symptomatic therapies. They are already de-risked, obviously, on approval.
Yes.
Investors are tracking their sales. How do you position a one-time gene therapy against the CMIs, and how does that resonate with cardiologists?
Yeah. Look, I will answer that a couple different ways. One, TN-201 remains the first and only product that is going after the underlying genetic cause of the disease, and patients with this particular mutation, we know on average present more severely. We also know that the majority of these patients present with a non-obstructive form of disease, and as you know, Joe, we do not yet have an approval for either of the CMIs in the non-obstructive form of the disease. So 70%+ of the adults and 90%+ of the children with this mutation have the non-obstructive form of the disease. So there is still a lot of unmet need there, and there is still not an approval. But let us assume, CMIs have been a great advancement for the field, and let us assume that there will be an approval for maybe Cytokinetics gets that approval.
They hit an endpoint, though the effect size was small. I think it is a large enough population, I mentioned 120,000 patients in the U.S. alone, that I think there is room for multiple products, and I think the market is betting on that, right? People talk about the Cytokinetics product being a multi-billion dollar opportunity. They talk about, mavacamten, the Bristol Myers Squibb product, being a multi-billion dollar opportunity. And every time there is a new entrant, the market gives them credit for it being a multi-billion dollar opportunity. I think that is the way the market is saying it is a large opportunity, there is room for many products, and TN-201, I truly do believe in my heart of hearts, that there is a room for this to be meaningful in populations. Now remember, not all patients respond to CMIs, right?
In fact, some patients who are being referred to us are patients who have not responded well to a CMI, including the obstructive form. Some patients have told us they prefer a one-time dose over a lifelong chronic therapy, especially for an older population. We do not have the I know reductions in LVEF, ejection fraction, is one of the side effects, unintended or undesired side effects of at least some of the CMIs. We do not have that. We do not see that. Our mechanism wouldn't cause that. I think there's just enough here to say that there's probably room for TN-201, and that room may be greater in some populations versus others, right? Maybe in the obstructive population in adults, there's less room. We might be considered more as for the more severe versions of those patients.
Maybe in the pediatric non-obstructive patients, it's a lot of room to play there. Maybe in the non-obstructive adults, the jury is still out, depending on what happens with approval for one of the myosin inhibitors. Bottom line, big opportunity, a lot of unmet need. TN-201 profile is distinct and differentiated, and we think there's a future for it.
Right. It's a very difficult disease, so it might be difficult to discuss potential combinations.
Yep.
What do you feel or, albeit even anecdotal feedback, have you been getting from cardiologists? You really-
Yeah.
touched on a lot of the key points there that I think would be attractive to them.
Yeah.
Anything else you could share?
I will say two more things. One, I will say that in the data that we released, we were pleased to show both at the AHA meeting and last year, as well as the recent update, we're making explicit comparisons of the amount of hypertrophy reduction that we're achieving after a single dose versus what has been seen with the CMIs, and where our data compare favorably. A single dose of TN-201 is showing a reduction in multiple measures of hypertrophy, LVMI, LV posterior wall thickness, and interventricular septum thickness. So by multiple measures, we're showing both on a relative basis, a percent reduction, as well as on an absolute basis, millimeters of thickness, that we're doing as well as them at this early time point. Six patients versus hundreds of patients. It's still, we're in the zone. I think that speaks well to TN-201.
Not claiming superiority, not claiming equivalence, just saying we're in the right zone compared to those data. That's after a long time of chronic dosing with some of those products. That's one thing I'll say. I think people notice that, because at the AHA meeting, KOLs were asking, when will we see remodeling? In the HCM population. Then our presentation came up. It's like, well, we're seeing remodeling. It's already happened. There was a note that came out, and I will just say that where somebody did market research on the other side of our data release and polled, I think, 20, 25 physicians about our data set and the confidence in that and the interest in it, and it was very high. It was very positive. That sort of corroborated some of the work that we had done.
Two different sources, some work we've done, some work that a third party did. When we look at it, there's clear interest and enthusiasm for what we're trying to do here. We're still early, and people want to see more data, and that's completely reasonable. I would say that the feedback has been good.
No, that's helpful. I guess, we'll talk about this more at the end with regard to the upcoming milestones, but since you mentioned it already, you said maybe a little more about what we can expect in the second half, and that was also, it sounded like potential paths forward or what indications.
A little bit more data. We're pleased with what we're seeing. One of the things they formally have not declared is the dose that we'd want to take into pivotal studies. We are seeing good data and durable data at the 3E13 dose, which is the first dose. Remember, those patients, the first two patients dosed there were dosed two years ago. Now when we're talking about improvements, whether it's on circulating biomarkers or hypertrophy or feel, those are improvements now that have been durable out to two years. That's positive for us, and after a single dose. At the higher dose, we're beginning to see either improvements in hypertrophy that are happening faster or deeper. We're seeing some better improvement in feel and function for KCCQ and for six-minute walk test and early signs of peak VO2, but we don't have all the data.
Second half of the year, there'll be meaningful, important, additional data that might help us make a final determination of dose three or six. We like both right now, and maybe the data will tip us over in one direction or the other. That's something to look forward to. As I said, we plan to give an update on where we are in our conversations with the FDA on both this program as well as the next program we're going to talk about with TN-401. One thing, because of the heterogeneity, I mentioned all these different populations, adults, pediatrics, obstructive, non-obstructive. I think the expectation we want to set with investors is we'll be transparent, we'll tell you where we're at. But it's not going to be a single big bang. Like here's the reveal.
Across every population, we have a line on these endpoints and this statistical analysis plan. That's just not feasible. We would hope to be able to communicate this population, there's clear alignment, clearly a path forward, and we're moving forward here and still working on achieving alignment on some of the other areas. I think it'll be alignment or it'll be an update on where we are with our discussions and flipping some cards, but other cards still to be flipped into 2027 as we continue to generate data and have discussions with both the FDA as well as the EMA.
No, of course. That's very helpful either way because the way I've always put it is that investors pay for visibility, and of course, with additional clinical data, hopefully you should be able to attract a lot more physicians to take part in the clinical trial. That would be the-
Yeah.
the wish that I'd look to see. No.
Yeah.
That's very helpful. Want to be able to jump over now to-
Yeah.
TN-401. Obviously, I said earlier that I think visibility and promise has really been increasing here based on your recent data releases.
Yeah.
Maybe you could start with a little introduction on what TN-401 is.
Yeah. TN-401 is going after the leading genetic cause of arrhythmogenic right ventricular cardiomyopathy, and this affects about 40% of those patients, and we estimate that to translate to roughly 70,000 patients in the U.S. alone. Like TN-201, this is an orphan, but it's a large indication. Again, I think investor and strategic interest is high here because we're not talking about ultra orphans. This is defined, the hallmark of the disease is electrical instability and different forms of arrhythmia with the potential of sudden cardiac arrest and death being a pretty significant source of morbidity in this condition. There's no approved pharmacological agents here. People are using generic medicines to try to manage the arrhythmia here. Nothing yet approved to address the underlying genetic cause. Of course, we're not alone in advancing a gene therapy. I know we'll talk about that.
That's TN-401 in a nutshell. It's an AAV9 gene therapy giving a full-length copy of the human gene into the hearts and with the intention of improving the electrical instability of these patients. So far, so good. The data release we just did really proved that we are achieving what we set out to achieve.
Oh, perfect. Great. Thanks for that intro. I will throw in some comments here as part of my question that will discuss the data, and of course, you will pepper in a little more data commentary.
Yeah.
Hopefully.
Yeah.
As you engage regulators, because this is very similar to TN-201 in the sense that there is a lot to look at.
With regard to the path of PKP2-associated ARVC, which endpoints are your favorites, and do you believe what you showed recently, the PVC burden signal of about 64% reduction?
Yeah.
is robust enough to-
Yeah.
serve the registrational endpoint?
Yeah. Let me, a couple of comments here. When we presented at ASGCT, we were pleased to have been accepted as a late breaker presentation, so it was a live presentation audience, very well-received data. We presented data for the first six patients that have been dosed with TN-401, and all six had meaningful improvements. That was the headline. Particularly in the hallmarks of electrophysiology or electrical instability, PVCs and NSVTs, we saw meaningful improvements in both for the patients who had elevated data at baseline. Safety, the product was well-tolerated at both doses. One thing that's different from TN-201 here, we do not deal with that. We are dealing with a single population that presents with high electrical instability. That simplifies the story a little bit in some ways. We are not dealing with a pediatric population or an obstructive rhythm.
It is all of these patients have high uncontrolled electrical instability despite standard of care medications and despite interventions like ablations. On that backdrop, we did this, bless you, we did this a single dose of TN-201. We saw, on average, a 60% reduction for dose cohort one, on average, a 67% reduction for dose cohort two, so the average of 64 that you were referring to. Individually, some patients had reductions of 30%, some patients had reductions of as high as 80%. This average of being in the 60%-67% range, yes, physicians would consider this clinically meaningful.
In fact, when we release the data, I'd invite anybody who's listening to this, if they have not already done so, look at the data release that the company did after ASGCT, where we included a KOL, a back and forth, a dialogue with one of our KOLs, Dr. Judith Sessy from the Mayo Clinic, and Dr. Whit Tingley, our Chief Medical Officer, had questions, covered the landscape, the unmet need, the patients, how they present, and also talked about objectively how do they look at these data. And he said, yes, I think if you're at a population level, you're getting above 50%, you are in clinically meaningful zone. We know from the literature and we know from modeling that there's a direct correlation of reduction of PVCs and NSVTs, which are frequent, and it's happening every day.
There's a direct correlation between achieving that and reducing the risk of rare but severe ventricular fibrillation events, including and up to leading to sudden cardiac arrest and death. So this effect that we're achieving here mathematically translates to lower risk of a much worse long-term bad outcome, like sudden cardiac arrest. Physicians recognize that, they know that, and so they've appreciated our data. I would also say that people have noticed that our data have been, so far to date, there are others in this space, the deepest and most consistent and most consistently deep reductions compared to others. All six patients had a reduction in PVCs, and of the two patients who had elevated NSVTs, they both came down.
To the best of my knowledge, with the data that's in the public domain, our other peers do not yet have the same kind of depth and consistency that we're showing in the improvements in electrical instability, so we're feeling good about both our efficacy and our safety data. And the KOLs are, too. Last point I'll make, like I said on 201, somebody did some market research and asked KOLs immediately after our data release, and very similar, we got very high marks from KOLs on the TN-401 performance to date. People showed high confidence in the data, and a high interest in participating in studies and prescribing if a product like that was available. So I think we're getting validation from the outside. It's not just we're drinking our own Kool-Aid, but we're getting validation from the outside.
No, absolutely. Data are everything.
Yes.
With that said, look, I am going to ask it this way because this is my job. Of course, it is your comfort level to which you would like to talk about the competition you were referring to.
Yeah.
Or competitors. Of course, this is Rocket and Lexeo.
Yeah.
Again, all with relatively small numbers of patients.
Yeah.
Do you view, and this could be an entirely separate scientific call, but differences with regard to the capsid, the construct, the dosing regimens, early safety profiles, where do you feel differentiation might exist?
Yeah. Look, all three companies are. The one thing that everybody is trying to do is use AAV to deliver a full-length copy of the human gene. That is where they are all similar. After that, there is a lot of differences, and how those differences translate to differences in results, I am not smart enough, and I do not think even the field is smart enough to know. We are using AAV9. Others are using other capsids like AAVrh10 and AAVrh74. We think AAV9 comes with the best validation from both a safety perspective as well as transduction of the heart. We like this, our selection of capsid. All three companies are using cardiac-specific promoters, but not all cardiac-specific promoters are created equal, so it is possible that that introduces some differences.
I believe two out of three of the companies, us and Lexeo Therapeutics, are using Sf9 as the manufacturing platform.
I believe Rocket Pharmaceuticals is using HEK. How does that translate to any differences in how the product is expressed, translated, whatever? Who knows? Doses, Lexeo Therapeutics and us, we are both in the two to three range for the first dose, and 6E13 for the high-dose cohort. Rocket Pharmaceuticals started at 8E13, and they are not escalating from there. The fact that we have good data and the most consistent and deep data at even 3E13 compared to what I think we have seen with other products at 6E13 or even 8E13, we like that. We like we are sitting there, that even at 3E13, we are getting better data than others are getting at higher doses. Which of the particular elements of the product or the manufacturing is contributing to that, we do not know. Is it just a law of small numbers? Too early to say.
We are not declaring success, but right now, early days, we are pleased with the data that we have on both efficacy and safety. Look, the competition is good for patients, and ultimately, there may be room for more than one product, right? I think it is too early to call winners or losers or best in class, first in class, but we like the position that we have with the safety and efficacy data that we have generated to date. Each company is engaging with the FDA, and maybe that will be a good. I did not answer your question earlier about endpoints, so we can go there next. We will have to see what each company is able to negotiate about a path to pivotal studies, both in terms of timing and endpoints and design. There may be some opportunities for differentiation there as well that will materialize.
We can talk about endpoints next, but I think that is my overall take on the competitive landscape today.
Yeah, no, look, someone else to do the heavy lifting for the regulatory standpoint is not always a bad thing.
Right.
I think it's an important question with regard to the delivery viruses and the promoters and what have you. Of course, you're bringing me back to my early days as a virologist.
Yep.
It's like you're having me geek out as well.
Yeah.
Maybe if you could comment on commentary, then we can link the both assets together with regard to internal operations.
Yeah. But commentary on what, sorry, specifically, Joe?
Oh, the endpoint.
Endpoint. Yes. Yeah. So look-
Yeah. Go for it.
I think you had asked us earlier what do we think is our preferred endpoint.
Right.
Each company may be doing something slightly differently, but we have generally said that we are supportive of all the things we are measuring, and we are measuring a lot of things. But all the things we are measuring, we think that PVCs, plus or minus NSVTs, but PVCs are a logical endpoint, and we say that objectively with KOL feedback. If you look at the papers, the papers generally emphasize PVCs as the predictor of when you need to get an ICD or predictor of long-term mortality. There are other factors as well, including NSVTs. There was recently a paper that came out that we were pleased to see, where several KOLs from around the world got together and wrote a paper and basically put their thumb on the scale of PVCs as a preferred endpoint in ARVC.
They were not talking specifically about PKP2, but they were talking about in the field of ARVC for a variety of reasons, PVCs may be the preferred endpoint. There was actually a former FDA leader on that paper as well. If any of your audience have not yet seen that paper, I would point to that as it is one thing for us to say we like our stuff or we like that endpoint. It is another thing when somebody on the outside says it. So I think that is good objective comparisons. Whatever the endpoint we select here, Joe, what I would say is one advantage that we have, and I think in terms of these discussions with the regulators, and making the case for a particular study design, is that we have the largest natural history study in the world. So we have something called RIDGE.
Our interventional study is called RIDGE-1. Our non-interventional or natural history study is called RIDGE. More than 185 patients at more than 20 sites in six countries. That is more than 2,500 patient years of data, including some retrospective data on these patients as well as we are prospectively following them. That is 185 patients we are actively following. That gives us an advantage in terms of, I think, patient recruitment, particularly once we get into pivotal studies, but also for these discussions about endpoints. What is a good endpoint for accelerated approval? What might be a good endpoint for full approval?
When you are dealing with endpoints like PVCs that are so highly variable, you kind of need to solve that with a large data set to help narrow in on the answer to these questions, and to be able to make statistical arguments about why a particular design, whether it is a single arm or external control or placebo controlled, there are very many different designs that are possible. The natural history gives us an advantage to help put the data and the statistics into perspective. I think in addition to the positive data and efficacy and the safety we have, we also like our natural history study to support the arguments we are going to make about endpoints with the FDA, and we have committed to give an update on that by the end of the year as well.
No, that is very helpful. For us, it is like what I alluded to earlier is I wanted to link both assets, TN-401 and TN-201.
Yeah
With regard to the important decision tree that you are going to have upcoming, and that is what is the gating step for a pivotal start, and how do you look to sequence the two, especially given their shared manufacturing and capital requirements?
Yeah. Well, look, first thing I would say, Joe, is I will complicate the question further. We have spent most of our time talking about TN-201 and TN-401, but as you may recall, one thing we introduced earlier this year is our TN-301 small molecule. With the time that we have allotted today, we cannot do a lot with that today here. That is a very exciting other asset that we've reintroduced to the world, already clinical stage, already completed a phase I, doing some phase II enabling work.
This is our highly specific HDAC6 inhibitor with broad clinical utility in everything from large cardiac indications like HFpEF to cardiac adjacencies like PHF, PF or PAH, to neuromuscular conditions like with cardiac and skeletal involvement like DMD or other muscular dystrophies. This is an incredible asset. It's a rare pipeline and a pill in industry. We've indicated that we're going to give an update on our plans for that asset in the second half of this year. Which indication, what design, what catalyst, moving it forward on our own or with a partner, I think all that to come.
So in a way, your question is we got to take an even bigger step back and say, what's the best way to move Tenaya forward from here? Recognizing that we have three clinical stage assets, TN-201, 401, which we've covered today, 301, which I just touched on. I think that's going to be the exciting part about the next couple of months between now and year-end, is that we do intend to paint a picture of this is where we've landed on regulatory alignment on the gene therapies. This is our desired plan on 301. What's the best allocation of capital for Tenaya going forward to maximize patient impact and shareholder value?
The answer may be let's go full bore on one, or let's go partial bore on three or two, or let's spread out on three, but then focus within a particular subpopulation so that we can manage the spend and burn. More to come on that front, Joe. Let's just say that we have high conviction in all three assets based on what we can see today. That's more to come. That would be a good problem to have if you have three clinical-stage assets and you're picking. You're not forced to back a particular asset because that's the only thing you've got, which unfortunately, some companies are in that position.
If we have three solid assets, then the ask is like, okay, we want to raise enough capital to do X and Y or X and Y and Z, or X and Y or X and Z, whatever it is, whatever that permutation is that makes the most sense for shareholder value and patient impact, that's what we'll be revealing or thinking by year-end. So stay tuned. Good reason for your audience if they haven't already done so, do some homework on all three clinical programs to meet us certainly after the conference, during the conference and after the conference, so that we can engage deeply in all three programs ahead of catalysts coming up in the second half of the year.
Absolutely. That is very helpful. Faraz, these commentary were extremely helpful for the listeners. Like you said, I urge everyone to really take a look at the data, take a look at the papers, get in contact with the company, me, or what have you, so we could help out and thanks again, and looking forward to the updates in the second half.
Yeah. Thanks a lot. I guess I would be remiss, my CFO would shoot me if I did not say, look, our cash position, we updated it with the last earnings release. We have cash through Q3 of 2027, so we are still sitting on more than a year of cash on hand. That puts us in a position to get to these catalysts and then engage with investors about how we are building the company from here. But factually, that is our cash runway and cash position as of their most recent earnings. So looking forward to seeing some of you at the ATW conference, either at the meeting or afterwards. Thank you, Joe, for the opportunity.
Great. Thank you, Faraz.