Okay everybody, thank you. Welcome to our next session for H.C. Wainwright's Genetics Medicines Company. My name is Joe Panginas, Managing Director of Biotech here at the firm. Very happy to have with us as our next presenter, Tenaya Therapeutics. Part of my fireside chat today will be with Faraz Ali, the Chief Executive Officer. Faraz, thank you very much for being here and I know we have a lot to talk about.
Glad to be here, Joe. Thanks for having us.
You bet. Obviously, you know of different aspects to your pipeline, but we're going to have the discussion revolve around your genetic medicine components. On top of that, you've been quite busy and the data have really begun to flow in earnest. Right off the bat, you have two assets, TN-201 for MYBPC3-positive HCM patients and TN-401 for PKP2-positive ARVC patients, both of which are AAV9-based vectors and already in the clinic. Of course, we can have a separate talk entirely based on my background as a virologist, just on your actual vectors and what have you. We'll stick to your assets today. First off, can you start by describing the profiles and the designs of both TN-201 and TN-401 and what their differentiating properties are?
Yeah. Great. Joe, it's great to have a virologist here and keep me honest too. TN-201, these are both AAV gene therapies as you mentioned. TN-201, the design is pretty straightforward. It's an AAV9 vector that's delivering a full-length copy, functioning copy of the human MYBPC3 gene and it's doing so with a cardiomyocyte-specific promoter. Just worth noting that that is actually an innovative cardiomyocyte-specific promoter that we designed for which we have IP because we had to do some optimization of the cassette to fit. MYBPC3 is a large gene, so it doesn't optimally fit in an AAV within a carrying capacity. We had to do some clever molecular design of the overall cassette as well as the specific promoter in order to make it fit and to make it express optimally. That's one of the sources of IP in terms of overall product differentiation.
Obviously, this is a distinct mechanism of action versus the current standard of care and versus current pipeline therapies, which I know we'll discuss later in the discussion here today. To our knowledge, the only therapy addressing the underlying genetic cause of HCM patients with this mutation. TN-401 designed very similar, also using AAV9, also using a full-length functional copy in this case of the human PKP2 gene and also using a cardiomyocyte-specific promoter, albeit it is worth noting that this one is a different cardiomyocyte-specific promoter versus the one we're using in TN-201. This gene is smaller. We did not have to do as much clever molecular engineering nor use of a novel promoter in order to make this fit optimally. Over here, I think again a distinct mechanism of action versus current standard of care.
This is actually addressing the underlying genetic cause, very different versus antiarrhythmic medications or ablations or ICDs. Both programs use AAV9 and I would argue that in both programs that is an important factor. AAV9, as we know by now, has got the largest safety database of any AAV in the world. It is the most well understood, it has been the most used commercially. Zolgensma has been commercialized in now more than 50 countries, more than 4,000 patients by Novartis and that's using high-dose AAV9 and that's been used successfully. We know a lot about this vector and we know a lot about its performance in the heart because of the good work of our friends and peers at Rocket Pharmaceuticals and their Danon disease program.
We know that it gives robust expression versus other capsids based on our preclinical models, both in vitro and in vivo in mice and NHPs. One perhaps manifestation of this is that we're operating in the clinic at lower doses compared to some of our peers. We really like the design of our products.
Absolutely. I think the engineering that you've gone through and accomplished is great credit to you and the team in the sense that a lot of AAV vectors are out there. You have to use two vectors based on the sizes of the genes and what have you. Kudos for that. With regard to 201, I just sort of want to start off with a profile type of question. HCM is an indication that has been growing with a lot of excitement around it based on the cardiomyosin inhibitors, pardon me, such as Camzyos and aficamten. I've been covering Cytokinetics essentially feels like forever now. They have a lot of successes coming up for them. Where does 201 fit here based on its population targeting, and how does that inform your next steps for the program before we get specific data?
Yeah, sure, Joe. Look, it's an exciting time for patients with HCM. We could not be happier for that patient population that was underserved and underrecognized, and there's a lot of disease severity here. It's great to see that they now have an increasing slew of options. So far, the CMIs, Camzyos, as you referred to, has been approved for the obstructive form of the disease, obstructive hypertrophic cardiomyopathy, but importantly not yet for non-obstructive hypertrophic cardiomyopathy. This is important because 70% of the patients that we are addressing with the leading genetic cause of hypertrophic cardiomyopathy, which is due to the MYBPC3 mutation, 70% of them have the non-obstructive phenotype. They cannot, they are not eligible for Camzyos, or as the only approved therapy right now. Importantly, Camzyos recently failed to hit the primary endpoint in their large study with the non-obstructive population.
We've said that, and it's to be what will happen with aficamten that I know you're covering. We will get some of that data, perhaps, fingers crossed, there next year, and certainly for patients, our fingers are crossed. I think that sort of highlights what we've said along non-obstructive is that it is, of course, part of the same family. There are some unique features of it, uniquely high severity that makes it harder for the approved medications, and they're not eligible for myectomies. It's a distinct population. TN-201, right. I mean, we think the mechanism of action is relevant for all phenotypes, the obstructive and non-obstructive form of disease, because it's the only therapy that's addressing the underlying genetic cause. As I mentioned earlier, it's the only therapy that is restoring the missing protein.
Of all the therapies that are out there being pursued today, it's the only therapy that could have a one-time durable impact compared to all of the other therapies. It's also important to just differentiate that due to its mechanism, it is not expected to negatively impact ejection fraction. That is one of the liabilities of Camzyos, is that it's got a black box warning because the mechanism can cause a reduction in EF that could be life-threatening. That is not something that's anticipated with this mechanism of action. Also, I'd argue that this is possibly the only therapy that would be able to address the very severe infant and pediatric patient population. We actually presented a poster about this population in the past, one last year from the Share registry.
Recently, we shared data at the European Society of Cardiology from our MyClimb natural history study, really capturing the burden of disease and the severe patient population. What we showed over there, I mean, the homozygous infants die within the first days, weeks, or months of life, and the homozygous and the compound heterozygous events who are severe, they experience life-threatening symptoms within the first five, six years of life. I think this is a situation where it is not clear whether a small molecule that is inhibiting the myosin head will do enough to address the very complex and severe and rapidly progressive presentation of the younger kids. What does that mean for this program? We continue to be excited about the possibility of this profile across the entire population, obstructive and non-obstructive adults and children.
I think as we generate more data and as the field progresses, we'll learn more and then be able to make more rational choices about where to focus development and where is the optimal early approval point for TN-201 and what life cycle management can look like over time. We're quite excited. It's a great time in the field, and I think there's a lot of good prospects for TN-201 in all populations.
That's a great setup. I really appreciate that. Obviously, that's a great segue to talking about data now because that's the biggest thing that you guys, investors and physicians, care about the most. You recently announced positive interim data from the ongoing MyPeak-1 study, which we thought is intriguing, exciting, and importantly, across multiple assessments, all of which we believe are beneficial to this patient group and the profile that you were just talking about. We even consider these patients in these early cohorts are younger and more severe compared to the average HCM patient, which you alluded to based on whether they're homozygous or heterozygous. With that in mind, what are the key highlights from the data that you shared earlier this year and what updates can we expect from the late breaker at AHA featuring the MyPeak-1 study? Sorry for the long lead in, but.
There might be an appropriately long response. Right. This is the meat of it. Right. Yeah, it's an exciting time, I said for the field. You're correct to point out the severity, the unique severity of these patients. We already knew from the literature that patients who present with these sarcomeric mutations like MYBPC3 present on average more severely than patients with a non-sarcomeric version. In fact, that's why often the literature segregates the sarcomere positive versus sarcomere negative patients, because these patients on average tend to be more severe. The first three patients that we recruited in the first dose cohort were very severe. You could even argue that their profile in oncology, we call them refractory. These patients have received standard of care medications. They were not eligible for a myosin inhibitor because they're all non-obstructive. They all received ICDs.
All three of them had myectomies, meaning they had open heart surgery to remove excess tissue to relieve the obstruction that they were experiencing. Despite that, they are presenting with severe and progressive disease with very large and very thick and hard elevated biomarkers and New York Heart Class 2 and 3. These are patients that have failed the best that modern medicine has to offer them today. They're coming in and for gene therapy, the very first patient, in fact, experienced everything I just described by the age of 27. That tells you something. Against that backdrop, we were quite excited by the data that we were able to present at the American Heart Association earlier this year. That data set, what we were able to show, safety and tolerability of TN-201 in the first dose cohort, which is a low dose 3E13 vector genome per kilogram per dose.
By the way, I say only low compared to some very ultra high doses in the E14 range. We're not in that range, but a dose that is predicted to be efficacious for preclinical models. We saw evidence from the biopsies of high transduction measured by vector copy number, of robust, durable and even increasing RNA expression, as well as evidence of protein increasing in parallel with the RNA increase from the first two patients. Two out of three of the patients saw an improvement, a significant improvement, in their cardiac troponin I, an important blood-based biomarker that got them close to or in the normal range. Two out of three of those patients saw a significant improvement in one or more measures of hypertrophy, and when I say significant, I'm generally saying greater than 10%.
All three patients had gone to New York Heart Class I, which means in practice that they do not have disease, that the cardiac disease is not affecting their daily living. That's quite exciting for the first dose cohort for these refractory patients and at an early time point. Not all of these patients have even hit the one year time point. That was the ACC data. What are we looking forward to with the AHA data? We're clearly looking for more supportive safety and tolerability data, this time from both dose cohorts. We fully enrolled the second dose cohort and already have DSMB clearance to proceed at either dose and in an expansion cohort. Excited to share more data on that because safety is all important. We unfortunately learned that the hard way for some programs over the course of this summer.
There will be additional biopsy data from both dose cohorts. Importantly, in the first dose cohort I mentioned some positive early biopsy data. However, we didn't have the benefit of a baseline biopsy. In the AHA presentation, this will be the first time that people will be able to see from at least one patient, the third patient in Cohort 1, what does their protein look like with the benefit of a baseline biopsy and then early data from some but not all patients in Cohort 2 of protein expression, with the benefit of the baseline biopsy. Is there a difference, is there a measurable difference between the first dose cohort and the second dose cohort with the benefit of baseline biopsy? Why is baseline biopsy important?
Because we are producing a protein that is indistinguishable from the endogenous protein, and you need the baseline in order to accurately quantify how much additional protein you're getting. Additional information that we're going to get that we're quite excited about is just additional supportive clinical data from the first dose cohort. Cohort 1, all three patients will be at least at the one year mark. You could argue this is the first time we're presenting full cohort data at the one year mark. We look forward to sharing. Where do we stand in terms of durability of the effect and any deepening of the effect, whether we're looking at the blood-based biomarkers like cardiac troponin I, looking at the measures of hypertrophy or your class? All three patients are at New York Heart Association Class 1, so they can't have a deeper effect. Is it durable?
I will remind you that in some of our peers, Rocket Pharmaceuticals and Lexeo Therapeutics, we see a benefit that seems to improve over time. We're beginning to get at a point where we can say the same about our program as time goes by, given that now all three patients are at the one-year time point. It's been an exciting year for us so far and we're really looking forward to this data release. I think it'll be an important one for the program.
Absolutely. You made me think of something too. Before I ask, I don't want to overstate this, but when you look at a lot of dose escalation studies, you are not just providing, oh, here's the first three patients and here's some anecdotal data. Like I said earlier, you looked at so many different things, whether it's the protein, the expressions, the physical characteristics, NYHA class reductions. You just did a lot there. Kudos to you again.
Yeah, it's worth pointing out. Thank you for that. I will just say that it's important to also note that this is being presented at the AHA. It's been selected as a late breaker on November 8th in the morning. It's going to be in the main tent, right? Not that there are tents anymore, but you know, the main platform this year is an important meeting at the AHA where it's also a joint meeting with the HCM Society. There's a particular focus on HCM data at this conference. We're super pleased that Dr. Melinda Tsai, who's the lead PI who dosed all three of the first three patients and who also presented our earlier data releases at ACC, has been invited to the main platform to present these data. It's an exciting unveiling for us on the TN-201 program with a defined date that investors can really.
That's fantastic. The thing that you mentioned, I'm hoping to get a little bit of a reminder from you because obviously this was a somewhat recent event. When you talk of the heterozygous patients and, you know, indistinguishable from the native protein, you know, that might be lower. What have you, the types of commentary or data that you had from a KOL that discussed how do you discern, you know, the two from each other and the potential benefits. Again, I highly recommend that those on the call right now go back and listen to Tenaya's KOL call.
Hopefully I appreciate the shout out and that because that's actually relevant. Even though we did that in the context of upcoming data presentation for TN-401 and we'll maybe refer to that there. The methods we described were first employed in the TN-201 program. Most gene therapy programs are dealing with homozygous populations where there is almost no protein, and so anything that you produce is often not only quantifiable, but actually more easily quantifiable and also easily visualized. You go from a background of nothing and then you could, with IHC, show something. We had to solve years ago the problem of what do you do when there's a lot of background protein, and now you're trying to quantify something that may not be as visual but you want to be robust in your methods.
The mass spec methods that we used on the TN-201 programs, I think that gives us a lot of confidence about our methods. It was first described by Dr. Mike Previs, who was on our call. One of the things we really show is that with using mass spec and by normalizing to another protein that's inside the cardiomyocytes, that leads to the most robust results. There was some great data that was presented there that showed that if you use other methods, you would not get an accurate picture of protein. We're using that success and applying that also to our TN-401 program, which I'll talk about in a second. I think this is important. I want to sweat the small stuff here for a second, Joe.
In a world where the FDA is granting the possibility of an accelerated approval based on a surrogate biomarker, and one of those surrogate biomarkers is protein, we better be robust about protein and how we do it. We have been. We like our methods. Those methods are different than some of our peers, as we'll talk about in the TN-401 program. We stand by our methods, which is why we did the KOL webinar, and yes, thank you for the plug. For anybody who's watching this, if they haven't had a chance to do so, they should look at that. Of course, it's also available on our website, as are the slides.
No, absolutely. I just think it's huge that you're addressing this now and not waiting for later stages where you could get potentially dinged for it.
Exactly. You nailed it. Thank you.
Let's just switch gears a little bit and talk about 401. Can you take a moment to describe PKP2-associated ARVC and the unmet medical need, and then we could talk about the clinical side of it?
Yeah, I mean, this is another severe cardiomyopathy. With TN-201, we were talking about the leading genetic cause of hypertrophic cardiomyopathy. With TN-401, we're talking about the leading genetic cause of arrhythmogenic cardiomyopathy. This is due to the PKP2 mutation that accounts for about 40% of all arrhythmogenic cardiomyopathy. Their estimates vary, but, you know, 50,000, 70,000 or more patients in the U.S., so it's an orphan, but a large orphan disease similar to TN-201. It's a severe, progressive disease leading to early morbidity or mortality. One of the hallmarks of the disease, of course, is the arrhythmia. That's what's in the name. One gruesome statistic that I like to share about this is that for about 25% of the patients, their first disease presentation is sudden cardiac arrest and sudden cardiac death. By the time you find out that you even have this disease, it's too late.
That really captures the problem. Very high unmet need. There's no approved therapy that addresses the underlying genetic cause. People use antiarrhythmic medications, they use ablations, they use ICDs, but nothing really is addressing the underlying genetic cause, which is, of course, leading to a loss of the PKP2 protein. There's a very significant impact on the quality of life of these patients due to exercise restrictions that they're asked to do, so that they don't exacerbate the underlying cause and they don't trigger more arrhythmia. There's also a lot of fear and anxiety associated with shocks, whether appropriate or inappropriate, among the patient population. It's a bad disease.
Absolutely. No, I appreciate that. Yeah, it is. Maybe we could translate a little bit. I mean, you have a nice preclinical data set, if you'd like to summarize that a little bit, especially how those data could translate. You have an ongoing Phase 1b called RIDGE-1 as you prepare to release first data from that trial.
Great. There's a very severe preclinical model that replicates many of the hallmarks of the human disease in terms of arrhythmia, fibrosis, enlargement of the heart, and early mortality. We've been able to demonstrate that after a single dose of our TN-401, we can prevent the arrhythmia and really normalize it. We can prevent the fibrosis, we can prevent that adverse cardiac remodeling and the enlargement, and there's a very high survival benefit. Quite a lot has been demonstrated both in our in vivo models and our in vitro models. We're able to show that the desmosomes, which is where this protein is located, are forming again, that they're firing properly. All of this data has been presented and published in a peer-reviewed journal. I'd refer to people there. It's a good carryover then to what our expectations are for the clinical program.
The first data release, we haven't announced exactly when it's happening, but it is happening in Q4.
You're not going to do it today?
I'm not going to pull out a surprise here, any joke, but of course this is an early data release from the first dose cohort. First and foremost, safety. That's, I think, par for the course for all of these studies. We already did announce that we got DSMB clearance for the first dose cohort and have already started dosing dose cohort 2. We'll provide a little bit more of a picture of safety. Obviously, early biopsy data to demonstrate how are we doing with transduction, RNA expression, and protein. Importantly, all patients over here do have baseline biopsies built in from the beginning, and we already referred to the robustness of our methods for measuring protein earlier in our dialogue. We haven't guided. Safety and biopsy data is really the focus of the data release. How are we doing? How are we doing compared to our peers?
Are we doing compared to other programs and protein? How are we doing relative to the normal range? I think those are the things to look for. We haven't guided to what else we might include now. We are not operating in a vacuum here, Joe. There are two other companies that have presented some data earlier this year, and they did choose to include selectively some data, e.g., pDCS, NSVT, and maybe other things. We're being thoughtful about what can we include here that might allow for some comparisons against the programs. Any comparison is going to be imperfect, partly because, as I mentioned, protein methods are different, partly because these are early data and the three companies are operating at different doses. I think there'll be enough data there to enable some early comparisons with other program and other data that have been released.
I think too early to call anything conclusively. My guess is that as these data mature into the first half of next year, as we also get data from a higher dose, we've been able to escalate, as I already mentioned, from 3.3e13 to 6e13. The picture will become more clear for investors across all three programs. Importantly, it's also probably important to set expectations of what not to expect. Unlike TN-201, where there are some other data points, some of those are not as relevant here. For example, you don't have a lot of elevation of blood-based biomarkers like we talked about cardiac troponin I in the context of, or maybe NT-proBNP in the context of ACM. Not relevant here. You don't really talk about the reversal of the hypertrophy in this population because any cardiomyopathy that you're seeing is progressing at a reasonably slow rate compared to HCM.
We don't have that to share. The vast majority of the patients are already at New York Heart Class 1, so there's not a we took a patient from New York Heart Class 3 to 2 that might happen. Rocket certainly showed that is possible. If they're already at New York Heart Class 1, which is the vast majority of the patients, then you don't really expect to see those kind of changes. It's important to set expectations of what we're going to provide, what does it make sense to provide, and the gray area where we might do a little bit more than our guidance just to meet the moment compared to some of our peers who have also released data early this year. Hopefully that helps.
No, it certainly does and it's understandable and I can understand that you're probably subject to a lot of external pressures too. Just leave it at that from where it might be coming from, you know, with regard to releasing more data than not. Up till this point the company has always been very temperate and thoughtful with regard to its data releases and you're not just going to necessarily rush to, you know, throwing out one that might not be interpretable by many. You want to, like you said, compare apples to apples to oranges. With that said, hugely looking forward to AHA for the next update for TN-201. I want to thank you for your time today. Very helpful comments and enjoy the rest of your day.
Thanks, Joe. Thanks for the opportunity. As always, investors who are watching this, we'd love to hear from them and they can reach out to us or to Michelle Corral, our VP of Corporate Communications. Set up some time to talk either in advance of these data releases or around the time immediately after. Thank you.