All righty, I think we're gonna go ahead and get started. Thank you all for joining us in the room and online for the 44th Annual TD Cowen Healthcare Conference. I'm Joe Thome, one of the Senior Biotech Analyst here on the team at TD Cowen, and I'm joined by my colleague, Anvita Gupta, and also three participants on our Genetic Medicines panel. We have Gaurav Shah, the CEO of Rocket Pharmaceuticals, Faraz Ali, CEO of Tenaya Therapeutics, and Matt Kapusta, CEO of uniQure. So thank you all for joining us. Maybe just to start things off, we're gonna start with a few thematic questions and then kinda dive into some company-specific questions.
But obviously, a lot of chatter at the FDA on kind of maybe increased flexibility of gene therapy approaches, wanting to get more gene therapy approaches through the process. Maybe what have you seen over the recent years? Are the companies feeling this as well? Is there more flexibility on clinical trial design, enrollment criteria, regulatory path of the FDA, or have you felt this shift on the company side maybe?
Yeah. Thanks for having us here.
Yep.
Good to be among buddies.
Friends, yep.
Yeah, friends. So I would say over the course of six to seven years in setting up these clinical trials, there hasn't been that much change as people might otherwise imagine. I think if you're having mutually educational, iterative dialogues with the FDA, sort of with a tone of respect and true understanding, you can get to the same place. Has it been easier in the last one year or so with Dr. Marks and Dr. Verdun there at the FDA? It's been easier to have dialogue and get access, but once you have the dialogue, the trial designs have been pretty consistent and I think appropriate for smaller diseases. That's my view.
Yeah, I would support that. I think that certainly the overall environment for the field, the temperature has changed a little bit. I mean, the headlines were all about clinical holds and safety events and manufacturing problems getting in the way of clinical development or approvals, and it feels like that has gone down a bit, and I think that the field has learned. Certainly, we're hearing all the right things from Dr. Marks, and but that's a more recent phenomena. I think for it hasn't dramatically changed yet the... You know, we're not radically changing the way in which we do drug development. You know, dose a couple of patients in a dose cohort, escalate, go to a second cohort. I think there's still conservativeness, and then that applies to both of us.
If you look up pediatric indications, right, you know, with a lot of severe unmet need, all the current statements from the FDA notwithstanding, it hasn't changed the fact that you guys had to dose some adults before you could get to children, which is where the majority of unmet need is, and we have to dose adults before we can get to these homozygous infants who die within the first days, weeks, and months of life, right? So I think there's good sort of thematic stuff that's going on up here with Dr. Marks, which we like. It hasn't yet translated to fundamental changes in the way that we're designing and advancing clinical development, but there's hope for that. I'd rather have that thematic positive signal than a negative one, and so there's, I think we have to see how that plays out.
It seems like maybe the FDA is warming up a little bit over the past year, but definitely maybe two years ago, it felt like on the genetic medicine side, the EMA was a little bit more allowing of new therapies maybe to start studies ex U.S., and then the FDA had a few more questions before maybe issuing an IND. I think, Matt, we'll start with you. Do you find that there's a difference in guidance or acceptability of data before starting a clinical trial in the U.S. versus ex U.S.?
I think it depends. I think we've had situations where, around CTAs or INDs, the, you know, EMAs had very technical, very specific questions, where they really wanna drill down. There's also been situations where, whether it's gene editing or even in some of the, you know, hearing disorder trials, where they're just willing to allow studies to begin in younger patients, which, you know, for a lot of the rare diseases, it's very important to medically intervene earlier. And so they, the arguments that resonate with, well, it's kind of not ethical to do a safety study with a one-time administered therapy because you can't go back and treat them, doesn't sometimes resonate as much with the FDA.
When we were having some of our initial discussions for Huntington's, as an example, you know, one of the first thoughts that came out was, "Well, can you do a unilateral, you know, hemispheric infusion?" And it's like: Well, no, you, you're not gonna treat the disease that way, and then again, I can't go back in and retreat that patient. So, I think there's, you know, I do think they, they do look at risk-benefit, but I think they will, very much try to weigh in on what do they know about patient safety. And if it's a brand-new modality, I think they will have a higher bar. If it's a lower unmet need, they're gonna have a higher bar.
I don't think there's really a one-size-fits-all when you compare EMA and FDA approach, but it does seem like EMA's had a little bit more flexibility in clinical study design and patient population.
Yeah. I mean, I would say the bottom line is that there's still enough differences from jurisdiction to jurisdiction that forward-looking companies should probably be exploring global opportunities for development. The gene editing companies certainly have gone with CTAs in Australia and New Zealand, where they can get a faster clearance. Factually, BioMarin got their first approval for Roctavian in Europe. Factually, bluebird got their first approval for thalassemia and for LentiGlobin or ZYNTEGLO in Europe, but before U.S. And then factually, gene editing for sickle cell disease was approved by the U.K. MHRA, technically before the U.S.
So I think there are still those seams of difference, and companies, it behooves companies, I think, to explore those seams and to see whether you can get some path to getting something done faster, ex-U.S., than the U.S.. So I think we should think globally.
Reimbursement is like a totally different-
Yeah.
- layer, you know, of, of that, at least clinical scientific perspective.
Yeah, I would echo a couple of these points. There's a lot of differences depending on the jurisdiction and where, who you're dealing with. Who are the members of the scientific advice working party? Who are the actual members? Who are your rapporteurs and co-rapporteurs? That makes a big difference in how stringently they're going to look at both CMC and clinical. In general, I would say the FDA has been a little bit more stringent about things like potency assays and specs and, and product release criteria. So starting here probably gives you a leg up to then a universal slice of the escrow. So that would... That's how I think about it.
I would just say the orphan playbook dictates that you got to think globally, right?
Mm-hmm.
So, going back to, I've been in this orphan for 23 years. Back in my time at Genzyme, people who weren't in the orphan space used to get shocked at, like, how global we were at such an early phase, and that's partly because you had to find the patients.
Mm-hmm.
A good example currently in the gene therapy space, I would say Ultragenyx, where I have a tremendous amount of tremendous respect for Emil Kakkis and his team. You look at their gene therapy studies right now for OTC, GSDIa, and others, they are not in multiple countries, they're in multiple continents and multiple countries within those continents. So that shows that there is a way to, you know, get a bunch of sites activated in a bunch of countries and then hopefully more rapidly execute on your studies.
Reimbursement was mentioned. I see along with this conference, we do KOL panels, and we survey physicians and payers, and often the gene therapy approach might be preferred by our physician polls, and then obviously, the payers could be their least favorite option for modality, maybe suggesting that they don't want to pay for it. So how early do you think about the payer dynamics and reimbursement when you're developing a gene therapy? Is anything too early to start thinking about this? And maybe what are some of the new mechanisms to pay for these approaches, if there are any? Matt, maybe we can start with you.
Well, I can tell you for hemophilia, I mean, so, you know, this got approved in the U.S. at the end of 2022. In 2016, 2017, we were already doing payer market research and market access work. So there, I mean, these are not huge investments, but you have to be navigating and laying out the landscape and be thinking about healthcare economic arguments associated with all of these approvals. Because, I mean, this is a completely new paradigm where you have one-time administered therapies for significant price tags, and, you know, the payer infrastructure is just not really set up that way. So, I think it is something that, you know, it's never early enough to be able to get under the hood and really understand the dynamics associated with that.
Happy to support that. I mean, a former commercial guy, I don't think you can ever be thinking about it from early enough. So I can say, before we dosed the first patient with TN-201, which we did last year for gene therapy for the leading genetic cause of hypertrophic cardiomyopathy, I know we'll talk about it later, but we had already had global market research in hand from physicians, patients, and payers. So in the context of payers, both U.S., private and public, as well as in Europe, multiple jurisdictions and HTA representatives, who are the ones who ultimately kind of become the gatekeepers to price and value. We already had feedback from them before we even completed the designer study because we wanted to know: What are the endpoints that they will be anchoring on?
How do they see the unmet need? What are they looking as comparators? And so we wanted to know, even in the design of our early studies, because in gene therapy, we know that some of that early positive data and there's some poster children for that, can lead to rapid acceleration to an approval. So you want your phase I/ II study to have endpoints, that if they move in a certain amount, in a certain direction, that that will be meaningful to payers.
Mm-hmm.
So we had already gotten that feedback under our belt before we finalized our clinical design and our first IND.
That's great. I think, I think you can't start early enough thinking about payers, and it has to start before you actually select an asset.
Mm-hmm.
Because gene therapy is not a nice to have. There's toxicities, there's potential risks, and no one's gonna take a gene therapy if they're gonna get a little bit better. They have to be getting a lot better, and I think a fatal, devastating type disease. Otherwise, it's just not gonna work. And, and if you have that, then you can ultimately tell the value story and charge a high enough price that makes sense. So you have to think about it even before asset selection.
Mm-hmm.
I certainly think that engaging payers early is helpful, but we're also small biotechs, so you can't spend so much resources in the commercial at the early stage, you can't actually develop your product. So there's a balance there.
Yeah.
Great. And maybe, on the manufacturing side of things, seems like there's been a hard push for in-house manufacturing and then maybe an increased reliance on [CMOs]. It seems to ebb and flow a little bit. Obviously, during the COVID pandemic, in-house was really important for kind of keeping timelines up to the company, it seems. But maybe how important is in-house manufacturing and kind of controlling that? And then the second part of that is how important is it kind of keeping your manufacturing consistent between sort of your initial phase I/II , and maybe the pivotal side of things, and that obviously, a large manufacturing presence with this?
Yeah. So let me just answer the second part of that. I think with any biologic, but in particular, the exquisitely complicated, biologics that gene therapies are, particularly AAV gene therapies, you know, the, the more consistent that you can be through all phases of development, all the way back to even doing animal studies, if you can—you're obviously using—you know, you're not using GMP material to dose mice, but if you're using the same fundamental processes, and basic methods, that I think is going to be critically important. I mean, not only is it critically important because, you know, classically, we know the process is the product, but it, it legitimately can lead to meaningful changes of quality that could impact safety and efficacy.
Last but not least is that we know the FDA is highly focused on CMC aspects, right? And the majority of complete response letters, right, have been associated with CMC deficiencies. So it's important. There's no doubt when we look back at the HEMGENIX story, that our ability to control supply and manufacturing was no doubt integral for our transition from what was AMT-060 to AMT-061. That being able to go in and show chemical comparability down to the team in conjunction with animal data, I think really got the agency comfortable with transitioning that program in a highly efficient way. Having said all of that, it is a critical core competency. It also becomes increasingly more expensive to support.
So I think that there is a time, and a place, and a stage to really make those investments. And I will tell you that there's no doubt from, you know, even going from early phase I/II material to phase III material, and then phase III material to process validation and commercialization, that's not like linear. That's like a step function of investment that is required. So it is a very expensive endeavor that there's no doubt you can't have 100 gene therapy companies all saying it's part of my strategy to build out this internal core competency. It's not sustainable that way, particularly in these markets.
Yeah, I think, to really make these products successful commercially, you have to think about cost of goods. And for that reason, early investment in manufacturing is make or break. In our case, we have two platforms. All the AAV is, is in-house. Some of the lenti is in-house, but much of it is outsourced, and, we may bring that in-house long term as well. And so that's one advantage, cost of goods. The other advantage is you want control, and you want the ability to make process improvements iteratively, even patient by patient, right? At times, maybe not each patient, but a cohort of patients in one trial, a cohort of patients in another trial, you might see process improvements and make them, and see how they influence the clinical trial. It's very hard to do this in partnership with an external CDMO.
For all those reasons, I think keeping it in-house is probably, probably good.
Yeah, I would say, like, you referred to the ebbs and flows, but you're talking to three companies that made its choice, and I don't think any of us regret the choice of internalizing manufacturing. Part of Tenaya's strategy and within our focus on heart disease, we're looking at both rare and prevalent forms of heart disease. And to Gaurav's point, there's no way you're gonna get to costs of goods that are in the right zip code to be commercially viable unless you make investments in manufacturing, and not just invest in your standard upstream, downstream potency assays, but you need, like, scalability.
The average CDMO today is, I think, doing a fine job with rare diseases, but they're not necessarily doing the research into the breakthroughs you need at the starting material to be able to come up with, you know, a cell line and something that can scale up, not just to 1,000. We've already scaled up successfully to 1,000. We've successfully produced all the material we need for our early gene therapy studies at the 1,000 L scale. But what does it look like to get to 5,000? What does it look like to get to 10,000? We have to ask these questions ourselves. The antibody space did not get to where it is today until they solved manufacturing problems, and now we have those, you know, massive football fields of bioreactors from Genentech in Vacaville, right?
It's like you had to achieve those breakthroughs in order for the promise of monoclonal antibodies to be, you know, what they are today. And I think the same is gonna be true for gene therapy. So we're committed to not only the upstream, downstream process for our rare diseases, but even doing research into how to improve scalability. We're just not gonna get that from a CDMO. I would also say is that potency assays are all important for approvals, and that's another thing where I think you wanna have that technical expertise in-house. So, I would say with the capacity that has come on from the CDMOs, that's improved the wait time to get a slot that used to be horrible back in the day-
Mm-hmm.
and it's improved costs.
Mm.
Right? Their costs haven't gone down. Actually, the cost of a GMP run with a CDMO, and I know because we've talked to our friends at the ARM board who are on, represent CMOs, their costs have gone up. So, so the break-even point of how many runs you have to do in your own facility after you've constructed it, to when you get to it was made more sense for you to own a house, that number, that math hasn't actually changed.
Mm-hmm.
Maybe the markets have made it, the cost of capital equation change-
Yeah.
but the math of having your own facility through the life cycle of a drug development has not changed. It still makes a lot of sense to have internalized it.
You alluded to maybe some of those criteria that the FDA require. Maybe just quickly, is the FDA? Does the FDA know what they want? Is it very clear when they tell you in terms of empty, full, capsid, and what the product is for?
It's user-defined.
Mm-hmm.
We have to figure it out and propose something, and then justify it, and demonstrate that we could reproducibly and consistently create and release that product. They're not going to tell us. They might have some guidelines and guidances, but at the end of the day, it's like we're creating this piece of work or this piece of music, and they're saying yes or no. So that's the way I think about it.
Spoken as a musician, a Grammy Award musician. Grammy-winning musician.
It was a long time ago.
Yeah. Yeah.
Perfect. Well, maybe we'll dive into some company-specific questions and kind of just go around the panel here, but maybe, Matt, we'll start with you. Maybe starting with AMT-130, it definitely seems the most topical right now with investors. So we've seen the 18-month high-dose data, the 30-month low-dose data that were shared in December. We are seeing several clinical functional measure benefits across versus natural history. But maybe if you could just outline kind of the key high points that we've seen in the data so far, and where does this program sit in development?
Yeah, I mean, the enthusiasm that we have that we also see reflected in the patient community and the clinical research community is really around the functional data. I think the, you know, biomarkers are important, particularly and from a regulatory point of view. In the end, what the patients care about are clinical outcomes. Huntington's is complicated, right? I mean, we know CNS diseases are complicated, but deep brain neurodegenerative disorders are even more complicated because you can't take histopathology and do biopsies, right? So you've got to use indirect methods. We made the decision for Huntington's to administer directly into the brain. I mean, this is a one-time administration, and it was more important to us to ensure that we had the proper biodistribution. That has obviously impacted the ability to measure certain biomarkers.
But what I think excites us the most is that we're now getting to a point where we have 2.5, this summer will be three, up to three years of follow-up data. So for even a slow-progressing disease like Huntington's, you get into that two-to-three -year measure, and if you're preserving function evidenced from what these patients had at baseline, the potential that that could be noise or randomness is just simply a lot lower. So we're now getting to a point where we're beginning to have critical mass of patients that are moving into that sweet spot, and I think that's where it becomes very interesting. The other piece of data that we looked at is neurofilament light.
We know because of our procedure that there are increases in neurofilament light, just simply because of the mechanical aspects of introducing a catheter into the brain. That takes some time to wash out. But we're also getting to a level of follow-up, we're beginning to see patients now that are going below baseline, which shows a stable or reducing level of neurodegeneration within the brain. So all of this, I think, is interesting. The big thing really is, what is the clinical regulatory path forward? And, you know, we're like, y ou know, I use this stupid analogy, like, I feel like I'm in a jungle with a pocket knife-
Mm-hmm
... trying to carve myself a path, and that's truly where we are, but we are in a position now where we're anticipating regulatory interactions. We expect to have clarity on the path forward. And I also think one of the beauties of a gene therapy that I think we all can relate to, and I'm looking at Gaurav as well, is, you know, even in early clinical studies, because you have patients that theoretically are on drug for life, you can legitimately just follow patients and accrue data, and that data becomes more robust, more powerful with the longer the follow-up data is. Right? I mean, we had a handful of patients, right, and we're able to get a fantastic alignment with the FDA. So, you know, we're now at a point where we have, you know, over 30 patients that are treated with AMT-130, again, getting multiple years of follow-up. And, and as we watch these patients, our ability to leverage that phase I/II data, that investment that's already been made for regulatory purposes, I think will be really interesting for us to discuss with the FDA.
And alluding to this, obviously, historically, we've seen some therapies approved through the accelerated approval pathway, using almost NfL as a biomarker, obviously in the ALS space. But here there is a benefit clearly versus natural history. I guess, how do you think you can make the case versus the FDA? What is your base case? Is there an accelerated path here? Would you do another phase III? And then you indicated, obviously, interacting with the FDA. When do you think you'd be comfortable, you know, kind of releasing the next steps to the street?
Yeah, I mean, there, there are three questions, three core questions that I think we want to explore. Firstly, we haven't even yet shared our data with the agency. We want to share our data with the agency, share our observations, and get feedback from the FDA about the data that we have today. Secondly, we want to talk to the FDA about the ability to utilize a natural history comparator, because, if there's a requirement to do sham-controlled, very long, long-term studies for a generally slow-progressing disease where there's not great biomarkers, it's going to make it very, very challenging. And one of the benefits in Huntington's is that there is a plethora of natural history data that has been collected in, in a clinically compliant manner. So that's another conversation.
And then the third, as I mentioned before, is we are at the precipice and have the ability to collect long-term data from many patients in a phase I/II format. We want to understand how we might be able to utilize or leverage that data to demonstrate efficacy for registrational purposes. So those are a few questions that we wanna cover with the FDA, and I think when we can get clarity on that, again, which we expect this year, we'll provide, you know, public commentary in that regard.
And then on the last quarterly update, the company did allude to moving the program forward, potentially with, with a partner. I guess, how could a partner best help out this program? What would you be looking for in an ideal partner for this program, I guess?
Yeah, I mean, there's a lot of reasons why anybody partners. They can bring certain expertise. They can provide commercial wherewithal, right? CSL had commercial operations in 80 different countries. They can, they can provide an opportunity to share risk, and they can provide an opportunity to fund. I think that, what we specifically stated is to the extent that a phase III study was required, you know, our view is that, you know, that, that's gonna cost maybe hundreds of millions and require a number of years of commitment. And that if we were gonna be doing something like that, we would want to partner the product as opposed to, you know, going on a path by ourselves.
Now, what I will say is that there's still the ability, you know, when we extrapolate the trends from our phase I/II, there's still the ability to possibly demonstrate statistical therapeutic benefit from just the patients we treated in our phase I/II.
Mm.
Right? So that investment's been made, right?
Mm-hmm.
We're just following up patients. But it's possible the FDA would like to see a phase III study, and, you know, that's the kind of opportunity that I think would really lend itself to a larger partner.
Perfect. We'll be back, but we'll go around the panel a little bit. Maybe to Gaurav, maybe if you could start just by briefly reviewing the design of the pivotal Danon trial, how many patients enrolled, and maybe what is the status of patient enrollment in the study?
Yeah, so it is a single-arm, open-label trial, 12 patients.
Mm-hmm.
The endpoint is 12 months of the co-primary of protein expression, plus LV mass index. Yeah, so there's a two-patient safety run-in, after which we have to wait a little bit before enrolling the rest of the trial. It was quite a journey to get there with the FDA, but when it happened, it happened really quickly. Once they see that LV mass is indicative of worsening Danon disease, the dialogue happened literally in two minutes. Then we were able to get around a table with 30 people from the FDA. Up from top to bottom, everyone aligned that LV mass index makes sense along with protein expression. There's no comparator. It's really the patient is their own comparator pretreatment.
We are also running a separate parallel natural history study to help inform our assumptions, fortify our assumptions. We've decided not to give any enrollment updates or guidance.
Perfect. And then, in terms of that LV mass change at 12 months, I guess what supportive data do you have that you're A, I guess, gonna succeed on this endpoint? And if you do succeed on this, is it clear that you could file for approval on this?
So when we look at our natural history, without any treatment, these patients have an 8%, on average, increase in LV mass year- by- year. This is compared with the treated patients in phase I. All the low-dose patients that were appropriately treated had at least a 10% reduction at one year, and in fact, all the patients who were appropriately treated reduced their LV mass over time. So our intent is to get the data from these 12 patients on file.
Mm-hmm.
Of course, it's an RMAT designated therapy, so we'll be able to have ongoing dialogue with the FDA.
Perfect. And obviously, the trial size, the 12 patients, but how large do you view the Danon opportunity in general? And maybe what can the company do to potentially increase that, I guess, over the coming years?
Yeah. So, this is a very good question, and a lot of people have this question. We're very confident, and there's been no change from our primary thesis that this population is 15,000-30,000 patients in the U.S. and Europe. We've validated that through multiple top-down and now bottom-up methods as well, and at the right time, we'll be able to publish this immediately.
Perfect. Then, maybe on the CMC and manufacturing side of things, obviously, we touched on that a little bit in the overall discussion. But, I guess, how comfortable, I guess, are you on the CMC side of things with the FDA and their guide to the package?
Very comfortable.
Yeah.
Yeah, there's really no issues there.
And then with the LAD-I filing, potentially, there was the slight delay. Maybe if you could talk about what led to that and if there's any implications for the rest of the pipeline.
Yeah, it was, it was just CMC information, clarifying requests for CMC. And it was not anything that needs new data or new experiments. I think, as Faraz mentioned earlier, the FDA has changed recently, and this—I would say this is a good thing, that we have a delay, but we know who the reviewers are, we know what they want, and it actually, in our mind, increases the chance for approval.
Now moving on to Faraz, we have an important data catalyst coming up in the second half of this year, which is the initial data from the phase I-B study of TN-201 gene therapy for HCM with a specific mutation. So to level set for everyone, can you take us through the unmet need in this indication, the market opportunity that TN-201 should see, and then how are these patients diagnosed and managed today?
Great. Thanks, Anvita. Thanks for the opportunity to talk about it. Yeah, so TN-201 is addressing just a level set, and for those of you not familiar with it, we're addressing the leading genetic cause of hypertrophic cardiomyopathy, and it accounts for about 20% of the patients. So rough math, 600,000 patients in the U.S. alone with hypertrophic cardiomyopathy, and translates to about 115,000-120,000 patients who be predicted to have this mutation. It's a severe disease, severe progressive genetic disease, huge phenotypic heterogeneity. One way in which I sometimes describe it, because everybody knows about Danon and Rocket, so I just often use them as the comparator. Our average patient is actually less severe than the Danon patients who, you know, generally present early in life.
But the most severe patients are worse. We have some patients who are asymptomatic adults. The vast majority are heterozygotes who have severe symptoms, including heart failure, risk of arrhythmia, a need for heart transplants, a need for medications. And the most severe patients are actually homozygous infants who die universally within the first days, weeks, months of life. There's no example we yet have of a child living past the first year of life. And then there are some severe pediatric kids who get heart transplants or ICDs within the first decade of life. So there's enormous heterogeneity here. The most severe ones are even worse than the Danon patients, but the average patient is older. Unmet need is very high. They have heart thickness, the whole marker of the disease, hypertrophic cardiomyopathy.
They have risk of arrhythmia, which I think is a little bit more unique versus the Danon population. That's why they get the ICDs. They're... You know, for those patients who have the obstructive form of the disease, they have historically, the only real option for that was septal myectomy or septal ablation, to just literally physically remove some of the heart to relieve the pressure. And for the patients who have the genetic form of the disease, that's just a patch.
We now have accumulating evidence, and that's something that we'll share more in the future, that those patients are still progressing because we are not addressing the underlying genetic cause. They're still progressing after that surgical procedure, which used to be called a cure, still Class II, Class III heart disease, and they're now coming to us for gene therapy. The kids, they need heart transplants, and you get one heart transplant, you need a second and a third in order to even get to your adulthood, and some of the similar journey on the Danon side. Myosin inhibitors have been approved, or one myosin inhibitor, Camzyos, has been approved for adults with HCM, with the obstructive form of the disease.
There wasn't as compelling data at the time, in the non-obstructive form, but now both Cytokinetics and BMS are pursuing that. So there's just a lot of, i t's a large orphan, right? 115,000 patients in the U.S. alone. This is not an ultra-orphan by any stretch of the imagination. Might be one of the larger genetic indications for which an AAV therapy is being approved, pursued, and with a lot of unmet need and a lot of opportunity to do good. It's a lock-in key gene therapy. We understand the genetics.
We know that as a result of the this gene mutation, the average heterozygous patients has 60%-70% of the wild type protein, and what we're trying to do at TN-201 is provide a functioning copy of the MYBPC3 gene, produce the missing protein, and as we'll, I'm sure, talk about, it's all about how far between 60%-100% do we get to, and what kind of clinical benefit does that yield?
Got it.
Hopefully, that addresses the question.
You did outline a very large market opportunity, and you said previously that you did a lot of market research with the payers.
Yes.
What endpoints are you aligned with the payers on, on this?
I would say that instead of saying what specifically do the payers tell us, what I can say is, and I'll pay some homage here to Rocket and others, MyoKardia. You know, Matt gave a great analogy of using a knife to, like, whack through the bush. In our case, actually, we were we have the great fortune that two groups have, like, whacked a bit of a path for us. First, the myosin inhibitors, Camzyos, they showed that you can get a regulatory approval with fields and function endpoints, right? That wasn't known at the time that they launched that study, but eventually, they got approval of field and function endpoints.
And then, you know, Rocket and the alignment that they now have at the FDA on what might be the path to an accelerated approval with a surrogate endpoint, which may have read through to us, particularly for the severe pediatric population. So the way I describe the way we design our study is, yes, we took payer input into consideration. Yes, of course, we took physician and patient input into consideration, but we also basically looked at what were the endpoints that were used by the myosin inhibitors, and what were the endpoints being used by Rocket, and they're all there. This is a very data-rich study. We've got biopsies, we got six-minute walk tests, we got peak VO2, we got quality of life using the Kansas City Cardiomyopathy Questionnaire.
We got biopsies with, you know, vector copy number and protein expression. We have echoes that'll give us the size of the heart, the heart dimensions, the LV wall thickness, the mass of the heart, LVMI. We got circulating biomarkers, and of course, safety. So it's a very data-rich study. We're collecting a lot of information for each patient, and the hope is that as we dose patients, we'll see enough alignment and enough of those parameters that will help us decide what's the right... Similar to Rocket, what's the right parameter to focus on in which population for a potential future pivotal study? So we've loaded up these studies with more endpoints than you can shake a stick at.
Okay, so data-rich phase I-B?
Data-rich phase I-B.
How much data-rich can we get in second half of this year?
Oh, well, you know, I think we've, we've said very consistently that we are committing to three patients from the first dose cohort, and at least safety, at least the biopsy data and circulating biomarkers, and perhaps possibly upside a glimpse to either additional patients or echo parameters. And again, some whacking of the jungle has already happened. This is not unlike the first report given by our friends at Rocket back in December 2020. If we look back in history and see what they showed, it provides a good comp for what we're hoping to demonstrate in our first couple of patients by the end of the year. So that's the commitment. Might there be more? That'll be an upside, but that's the commitment.
Okay. Then what would increase your confidence in this program? What are you trying to look at, and what will make you very excited with this program to move ahead?
Well, first, we wake up every day pretty excited because of the unmet need and the opportunity to do some good. These patients really, particularly the most severe ones, don't have good options. And what would get us excited, of course, we want to see those early markers of improvement, biopsy data, circulating biomarkers. You know, we're looking for directional. I said it was a data-rich study. I'm really looking for some consistency in the various markers. We don't need 100%. We don't need to knock it out of the park with 100% of all the markers. Yet you need enough of them to be moving in the right direction and some internal consistency.
So, you know, in the case of Rocket and others, if you list in our website, if you look across the myosin inhibitors, Cytokinetics and MyoKardia, BMS, if you look at 4DMT and their work in Fabry cardiomyopathy, you look at Lexeo in Friedreich's ataxia, look at the folks at Rocket and Danon, and even this Imbria, with their small molecule and non-obstructive. What is consistent across all of these different forms of cardiomyopathy, different modalities, you know, but what they all have been able to demonstrate is that on some or more of their clinical endpoints, they saw movement that was interesting and meaningful within the first 12 months. So that's our reason to believe that, you know, across multiple sponsors and multiple modalities, they've been able to show some improvement.
Either it's New York heart class and/or LV mass reduction, and/or peak VO2, and/or circulating biomarkers and quality of life measures. So we'd be excited if we could join that pack that has already laid a bit of a foundation and see a dose effect, dose Cohort 1 to Cohort 2, and convince the FDA that as happened with Rocket after treating a few adults, that they would allow us to go to the children, 'cause we are already getting referrals. It's heartbreaking, but we are already getting patients who are diagnosed in the first days, weeks, or month of life with this most severe version of the disease, and the clock is ticking for them. The clock is literally ticking for them, and we're at a race against time to try to give some hope to those patients.
First things first.
Yeah.
Dose some adults, share some data second half this year, and then from there, lots of opportunities to expand the scope of that study to include other patient populations, including obstructive form of disease. We're starting with non-obstructive, including the obstructive form of disease, going to younger patients, going global, and all those things. So that's what's-- that's the excitement, the probable excitement for every person at Tenaya.
Yeah. So the hard endpoints are clearly, you know, what we want to see, but as it's the first look into a gene therapy, transfection levels and expression levels are always important.
Yep.
From the preclinical animal work, what did you see were the minimum protein levels that you need for efficacy, and how should that translate to in the clinic?
Yeah, it's a great question. Look, I mean, preclinical models, the only model we have to work with is a homozygous knockout model, so they have zero protein. So it's a very severe model. It more looks like the homozygous infants. You know, very, very rapid decline in these animals with zero protein. What we've been able to demonstrate in those animals is that at doses as low as 3E13, we can get to 100% wild type protein expression. At 1E14, we can achieve that as well. We've been able to show clinical benefit in the symptoms of these animals at doses as low as 1E13, and then it gets better at 3E13, and modestly better at 1E14.
So, if mice were men, we'd be really, you know, excited, if we could replicate that experience. We've, at this point, shown improvements in LV mass, improvements in survival, prevention of fibrosis, improvement in hypercontractility, improvement in end-diastolic function. I mean, the preclinical data is beautiful in multiple models, in vitro and in vivo. So, that's, that tells us, but that doesn't tell us what the threshold effect is.
Mm-hmm.
In the heterozygous humans, we believe that there's a threshold effect. We said that the average heterozygous human, if this is 100% and this is 60%, 60% decrease in your wild type protein is enough to have severe disease. You don't have to be down at 0% like the homozygous infants. You have 30%-40% reduction, you have severe disease. You're ending up on heart transplant list, you're ending up with an ICD, you're ending up with myectomies. So what is that threshold between 60%, 70%- 100%, that you need to get to, at which you get into-- tip over into functional cure? In mice, there's a tantalizing number.
The heterozygous mice could not be used for our preclinical studies because they have no phenotype, and they have no phenotype because they have 85% of the wild type protein. So at least we know in mice that 85%, and you are clear of disease. If that was true in humans, then that means we need to get from 60%-70% to something like 80%-85% to achieve that threshold. But we got to get into the clinic and see. What we are happy is that we are able to show that we can overexpress the RNA and get to 100% wild type protein, at least in the animals. Now, we have to prove that in the clinic.
H ow much time of the follow-up would you need to see the functional changes, or you expect to see functional changes?
So again, the whacking, the whacking done by Rocket here is super interesting, right? I mean, I don't know if Rocket-- I'm gonna put him on the spot. Did he know-- Could he have predicted a priori, sitting in December 2020, that a modest level of expression over time, right? The LV mass story, which wasn't even in the original data release in December 2020, but in 2021, 2022, 2023, the LV mass, to pick one parameter, kept getting better, right? So over many years, for reasons that maybe we're still all trying to understand. So I think-- I use that as an example to say that we don't yet know, right? There are some parallels between these programs. We're using AAV9, they used AAV9. We know AAV9 is a great capsid for the heart.
We know these are both genetic forms of hypertrophic cardiomyopathy, but ultimately, theirs is a disease. It's a secreted protein. They're starting at zero. It's an excellent disease. They're starting at zero, they're getting to maybe somewhere close to 20%. Ours is a disease of the sarcomere. They're starting at 60%, and they need to get to X, you know, percent. We don't know what that is. So there are some comparables we that support us, but we have to write our own story, and that's what we're gonna be doing in early clinical development. We're gonna look at these parameters and see what's moving, what's not moving. You can look at the myosin inhibitors, and you can see that they perform differently in a non-obstructive patient population versus the obstructive population.
You know, we just have to write our own story, and so we can make all the predictions we want, but ultimately, we have to prove it on the field of play with clinical data.
So there is a possibility that we could see echo parameters, echo data this-
We have guided to three patients.
Yeah.
Look, there's always the possibility we'll certainly have that on hand. It—I use the Rocket example as it wasn't there in the first-
Yeah
data release in LV mass in December 2020.
Yeah.
That came later.
Yeah.
Stroke output was included then, but that wasn't really a big of a story later. So we have to write our own story. We can't predict a priori what that story will look like. We got to get in there and generate the data. So we can have this conversation at this conference next year, and I'm sure I'll have a lot more, I'll have a lot of answers, and I'll have a lot of new questions at that point in time.
And another one here.
I might have some nerdy, nerdy protein expression questions for you later.
Ooh! Okay. If you have some nerdy protein expression answers now. Yeah.
Excuse me. Maybe going back to uniQure, yesterday on our CNS panel, we, we polled the physicians at what the most exciting modality is for refractory seizures, and gene therapy with AMT-260 was the number one pick, which was great to see. Maybe can you walk us through a brief overview of the 260 program, and maybe how big could this opportunity be?
Well, it can be... You know, I mean, it has the potential to be, to be very large. Obviously, we're, we're starting in a particular population, but but it is a really exciting opportunity. It is not a genetically defined disease, of course, but there's a lot that is understood about the biological pathways associated with excitatory seizures. And and what we know is that the level of innovation within epilepsy has, you know, has been not very strong. There's a lot of new approaches coming around, but it really, right now, you have three alternatives, right? The most widely used, the cheapest, and that works for a majority of the patients, is typical anti-seizure medications, and there's a whole bevy of approaches there. The reality is that, around 30% of patients have seizures that cannot be controlled by that.
So there are millions of people with epilepsy. The most prominent form of epilepsy is temporal lobe epilepsy, and so there are hundreds of thousands of patients that are refractory to anti-seizure medication, and then they really have two options. One is laser ablation, and the other one is, you know, a barbaric, we'll just actually remove the lobe where you have your sclerotic tissue. And despite how invasive that is and potential morbidities, and the fact that if you have a lesion on the dominant side, you know, it could impact things like language and development, there are still thousands of patients that actually endure that surgery. So it gives you a sense of the size of the opportunity, that even with surgical lobectomy, there are still thousands of patients.
I think it has the potential to be quite large. What we've decided is that, again, we are identifying patients with non-dominant seizures initially, that are refractory to at least two forms of anti-seizure medication, that are documented to be having at least two seizures a month. These are high-need patients, and then we are directly administering with what we believe ultimately would be an outpatient surgical procedure of a very focal, small amount of gene therapy into the sclerotic tissue of a microRNA that reduces a particular protein called a Pin1 receptor, which has been well-characterized and shown to be a trigger for neuronal and dendritic excitatory function. And so we've done experiments in a disease pilocarpine mouse model that shows that we can dramatically reduce seizures.
We've done experiments in actual human tissue of epileptic patients, where we can show a dramatic reduction in the electroexcitatory nature of the tissue. And so we're very excited about this, particularly because, you know, we talked about Huntington's and how complicated that is, and it's a huge unmet need, no doubt, but it is a slow progressing disease with more complicated endpoints. Here, it's almost more akin to hemophilia, right? In so much that, we can look at the actual clinical outcomes, which is really seizure frequency, and within a period of, you know, it could be, you know, as little as four months, eight months, with a modest number of patients, you know, we can evaluate our impact on seizure frequency.
How are you thinking about disclosing initial data from the study? Obviously, you just mentioned some of those endpoints. The first part is open label. Maybe what should we expect in terms of the initial read, and is there a clear bar for reduction in seizure frequency or seizure freedom that you're shooting for?
Yeah, I'm gonna turn to Faraz to answer that. No, but you know, it's the same-
I'm excited for you.
No, it's the same. I think, you know, the questions that we all have, and this is an open label format, we're gonna be collecting data in a way that is obviously different than Huntington's and more alike to what we were doing for hemophilia. And the question that we always have to answer when we're doing it in open label format is, you know, at what point does data become meaningful? There have been situations where people have done anecdotal reports on data after six weeks, and then there are situations where I think you need to have more data. I think we'll provide guidance when we begin to enroll the study. We expect to begin to enroll the study in the second quarter.
I think, you know, we probably will not be doing patient-by-patient reports, but I would say that, you know, our view is that, you know, a minimum of four months of follow-up on, you know, more than one patient would probably be a scenario where it has the potential to provide insight onto the early clinical outcomes associated with AMT-260.
Then the company is also advancing 191 for Fabry and 162 around the same time, obviously, starting patient enrollment and dosing now. I guess, how are you thinking about advancing those programs? Is it gonna be similar to epilepsy in terms of some of the readouts, or are those gonna be a little bit different?
Yeah, well, I think, for those programs, I mean, we're obviously excited about those programs. We're gonna be very disciplined about investment, and I think that our view is that with very modest amount of investments, we can generate early clinical data to assess our probability that we can achieve our target product profile. And I think that for Fabry and for ALS, we think that can be done relatively quickly. And, you know, there are biomarkers. There's [GLA] activity that is circulating in plasma for Fabry, and then there's obviously a validated surrogate endpoint in neurofilament light, which has been shown to be quite impacted by therapeutic intervention with the disease.
I think all of those can be collected on just a few patients in order to de-risk the investment and enable us to get confidence that we're gonna be investing further in those clinical programs.
Maybe we'll jump back to Rocket. The Fanconi Anemia program, maybe if you could just highlight your confidence in an approval here, and how big do you think this opportunity?
First of all, just to take a step back, Fanconi Anemia is one of the first programs that we started with. Some of my star colleagues in the room here, Jonathan and Henry, were there in 2016 when we licensed this in from CIEMAT in Spain. And a lot of the programs, I think, for companies advance the pipeline, and I think Fanconi Anemia is one of those where we advance the science. And we did that by not requiring antecedent conditioning before the autologous transplant of gene-corrected cells, right? Ex vivo lenti approach, different from AAV, but when gene therapy works, it works. And the Fanconi Anemia program, how confident are we in the data? The majority of patients are re-engrafting.
They're engrafting in with regard to stem cell correction based on MMC resistance and immunologic stability that's sustained over a long time. The majority of patients are demonstrating that. We're also. We've been able to identify a therapeutic index by which we can predict response. So in those positive predictive models, almost every single patient is responding. So that's gonna be part of our package. We're highly confident that there's a path forward here with both the U.S. and EMA. And then I think the second part of the question was the market opportunity.
Yeah
... is about 6,000-8,000 patients, U.S. plus Europe. It's a more rare disease than some of the cardiology indications, but they're identified patients. We know where they are. There's a worldwide foundation called Fanconi Anemia Research Fund, and they have access to these families, so they're pre-identified patients for the most part. So, the uptake should be rapid. There's also a lot of interest from patients, physicians, and even former transplanters who are seeing the value of gene therapy, because if you can give these patients, who otherwise are gonna have fatal bone marrow failure, leukemias and head and neck cancers, even with transplant, they get head and neck cancers.
If you can give these patients an option of a gene therapy, almost like a vaccine, early in life, so that they don't ever get anywhere near bone marrow failure, and there's no conditioning, almost a pristine safety profile, then the question I would ask, and they would ask, is why not? Right. So with that value proposition, I think we're confident about approvability as well as uptake in the market.
Perfect. And then maybe jumping over to the L-301 program for PKD, maybe if you could just touch on the supportive data that gives you confidence that the phase II will be successful, and then-
... Yeah, so as all of us know, when gene therapy works, it really works. You're replacing DNA with corrected DNA, and there's no more fundamental level of cure that one can achieve except by doing that. That's who we are as physical beings, right? And we saw that in PKD. I think in your notes, you had said 2 patients have shown efficacy. It's actually 4 out of 4 patients have shown between 3- and 7-point improvements in hemoglobin. Actually, 3 of them showed about a 7-point improvement in hemoglobin. These are patients who had a baseline hemoglobin after splenectomy, and they were transfusion dependent of around 7, and 3 of them are now around between 13 and 14, and another one is between 10 and 11, and potentially rising as well. So this is transformative.
These patients don't need transfusions. They feel well. Their other markers of hemolysis have also resolved. So I think this was more than adequate proof of concept in a rare disease. We have a agreement with the FDA to move forward with a 10-patient, single-arm trial, and we're very, very proud of that outcome.
When should we expect potentially some top-line data from the phase II?
We have no guidance on any data readouts this year. Sorry.
Perfect.
Okay. For us, we have the TN-401 PKP2 cardiomyopathy, which will be right behind 201. The IND was recently cleared. Any timelines there for this program, and then what is the market opportunity in CP?
So the timelines that we've guided to is that we'll dose. So the IND was cleared last year. In fact, we're very proud. That was our third IND clearance in 13 months, so just a small marker of just getting stuff done. And we've guided to dosing the first patient in that study in the second half of this year. So that's the public stated guidance. Of course, there's others in the including Rocket and Lexeo in that market. So I think all three programs had their INDs cleared last year. My guess is all three programs will dose their first patients this year, and there'll probably be comparisons that will be made in the following year. So market opportunity, I think this is where there's, you know, a law of small numbers.
There's varying ways to approach sort of the epidemiology here, but, we say that there's about 70,000 patients in the U.S. I think you, you guys say 30,000-50,000 in the U.S. and U. Bottom line is it's still a large opportunity, whatever epidemiology. With the epidemiology will solve itself over time as there's more genetic testing. I frankly think that this disease is underdiagnosed. For about a quarter of the patients, the first. Just to put this disease in perspective, for about a quarter of the patients, the first presentation is sudden cardiac death. So, you know, try to do your epidemiology when a quarter of your patients are dying, and, and you only know these numbers because some people choose to do genetic autopsies.
I didn't even know that term existed until I came across this indication and realized that people are doing genetic diagnosis after the patient died to find out why did they die all of a sudden and otherwise healthy. So I think there's underdiagnosis of this disease, and I think this is another large opportunity, which is why Rocket, Lexeo, and I, we're all interested in it. And there's a lot of unmet need here. Last year, the main patient advocacy group called the SADS Foundation, they conducted patient-focused drug development forum, where over two days they had physicians presenting about the disease, but also patients sharing their stories. This was horrible, right?
All these patients have ICDs, which prevent them from dying, but they have enormous exercise restriction because any kind of excessive, not even excessive, just normal exercise, will exacerbate the decline of their hearts, which the ICDs aren't gonna protect against. And then when they have these unpredictable shocks that hit them when their heart goes into ventricular tachycardia. So the burden of the quality of life impact, the psychosocial impact is quite enormous here. And so there's an opportunity to do some good here with the luck and gene therapy, and that's what all three companies involved here are trying to do.
We do have some time here, so I wanted to slip in one more question on, your preclinical pipeline. We don't get much time or opportunity to hear about that but want to give you the time for that. Yeah, for your early efforts in gene editing, cellular regeneration, new AAV capsids
Yeah.
would want to learn more about that and-
Sure
- What progress?
Well, first, I'll say there was factually a third clinical program, TN-301, small molecule, which we won't talk about today, for HFpEF, and it's super exciting program. We've generated a ton of science on it, successfully completed a phase I study last year, great data, clean, once daily dosing, good target engagement. This is for HFpEF. That's a large indication. That's, like, more than 3 million patients in the U.S. alone. And the, because of the mechanism of this HDAC6 specific inhibitor, it actually has a multimodal mechanism of action that has relevance, we think, across multiple diseases. So it's a pipeline and a pill. So we think the, the best thing to do for that program is to find a partner, which is what we... And then we're, we're having good discussions with folks.
So factually, that was our third clinical program for which we're not making any further investments, and we're gonna look for a partner, which allows us to focus on TN-201 and TN-401, and to continue to invest in our pipeline. So, I mean, we're just super excited about everything we do. In the average investor meeting, we just don't have time to talk about the preclinical stuff. And I'll just remind everybody, to our knowledge, we're perhaps the first and only company that has been purposefully built from the bottoms up to pursue precision medicine with 100% focus on the heart, right? And that means we have invested in the research capabilities. We have human iPSC-derived cardiomyocytes. We have in vitro models and in vivo models. We have engineered heart tissue, 3D models, and we have exciting data in cardiac regeneration.
We have exciting data in large indications, potential for gene therapy in large indications, and gene editing. So we did indeed release some early preclinical data last year, and we have several efforts going on in gene editing for different forms of genetic cardiomyopathy. We, as a company, we chose, I think, an approach similar to what Rocket did, but we just said, "We're gonna follow the science," and that makes us modality agnostic. So AAV gene therapy isn't always gonna be the right tool for the job. Sometimes it'll be a small molecule, sometimes it'll be gene silencing. And in the case for several genetic cardiomyopathies, which are dominant, gain-of-function mutations, gene therapy won't do anything for them. You need gene editing or gene silencing.
We have in-house efforts, as well as work going on on the outside, that in on a range of cardiomyopathies, and many of the existing capabilities we have, AAV capsid engineering. We've at this point screened more than 1 billion variants, and in our own in-house, with multiple diverse libraries, we have identified several capsids that vastly outperform 89, and so we're looking forward to deploying that in the clinic. We have multiple promoters of different sizes and other regulatory elements that allow us to not only target the heart, but even within the heart, turn expression on and off within different cells of the heart. That's the level of precision we're getting to, and that's gonna come in handy when it comes to gene editing.
And so yeah, we're very excited about those sort of the next horizon of opportunity that's coming up behind TN-201 and TN-401. And we have. I think there's growing interest in this whole field, I think. We all use the idea of precision medicine for oncology, but we're taking a page out of the playbook from oncology and applying it to heart disease, the leading cause of death in the world, more than all oncology combined. So this opportunity to take, not only going after the rare genetic diseases, but now take large indications like HFpEF and HFrEF, and begin to understand genetic drivers of that disease, and then to design products and to enrich clinical studies, to go after specific genetic variants within these large populations, that will open up whole new opportunities for [Teneya].
We've got the tools, and we've got the strategy to go after that, so excited.
With that, we're, we're at our hour, so thank you very much to our whole panel, and thank you for listening in.
All right. Thank you.
Thank you.
Yeah.