Welcome, and thanks for attending Canaccord Genuity's 43rd Annual Growth Conference. My name is Joohwan Kim, and I'm an associate on Whitney Ijem's Genetic Medicine and Rare Disease team. We're very excited to have the team from Tenaya Therapeutics here, and it's my great pleasure to introduce the Chief Financial and Business Officer, Leone Patterson. Tenaya Therapeutics is a clinical-stage company focused on developing, delivering, and curing the underlying genetic causes of heart disease. And so with that, I'll turn it over to the team for their presentation.
Thanks very much. Good morning, everybody. It's great to be here and super excited to present today about the progress that Tenaya has made. As a small company, we have made significant progress in the last 12 months, and the next 12 months ahead of us are even more compelling. We have three programs that are either in the clinic or heading into the clinic, and so for us, this is an exciting time for us and for our patients. There'll be some forward-looking statements that I make today, and these are disclaimers associated with them. At Tenaya, we aim to transform and extend lives through discovery, development, and delivery of potentially curative therapies targeting the underlying causes of heart disease. We have a very broad pipeline encompassing rare and prevalent indications, and we have integrated capabilities enabling discovery, development, and manufacturing of precision medicines.
The leadership expertise is fantastic at Tenaya. We have cardiologists, we have a gene therapy and rare disease experience as well, and our single focus is on heart disease, which is an important component when you think about the founders of this company and the vision that they had over six years ago, where they said, "Cardiovascular is a space that we need to solve for." And with that, that progress has been made since then, as I mentioned, three advancing programs, two in gene therapy, TN-201 and TN-401, and a small molecule program, TN-301. And on top of that, we also have additional programs that are in early stage development. So when you think about heart disease, we believe Tenaya is ideally positioned to lead the heart disease drug development revolution.
I'm sure everybody in this room probably has somebody they know who has heart disease. One in US deaths are attributable to heart disease, and it's a leading cause of death globally. Greater than 30% of heart disease risk is linked to genetics, which is the reason why Tenaya believes that precision medicine is the way of the future. In addition, clinical and regulatory validation for precision medicine approaches are increasing. We are modality agnostic drug discovery engine with programs that are in gene therapy, cellular regeneration, and precision medicine.
When you think about the spectrum of discovery across the various areas, we've got disease models, we have capsid engineering, we have promoters and regulatory elements, drug delivery, and also manufacturing is the last but most important piece that we've continued to build with now having our own GMP facility, which I will talk about next. We have in-house manufacturing capabilities that can scale from early research all the way through to clinical supply. You'll see on this slide here, our own GMP facility, which just over a year or so ago, was a warehouse, which was then developed into a GMP facility with capabilities of scaling up to 1,000 liters. So half the facility has been built out with clinical capabilities, and we have another half of the facility which we will build out upon the need for commercialization.
There's approximately 45 people that span across the early, so the process development, analytical development, quality, and control. And non-GMP through GMP productivity, and a very important piece for those of you who are familiar with gene therapy, how important analytical and assay development is to making sure that you have a process that you can measure and consistently produce product. And we continue to optimize efforts. We are using the platform of SF, SF9. There's obviously HEK293, and we look at both of those as we take programs forward into the clinic, which one we think is the best platform. So this is a very important part of Tenaya, is making sure that we have our own manufacturing within our control.
Now, going to the pipeline, as I mentioned earlier, just to see this in a format that shows the progress we've made. The first two programs, TN-201 and TN-401, are. One is right there, is close to being in the clinic very soon. We have an open IND for TN-201, for MYBPC3, a rare disease, but prevalent disease, and we'll talk more about that in a minute. But we have planned to dose the patient in this quarter, Q3. TN-401 is also a rare disease program, but prevalent disease at that, as a rare disease with PKP2 ARVC as the indication. And then there's also TN-301, which is a small molecule program for HFpEF, a very large indication with over three million patients potential.
When you look on the far right, you'll see that Tenaya's name is written next to all of these. These are all wholly owned programs for Tenaya, and we also have built these internally. These are all homegrown. So, talking about the earlier capabilities of the company, we certainly have the substance and development and ability to develop programs from the very start. So I'm gonna now talk about the gene therapy portfolio, TN-201 or TN-401. And when you think about gene therapy, its extensive and growing track record for AAV gene therapy and for the heart, we believe at this time is the best way for delivering. There's 20 years of experience now in the clinical programs, and 6 approved gene therapy utilizing AAV capsids, and over 250 ongoing or completed studies in AAV gene therapy.
Most importantly, over 5,500 patients have been treated across 40 countries. And it's important to bring that up because while gene therapy is still fairly early in its trajectory, we believe that that's still quite a bit of information that gives us data to believe that gene therapy can work as a modality. And when you think about one of those AAV9s in AAV programs is AAV9, and that's what we believe is well suited for our initial gene therapy candidates. Why? Because it has definitely a safety profile, with thousands of patients now dosed with AAV9. It's demonstrated tropism for the heart and has proven long-lasting transgene expression, which are very important pieces to remember as we now start going through our preclinical data and our programs and what we've seen so far ourselves in our own hands.
I pause here for a second because this is a patient who has MYBPC3 HCM, which I'm going to talk about shortly. Gabe is only eight years old, and while he may not be able to participate in our study, there are many other patients like him, behind him, or next to him that would benefit from the treatment that we can offer with our TN-201 program. So what is MYBPC3? It's a... Our program is a hypertrophic cardiomyopathy. It's the most common form of inherited cardiomyopathy. As I mentioned, over 115,000 patients in the U.S. alone. This is a global disease, so we're just giving you a, a metric that I think is important.
And when you think about rare disease programs, I think we talk about usually in the 10,000, 3,000, 5,000 patient populations, but this is 115,000 just in the US. And patients are in two categories, either obstructive or non-obstructive. But significant portion of the patients with MYBPC3 have non-obstructive, which is an important point I'll make, because when we run our first phase I study, which we're about to start, we will start with non-obstructive patients. The characteristics are thickening of the left ventricle, hypertrophy due to excessive contraction. The symptoms include shortness of breath, fainting, chest pain, fatigue, and then typical onset, early adulthood, but can begin at any age and progress variably. Younger onset are candidates with higher risk of mortality and morbidity, and the significant function impairment of the...
is a, is a function of the disease, and it can actually elevate risk of sudden cardiac death and heart failure. So for these patients, their choices are a heart transplant or they may die. And when you look at the different patients, whether they be the homogeneous or the heterogeneous patients, the homogeneous patients don't live beyond a year. And so while we'll hear about our clinical study in a minute, we'll start in adults, but we definitely want to be able to have the ability to get the pediatric patient population. I'll spend a few minutes on the mutation. Basically, it's mutations in the sarcomeric genes causing the HCM, where these patients actually have 60%-70% of the protein versus normal, and which results in the symptoms.
The loss-of-function mechanism of MYBPC3 results in lower levels of the myosin-binding protein, abnormal sarcomere function, and left ventricle hypertrophy and HCM. A gene replacement therapy, such as ours, is essential for these patients because of that. It provides a normal MYBPC gene copy to the cardiomyocytes. The transgene produces the MYBPC proteins needed to power normal heart function. If you think about that, it's like a lock-and-key gene therapy approach. Here's our preclinical evidence to support why we believe TN-201 will work for this patient population.
We have a single dose in a MYBPC3 knockout mouse model, which results in reduction in hypertrophy, durable improvement in cardiac function, and extended survival, which you can see from the three graphs on the bottom, starting with the heart mass, which reduces with a one injection, one dose, sorry, of TN-201, and heart function improves compared to the others. And then survival was basically obviously extended as well. Again, we like to have patients in all of our slides because it reminds us of what our goal is for this company, which is to treat patients who have the underlying disease. And here's another patient, Jason. And so what we're targeting is addressing underlying cause of the disease, disease-modifying therapy with durable response after a single dose.
It may halt and potentially reverse the disease progression, which is significant for these patients in terms of improving quality of life, and their only other option is a heart transplant. So let's look at the clinical trial that we're very excited to get started. This will be conducted as a phase 1b. It's an open-label, multicenter dose escalation and dose expansion study, and there will be two cohorts at this time. One cohort will be at 3 × 10^13. What's important about this, which I actually missed in the preclinical evidence, was that this is actually showing maximal efficacy at 3 × 10^13 in a knockout mouse model. So we expect with AAV9 that we should see same thing in a human.
We will dose up, though, to 6 × 10^13, because as, good drug development goes, you wanna make sure that you find the right dose that you will take forward into a phase III. In terms of the study objectives, safety and tolerability obviously key as a first-in-human study, but this is an open label study, so we will be able to measure other aspects of, endpoints, which I'll go through next. There is some eligibility criteria that includes, as I mentioned before, we will filter out and work on, focus on the non-obstructive HCM patients, and we also want patients symptomatic with New York Heart class 2 or 3, and, these patients need to have ICDs present, and we will also be screening for neutralizing antibodies.
So when it comes to the very exciting clinical study readout and data, we're anticipating, based on our enrollment plans, that we'll have data in 2024. And this really shows a schematic of how we might see those endpoints show up over time, and obviously, safety tolerability we'll see throughout. On the cardiac biopsies, we will be doing those at eight weeks and at 12 months, which should give us a really good signal into how much protein is being expressed or transduced in, into the heart. We'll also be looking at plasma biomarkers, echo parameters, exercise capacity, and obviously reported outcomes.
So we'll see this over the time period, and when it comes to data for 2024, clearly, we'll wanna have a good set of patient data in hand and a time course that will allow us to really provide some insights on what we think the success may be. But we will basically dose both doses, as I mentioned earlier, no matter what, because we believe for good drug development, you wanna find the right dose. So moving on now to our next gene therapy program, which is for PKP2 ARVC. This is a highly underdiagnosed cause of sudden cardiac death. The first symptom that may show up for patients who have this is sudden cardiac arrest, and this tends to happen in younger patients. We may have all heard about athletes who have suddenly had cardiac arrest.
Not all of them may have had PKP2, but there is a belief that certainly most of the times it's a genetic mutation that's missing for those patients. Again, this is a rare disease, but there's over 70,000 patients with PKP2 and ARVC in the US. alone, and nearly a quarter of those patients, of ARVC patients, present with sudden cardiac death. So basically, the progressive condition is distinguished by loss of cardiac muscle cells and replacement of fibrofatty tissue, and there are some of the patients will have symptoms that I mentioned. The first symptom may be sudden cardiac arrest. They're typically diagnosed before the age of 40, and they have exercise and physical exertion restrictions, life-threatening ventricular arrhythmias, and increased risk of sudden cardiac arrest. I can't even imagine living with that, knowing that every day that you may enter have in having cardiac arrest.
So there's a high unmet need here, which we believe a lock and key gene therapy, such as TN-401, will be huge for these, this patient population. And speaking of patients, this is a patient, Valerie. Valerie had earlier than this period... She's aged 28 now, but she was fairly young when she had her own event, where she has to be mindful every day of whether she's going to trip herself into position of cardiac arrest. And so just to cover on the target profile, address underlying cause of disease, disease-modifying therapy with durable response, with a single dose, just to bring that home again, a single dose of TN-401 may change the life of Valerie and other patients just like her. We are very excited about this program as well.
It's using AAV9, same capsid as TN-201, and we hope to have an IND filed in the second half of this year. We certainly learned a lot in the process of TN-201 IND, which we expect will pay off as we enter into the IND phase for 401 with the FDA. Why? Because we're using the same capsid. Two, because the manufacturing process is very similar, and we have a GMP manufacturing now up and running with many more dose batches under our belt, having now produced for TN-201 and TN-401. So we're well on track in our minds to have an open IND in the second half of this year. Moving on.
So looking at more into PKP2 and the proteins required for cardiac muscle, well, required to work together, and you can see here that TN-401 is designed to deliver fully functioning PKP2 gene, and basically, it's required to maintain structural. The PKP2 protein is required to maintain structural integrity of desmosomes. So what happens is, when the mutation exists, it disrupts the desmosomes and negative impact on gap junctions, ion channels, and signaling. Arrhythmias may occur and increased electrical instability. So our preclinical data sets so far have a few slides here, and I'll cover them. Basically, a low dose of AAV9 gene therapy restores protein levels in vivo, and again, this is similar doses to TN-201. This is at 3E13 vg/kg and achieves normal level, levels of desmoplakin protein expression.
Second set of preclinical evidence that we have is in a single dose in a cardiac-specific PKP2 knockout mouse model reverses the hallmarks of the disease, whether it be the arrhythmias or right ventricle enlargement, and also survival. So again, we believe a strong preclinical model allows us to have confidence as we head into the clinic. Third program, small company here, onto my third clinical program. TN-301 is a small molecule HDAC inhibitor, and what are we trying to address? Heart failure with preserved ejection fraction. Large unmet need in heart disease, and there are over 13 million patients with HFpEF. Characteristics include occurs when part of the heart stiffens and loses its ability to relax and fill normally. So HDAC6 inhibition normalizes several biological hallmarks of HFpEF pathophysiology, including risks associated with diabetes, obesity, aging, kidney disease, hypertension.
The inhibition shows evidence of direct and systemic effects on the heart in models of HFpEF. Preclinical evidence shows that we have direct and systemic improvements in key features of disease, with direct impact on the left ventricle function and also systemic effects on key pathophysiological areas, which you'll see from the diagrams here. In addition, we have tested TN-301 versus SGLT2 inhibitors and really shown that we have comparability in efficacy and superior activity. So we have now, the TN-301, we've actually completed our phase I for this program. It's a healthy volunteer study. There were two stages. There was a SAD, Single Ascending Dose stage, and then a MAD, Multiple Ascending Dose phase. We've completed that study, and we're now in the process of pulling the data together, and we'll present data at HFSA in October.
What have we said so far about this program and the clinical results? It's well-tolerated, and we've also seen target engagement. So when we present in our at HFSA, we'll have the data to support that. So to close in, to close up on my presentation, we are well positioned to deliver in 2023, with milestones, many milestones, and going into 2024. So far in execution on TN-201, we received IND clearance, we have Fast Track designation, and we are going to begin dosing patients in this quarter. For TN-401, as I mentioned, we plan to submit an IND in the second half of this year, and the ongoing production of the materials is being made, and also we have some global interventional studies that are starting.
TN-301, as I mentioned, we've run a phase I, we've completed that study, and we'll have results at HFSA. Lastly, I will say is that our cash position, we're well positioned with $174 million and planned operations sufficiently funded into the first half of 2025. Thank you.
Great presentation.
Thank you.
At this time, I'd like to open up the floor for any questions, and [inaudible]
So I just want to introduce Whit Tingley, who's our cardiologist on board. So if there's anybody who has any specific questions around the programs or the disease, he can certainly provide much more insights than I can provide.
I will start first. With regards to the PKP2 landscape, I think there's currently several different companies working on that area with AAVs. Can we get your take on the differentiator of Tenaya and kind of, I guess, also the state of the overall genetic landscape for PKP2?
Great question. So I'll start, and I'll hand it over to Whit as well. Look, we believe... Why do we believe in our program? I'll just start there. AAV9, as I mentioned in my presentation, dosed a significant number of patients, shown a safety and tolerability at actually at the doses we're at, much lower than the doses that have been used in previous studies. And also from the standpoint of tropism, we believe that AAV9 has that capability. In terms of one thing I would say is that it's not who starts first, who finishes first, and I think one piece to remember is from a manufacturing perspective, that Tenaya has really done a lot of work to make sure the manufacturing process that we have can be used all the way through to BLA approval.
So we've locked in that process at a scale of 1,000 liters, which is not to speak about other programs, but just to talk about ours, is a really important part of making sure you can get to the finish line first with no disruptions from your manufacturing process.
Yeah, we think that it's terrific for these patients that have had no options, that there is interest and competition, but we are very confident that our molecule will prove to be the best in class. The first thing we built when we were founded six years ago was a strong research group. That's why our whole portfolio is homegrown. We learned early on that every element of gene therapy can be optimized, choosing the right capsid and the right elements in the DNA sequence, including the precise sequence of the gene, the promoter complex, and other regulatory elements. All those and then manufacturability is another key component when you're designing the gene therapy. In both our gene therapy programs, TN-201 and TN-401, we have optimized all these elements.
We've compared head-to-head different versions, tested them in animal models for efficacy and tolerability, and that gives us confidence that we will have the best-in-class molecule.
One more question regarding strategy. Are you looking to potentially partner any of these programs in the future, or [inaudibe] ?
Yeah. Thank you. Yeah. Certainly, there's a lot of interest in all of our programs, as you can imagine, as they're entering the clinic. And I would just say that's probably the main point. The second point is that TN-301, as you saw, was three million patients potentially that you could affect, and the drug development for that program is, this is for HFpEF, can be challenging to do that on your own as a small company. So that one probably lends itself the best for finding a strategic partner at some point in the drug development future for that program. And there is a lot of interest, like I said, in all of the programs.