Good morning and welcome to the morning, well, I guess the last morning session.
Last morning.
Oh, you're going to break my heart, Faraz. Last morning session of the 2025 Global Healthcare Conference here in Miami, Leerink Partners. I am Mani Foroohar, Senior Analyst at Genetic Medicines , and I'm hosting this session. Faraz Ali, CEO of Tenaya Therapeutics. Faraz, welcome to Miami.
Yeah, thanks for having us here. It's my first time, hopefully not the last.
We can move the whole company down here if you like.
Yeah.
Not that I have any bias whatsoever.
None.
I assume you have a quick forward-looking statement you want to do before we dive on in.
Oh, we're a publicly traded company and forward-looking statements are on our corporate deck and then on the website.
Perfect. Let's dive into the balance sheet. You guys completed a recent transaction.
Thank you to Leerink for who our lead on that transaction.
I'm sure my counterparts on the other side appreciate it. I will say that this has been a tough, tough market across all equities, but especially for genetic medicines. Talk to me a little bit about where we are now in terms of balance sheet strength, runway, and align upcoming clinical catalysts with the updated cash runway.
Yeah. That is a great place to start. I will maybe first address the market sentiment and then the practicalities of the cash and cash runway and what catalysts we get with that, because we have a lot to look forward to. Tenaya is at a really pivotal stage in our development, and the cash we just raised really allows us to get to meaningful catalysts. Look, the market is the market. Cannot do anything about that. We cannot control the macro, but I think you just have to navigate that. Things may get worse before they get better. Genetic medicines, I think we are in a world of investors want to see just more clinical data.
I think there's a positive to this, which is that we are seeing that with a handful of patients across multiple modalities, whether it's gene editing or gene therapy, that you can get meaningful clinical data pretty early on. It may take a while to recruit those patients, sentinel dosing and the like with genetic therapy studies, but once you get there, there's pretty meaningful data. I think one thing that's been really positive that we've liked to see is that it's never been a better time from a regulatory perspective to be in genetic medicines, because they've really, I feel, bent over backwards to try to take that early positive data and convert that into alignment on possible pivotal studies. In our field, our two most well-known peers are Rocket Pharmaceuticals, who have AAV gene therapy for Danon disease and other cardiomyopathy, and Lexeo for Friedreich's ataxia.
On the regulatory side, they've shown that with a modicum of data, 5-10 patients at 1-2 year marks, that was enough in both cases for them to say that you can not only move towards pivotal studies, but move towards pivotal studies with the possibility of an accelerated approval based on a surrogate endpoint, which has previously been unheard of. It has been more a feature on the oncology side, but accelerated approval with surrogate biomarkers on the genetic therapy side has been less common. Now, not only Rocket and Lexeo, but across a range of different parties, PTC, REGENXBIO, Sangamo, and others, there has been that possibility that a small number of patients, compared to a natural history and with surrogate endpoints, could lead to full approval or approval with surrogate endpoints. It is a positive time for genetic medicines.
The markets will, I think, eventually reward these once we get past the jitters of some of their early commercial launches, as well as as we have some of these clinical successes turning into approvals. For Tenaya specifically now, we are super excited to have done this raise that, based on our recently announced earnings, that gives us a total cash of roughly more than $100 million. The use of proceeds of this raise is very, very clear. The raise gets us to important catalysts over the next 12-15 months. Where we are today, we're actively dosing in our TN-201 gene therapy study and our TN-401 gene therapy study. Where we're getting to, this is going to be a data-rich year to 18 months. TN-201, we're going to continue providing more data in the first half of this year.
In fact, we've been accepted for a late-breaker ACC presentation in March. We will provide incremental data on TN-201 and more in the second half of the year, TN-201, as well as not only dose cohort one, but early dose cohort two data. That is exciting. In the first half of next year, where we would like to be, is full cohorts of data for dose cohort one and dose cohort two at one to two year time points. That is a nice mature data point data set that we think that quantum of clinical data could lead us to a discussion with the regulators about potential pivotal studies in TN-201, either in the adult population or the severe pediatric population. That proceeds gets us to the point where we can generate that data that we were previously not able to do without the proceeds of this financing.
On TN-401, we're just one step behind. We're on track with dosing our first dose cohort and presenting data in the second half of this year from the first dose cohort. By the first half of next year, we'll have full dose cohort data for dose cohort one and for dose cohort two, early clinical data there. Really where we're going to, into the first half of next year, full dose cohorts on TN-201 and TN-401 at 1- 2-year time points. In gene therapy, I think that's become almost entry stakes for unless you have some biomarkers that are absolutely clear and well validated, like maybe in DMD, I think that's entry stakes in gene therapy to have full dose cohort data at sort of these mature time points. We're very excited about it, and the financing allows us to get there.
That's helpful. I'm going to take none of that bait on DMD regulatory pathways. Let's talk about hypertrophic cardiomyopathy, MYBPC3. We had a KOL event earlier at this conference, a fairly rich debate on how early data—and by early, I mean potentially preclinical large animal model, first couple of humans—can accelerate enrollment and how it's a little bit tougher when you don't have that in hand in indications where gene therapy is a little less understood by physicians. HCM is one of those. This is a frontier market for gene therapy, certainly in adults. In children, perhaps one could look at Danon disease and say that's a little bit different. Rocket would be the frontier company there if you go roll back two years.
Talk to me about how you think about the impact on enrollment and sort of physician receptivity to enroll larger pools of patients, or perhaps enroll patients more quickly, with a little bit more human data for the follow-up, early functional data. If there's a rationale to go back to produce some more preclinical data or disclose more preclinical data from the cat model, how do you think about the role of what are certainly nowhere near registrational data sets, but are those that can influence and potentially expand the interest and demand on the enrollment side?
Okay. Let me first take a step back and just say, just a reminder for those either in the room or on the webcast. TN-201, going after the leading genetic cause of hypertrophic cardiomyopathy, which is due to the MYBPC3 mutation, accounts for about 20% of all patients. That translates to a healthy epidemiology of more than 120,000 patients in the US alone. I say that because this is not an ultra-orphan by any stretch of the imagination, which, as you know, is where early gene therapies went. Now you see more people going into larger indications, and I think that's where the strategic interest is as well. There is high strategic interest in this program, partly because of its epidemiology and partly because of the unmet need. There is a lot of disease severity throughout the spectrum.
We can talk about that in a second, both in the adults as well as the severe pediatrics. That is a program people are characterized by the enlargement of a heart, fibrosis, arrhythmia, risk of sudden cardiac arrest, atrial fibrillation, need for myectomies, transplantation, and death. It is a pretty bad disease. There is no therapy out there that addresses the underlying genetic cause of this disease, which we think is what TN-201 has the potential to do. Our preclinical data set is outstanding. In our corporate deck, we have one slide where we show reduction of heart mass, we show improvement in heart function, and improvement in survival.
That is like the tip of a very tall pyramid of preclinical data that we have generated in a high bar, very severe in vivo model, as well as in our engineered heart tissue models to show contractility and improvement in other things.
I do not think, though, there is more to be done in terms of presenting that data. I actually think right now all attention is firmly focused on the clinical data that we are generating, and physician and patient interest will be moved by that. For patients, particularly, the early thing that they have been looking for was safety. That is why we made an announcement all the way back in October about the completion of the first dose cohort. That was a signal that we heard and sensed that the community was looking for. It is like, you have dosed three patients, it has been a while, we have not heard anything, we need to hear something.
We shared that data, we shared that update in October, and then in the TN-201 data release in December, being able to say that the early profile is well tolerated for TN-201 patients, no patients had discontinued the study, any events seen were consistent with what has been seen with other gene therapies, mild, moderate, reversible. We were quite pleased with that safety profile. I think the patient interest has certainly followed. We have certainly seen an uptick in patients coming forward. In fact, we have a mini pipeline of patients. I think the real driver of enrollment has been we're still in a sentinel period.
The sentinel period for gene therapy dosing, you dose, you pause, collect data for a month, you go to the DSMB, you get permission to dose the next one, and you've got to do that three times to get the clearance for the DSMB, which we did for TN-201 before you can get the dose cohort two. We're quite pleased. We announced, I think in our last earnings, that we have already dosed two out of three patients in the high dose cohort. Third is scheduled.
We're on track to meet our guidance to dose the second dose cohort in the second half and the first half of this year, which is partly why I can say with some confidence that in the first half of next year, we'll have full cohort data for the high dose cohort by the first half of next year because we're on track to enroll that dose cohort in the first half. We're very pleased with where we are with dosing now. Sentinel dosing is sentinel dosing, but we're getting through it. The data sets will follow. Patient interest is high. Physician interest is high. I think there's no risk. We've certainly, I think, more than 100 patients enrolled in our serostatus study, which was a marker of interest, I think, in the study just to measure neutralizing antibodies in the blood.
We've had more than 220 children, pediatric patients, enrolled in our natural history study, including more than 40 prospective patients. The interest in the program is real. It's palpable. We just can't wait to generate more and more data that will continue to build on the early momentum.
That's helpful. I'm going to hop down the pipeline slide to PKP2. This is a place where all the frontier players in genetic therapies for severe cardiac disease are obviously pursuing what is a very large market. Another very large epidemiology, somewhat heterogeneous patient population, but one where a lot of patients have interrogatable implantable devices. Talk to us about where we are in terms of what an initial data set in PKP2 will look like for you guys. How should we think about the goalposts on what's a good signal versus what's the underlying noise because these patients are not entirely without heterogeneity?
Yeah. I'm going to take a step back and then to take a step forward because one thing that's true in both programs, we didn't really talk about the clinical data on the first program, but what is true in both programs early on is that you want safety. I just referenced that safety profile for TN-201 being positive. That's also what we're looking forward to on TN-401 when we present our initial data release. In some cases, as we say, no news is good news on the safety side. Safety is important. In both of these studies, 201 and 401, we're collecting biopsies. Those biopsies give you measures of cardiac transduction, RNA expression, and protein expression. We're quite pleased with what we got in our early TN-201 data that was part of the data release that we did in December that we'll build on.
Evidence of high vector copy number using AAV9, which we think is a best-in-class capsid still for cardiac, high detectable measurement of RNA, and evidence of protein increase from 8 weeks - 52 in the first evaluable patient in 201. Similarly, on 401, that's what we're looking for in terms of early data biopsy data. Same capsid, so we hope to also see robust transduction of the heart, evidence of RNA increase, and evidence of protein increase. What the exact levels are, what's the exact level we need to be for clinical benefit, I think that is what these studies are going to elucidate. Both of those studies are looking for those things similarly, safety and good biopsy data. Clinically, obviously, we're looking for slightly different things. That's HCM from 201. We're looking for measures of heart thickening coming down.
Whereas in TN-401, we're looking for signs of improvement in arrhythmia. TN-401 is going after the leading genetic cause of arrhythmogenic cardiomyopathy, another severe disease. One gruesome statistic is that for a quarter of the patients, the first presentation is sudden cardiac death. It is a pretty bad disease. ICDs are used to prevent that risk of sudden cardiac arrest. ICDs are doing nothing to address the underlying genetic cause. Nothing. Their hearts continue to progress. You've just put on a patch to prevent them, which is important to prevent them from experiencing a sudden cardiac death event. They're exercise restricted. Their quality of life is terrible. They live in fear of these shocks that are going to come at them that, again, isn't being addressed because there's nothing addressing the underlying genetic cause. What are we looking for in TN-401 that's different from TN-201?
201, we're looking for that shrinking of the heart, that improvement in the LVMI. In 401, we're looking for those early signs of arrhythmia getting addressed. Now, there's a full spectrum of things that we're measuring in this study. Some of the early markers, the PD markers we might be getting are things like improvement in premature ventricular contractions or PVCs or non-sustained ventricular tachycardias or NSVTs. Those are things that we can measure using a Holter. Those are predictors of the likelihood of experiencing a ventricular tachycardia event that would lead to the ICD going off and shocking the patients.
Early signals, in addition to safety and protein, is seeing that improvement in those PD markers like PVCs and NSVTs, which we hope will be predictive of a reduction in the number of shocks that these patients experience and therefore also an improvement in their quality of life. Those are the early possibilities, I think, for probably all three companies involved in terms of what we'd be looking for in the gene therapy programs.
Let's talk about exactly those specific data points in terms of shock frequency. As you mentioned, there's a lot you can look at below a shock, obviously. You can interrogate the data from someone's implantable device at a much greater granularity than were they shocked. Below shock frequency, what is the frequency of PVCs? How sensitive is that as a metric that you can follow in a relatively brief period to show impact?
That's a great question. I think, again, this is one of those the study will, all three studies will elucidate some of the answers to those questions. We do know that the entry stakes is these patients are experiencing, literally, in some cases, thousands of PVCs a day. That is actually quite a high dynamic range and is elevated. I think that there's definitely potential to see that go down. You're correct. In addition to the periodic Holter monitoring from the ICDs, we can be interrogating all the things leading up to a shock, which includes the VT, so the ventricular tachycardia and those events that lead to eventually a shock. There's a lot that we can measure in this study. We're doing that. We're doing everything that we need to do there. Exactly how much this can change, shocks are very episodic.
PVCs are daily. VTs somewhere in between, certainly subclinical VTs. I think there's a full spectrum of data we'll generate. How fast that will resolve, that's what I mean by that will be elucidated by the study. We have seen in a small molecule study that was done with a generic molecule called flecainide that they actually were able to demonstrate some improvement in these electrophysiological parameters in a relatively short period of time. In gene therapy, we know that's a different mechanism. You're adding the gene of interest. It takes time to express. The fact that a small molecule was able to address and improve some of these electrophysiological parameters gives us that proof that you can achieve this, I think, especially if you're addressing the underlying genetic cause. Important to mention our natural history study.
We have enrolled more than 100 patients in our natural history study. I think it's the biggest natural history study for this specific mutation by far of anything in the world, either in any other company or academia. That's where we'll also be able to start drawing these correlations between PVCs and those PD markers like PVCs and NSVTs, VT, shocks, quality of life. We are gathering both retrospective and prospective data on these more than 100 patients. We are on track to enroll even more. That will actually support our discussions both internally as with regulators about what our approval, what should be the approval endpoint in this study, and what might serve as a surrogate marker for full clinical benefit in this indication because we are blazing a trail here. There is no regulatory precedent for an approval in this particular indication.
The natural history data, I think, is a very powerful tool in that regards, combined with whatever we generate from their early gene therapy study.
I think the other dynamic that I get a lot of questions from investors on this topic, and this is an indication where more and more investors are doing real work. We're going to get a lot of data from a lot of different companies. Let's talk about what the epidemiology looks like. The absolute number is quite large. The severity is certainly, and the stakes are certainly high. Let's talk about the universe of patients from a genotypic perspective and then how that translates to a range of phenotypes because this is not a perfectly penetrant disease. The market is a little more complicated than some other genetic cardiomyopathies.
Yeah. You know, I mean, I think every genetic cardiomyopathy, in fact, every genetic disease, I've been in this space for a quarter of a century now. It sounds crazy when you say it that way. So I've always seen I'm used to seeing pretty wide phenotypic heterogeneity even when you're talking about a single gene mutation. And that's no different for these cardiomyopathies and no different for PKP2. We say that our estimate is that there are more than 70,000 patients in the US alone. So it's a large indication, less than TN-201, but still not ultra-orphan, large indication. Our peers have put out other estimates, but all of them put it in that same category of tens of thousands of patients in the US alone and not an ultra-orphan, but a large orphan opportunity. The penetrance is I think this will also be elucidated more with time.
One is I think that there's probably a lot of underdiagnosis. When I gave that gruesome statistic of 25% of the patients, their first presentation of sudden cardiac death, those are clearly objectively severe patients who were not diagnosed in time. I think there's a high rate of underdiagnosis, including very severe patients because you are not capturing not every patient who suffers a sudden cardiac arrest is getting what "a genetic autopsy." Some of the most severe patients by definition are actually underrepresented in our epidemiological estimates. As genetic testing improves, we'll get a better sense of that. There are other patients who may have a lower arrhythmia burden, but their hearts are still progressing. They have fibro-fatty replacement, RV enlargement. They are progressing towards heart failure.
That segmentation of the population, I think you're absolutely correct in pointing out that that is less well understood. I think the combination of our natural history study efforts as well as what we learned through this gene therapy study, RIDGE study that we're running right now, and our peers are running as well, I think we'll learn a lot about both the epidemiology, the patient segmentation, and the role for gene therapy.
Let's hit that last point, which I know I'm going to sort of call upon some speculation, which I know is very dangerous. When we think about the role of gene therapy, where you have a very clear genotype that's common, and on a population scale, it certainly carries tremendously elevated risk. The individual patient risk is kind of somewhat complicated. By the time you know the individual patient's risk is, that's potentially an obituary before you know what you're doing. Talking about the right patients for a gene therapy approach in this phenotypically severe, genotypically clear, but unclear penetrance market, I know I'm beating a dead horse. Who is the right ultimate patient? What does that mean from a commercial standpoint?
First, I think one thing that is true not only for this indication, but I think gene therapy for any cardiomyopathy is that you don't want to treat patients too late, meaning that their heart has progressed to a point where there's so much underlying fibrosis. That's true on TN-201, the hypertrophic cardiomyopathy side, as well as on this side as well. You don't want to treat patients when they're so far progressed in their fibrosis. In the case of PKP2, fibro-fatty replacement, that gene therapy isn't going to have a sufficient effect. We were selecting for that in different ways to avoid recruiting those kind of patients. I think that's actually a minority of the population, but this is part of the work that we need to do.
Let's just start with the you need to catch them and treat them before they get to that point. You do need to have some evidence of arrhythmia because you just can't, it's not a penetrant enough disease. You just can't say, I have the genetic diagnosis, therefore I should get gene therapy. There's got to be some evidence that you not only have the mutation, but because of the incomplete penetrance, that it's actually leading to early signs of arrhythmia. That's where that sort of drawing that picture of PVCs and NSVTs, which are subclinical, but connecting that to clinical endpoints will help us make that decision better.
Look, I think there's going to be, commercially speaking, if we can prove that with gene therapy that we can really address the underlying cause, decrease NSVTs, decrease PVCs, prevent shocks, and improve the quality of life of these patients, including the removal of their exercise restrictions that they have to do even with the ICDs. It's not impossible to imagine a world where in the future you get a diagnosis, you're being monitored, and at some point there's a decision about, depending on your progression, other risk factors that we've come to understand, family history that you say, should this patient go first directly to an ICD, or should we first try out gene therapy and prevent the formation of the things for which eventually an ICD would be recommended?
Right now, the default is we're just going to slap an ICD on you because we want to prevent sudden cardiac arrest. What if we can show through our clinical studies that we have halted the VTs and halted the and there's no firing of the ICDs? You could start to make the argument that this could be first line. We're not there. We're not certainly trying to accomplish that in these studies. 100% of the patients will have ICDs in these studies. I do envision a future where we generate enough data that you can make a conscious choice about gene therapy versus pacemaker or pacemaker first, but still gene therapy because you still need to prevent the underlying progressive nature of the disease, which is going to cause fibrosis and possibly future heart transplant.
We spent a lot of time on one of the two more advanced gene therapy programs, but I do not want to ignore HFpEF. Talk to me about how we should think about the strategic value of that asset, how that end market has evolved, by which we mean end market for assets as well as the actual end market for therapies, and how we should think about the value of that asset as realistically most likely a partnered asset.
Yeah. The one thing you didn't do is name the asset. The asset that shall not be named, TN-301. TN-301, small molecule. Tenaya is modality agnostic. We pursue modality agnostic drug discovery. Early portfolio includes gene therapy, gene editing, silencing. Of course, this clinical stage small molecule asset, TN-301, that is originally developed for HFpEF, large indication, more than 3 million patients in the US alone. Very attractive opportunity. Outstanding preclinical data set, including head-to-head comparisons in a relevant animal model with SGLT2 inhibitors, were as good as SGLT2 inhibitors, which are clinically approved in HFpEF and even have added benefit on top of SGLT2 inhibitors in our preclinical model. A really, really outstanding data set preclinically that suggests that this could be a meaningful addition in the HFpEF population. A very, very nice clean safety study, healthy human volunteers, 72 patients.
We went as high in our dosing as we wanted to in our SAD and MAD study, evidence of target engagement, evidence of once daily dosing. What are we doing with that program? We have paused to explore partnership opportunities. I would say that the big takeaway right now is that we need to think about the opportunities for TN-301 in HFpEF and outside of HFpEF. The interest in this target has grown. We have had three strategic biopharma companies make investments in the HDAC6 inhibition space. Novartis did a deal with CKD, and Eli Lilly and Novo Nordisk have both made investments in early stage companies for a range of different indications. We have been singing from the rooftops about this might be a pipeline in a pill with a lot of different opportunities.
HFrEF is certainly one of those opportunities, large indication, deserving of a large partner to go after that. There are also other subpopulations of patients, including severe orphan indications, where we think TN-301 HDAC6 inhibition could be valuable. We are exploring that partnership space and potential to actually not just give up the molecule in its entirety, but potentially to co-develop in some of those severe indications. The proof of principle preclinically for HDAC6 inhibition has been demonstrated in heart disease and CNS and pulmonary indications, cardiorenal, even in DMD. There is now actually an approved therapy called Duvyzat, which is a pan-HDAC inhibitor that was approved last year in Duchenne muscular dystrophy. This is a severe, rapidly progressive genetic disease for which most people just think that silencing or gene editing or gene therapy is the only approach.
Here you have a small molecule pan-HDAC inhibitor that got approved based on full clinical benefit in a population that provided the proof of mechanism for HDAC6 inhibition because of its anti-inflammatory and anti-fibrotic effects, which is exactly what we've demonstrated in our HFpEF work. We think that the story is only getting better. Now we just need to figure out the right way to monetize it and advance it. That is what we're doing right now. Right now, I would say with the limited capital that we have, enough to fund TN-201 and TN-401 to important value inflection points. That will remain our focus for the remainder of this year and into next year.
Even as we explore opportunities to advance what we think is a very compelling and undervalued small molecule in our portfolio that can either generate value on its own if we can fully monetize it or in collaboration with a partner to move it to the next logical step, which would be a phase IB and then a phase IIA.
Great. I am getting the we're over time.
Thank you.
Thank you so much for this time. I am looking forward to seeing that data throughout this year.
Yep. Great. Thanks for having us today.
Thanks, Faraz.
Bye.