Thanks, Ash, for having us here on the beautiful West Coast at UBS. It's great to be here, so we're a gene therapy company. We have two platforms. We have an Ex Vivo Lenti platform, and we have an In Vivo AAV platform. The Lenti platform is focused on hematology indications. The AAV is focused on cardiac, although we may expand beyond that in the future, and the company is built around the thesis that gene therapy is most appropriate for rare, devastating diseases that can be fatal, especially in childhood or adolescence, and I think that's where the real value of gene therapy, which can be curative, is unlocked. We select our indications by a couple of different philosophical tenets, which include we want to target genes/proteins in the cell of interest that directly affect the full spectrum of disease. So we're not looking for chaperone or proteins that are one or two steps removed and one or two cells removed. We want to target the protein in the right cell. So it's on target. And that's very important because that's not always how gene therapy is developed. Secondly, we want to look at indications where we have a relatively quick path to clinic and regulatory approval. It doesn't take too many years. Hopefully, within one or two years, you can get to an endpoint. And third, we want to look for larger and larger indications as we create the company's value. So in this regard, we've put together six programs: three hematology, three cardiac, each increasing in size over the years. Great. Excellent start. So maybe I know, like, Danon disease is a big focus area for you, but I'll come to that. You know, just kind of like save the best for the last. So I guess that the recent updates that we have seen, right, like, one is just on, like, the Kresladi. So I know that you had received, like, a CRL. You're working with the FDA to try to resolve that. They had requested some CMC information and but no clinical information, right? So where are we in that process? Like, do you feel confident that you're marching towards, like, a potential approval? Yeah. So we're working with the FDA to clarify really what I consider relatively minor issues on around stability and sterility and validating sterility and stability. These are not product-related. They're not process-related. They're really crossing the T, dotting the I's, but they have to be done, right, for the therapy to become a drug product. And so we're in the process of that. We anticipate an approval sometime in the coming year for sure. And I think overall, yes, it was a CRL. It is a learning. It's a little bit of a stumble, but LAD is a very small indication. Out of the six, it's the smallest one. There's only three transplants a year for LAD in the United States. So we're not looking for big volume here. It is a PRV opportunity that will be important next year. But it's a great way for us to learn what to do and what not to do to solve this, develop the muscle memory that every company needs to develop to really learn how to turn this into a pipeline and sort of a plug-and-play scenario. And that plug-and-play scenario can then be applied to Fanconi anemia, PKD, and then the cardiac indications as well. So I think sometimes you go a little slower to go a lot faster. And I think this is that situation here. Got it. Okay. And then, like, for Fanconi anemia, so you are in the process of, like, this rolling BLA submission. Do you believe that this is some time, like, in 2026, like, you will be able to launch that? Just, Yes. Anything to outline in terms of, like, what's the regulatory path and what, what are you expecting there? Yeah. So we've submitted some of the modules. Some of the, you know, really one is outstanding. We're drawing from the LAD learning to make sure that we get it right with no hiccups, and then I think both of these products will become products on the market in the next, you know, in 2025/2026. Yeah. So this would be, like, sort of like catapult the drug, the, you know, the company into a commercial stage, biotech. And, just in terms of, like, anything that you can mention, where is the, like, the TAM going to be? Yeah. Or what have you done in terms of, like, patient identification initiatives? So for these two, LAD, the TAM is really not very large. There's only 400 known cases of LAD described in the literature. There are maybe 25 to 50 cases that we can treat for both severe and moderate LAD over time in a peak year. With severe LAD, it's gonna be a very small number. You can probably, you know, single-digit number, that we treat in any given year. So the TAM there is relatively modest. Again, the PRV opportunity there is important, as well as the opportunity to develop the infrastructure of qualified treatment centers, the supply chain distribution, and get experience with pricing and access, right? So all of that is LAD. Fanconi is where we start seeing more significant addressable market. There are 6,000 cases of Fanconi anemia that we estimate between the complement groups that we're going after, which are A, C, and G. All of Fanconi is probably closer to 7,000, 8,000, but we're gonna be able to target about 6,000. Half of those are already diagnosed. And the median age there is somewhere in the 30. So you can estimate the per year treatment that we can get to. So then it starts becoming significant, especially when you assume the price analogs of other Ex Vivo Lenti gene therapies that are out there. Yeah. All right. Great. So yeah, let's focus on the Danon, I mean, for this RP-A501, just can you if you can like remind us like this phase 2 potentially pivotal trial like what's the design? Yeah. Why are you focusing on these co-primary endpoints, LAMP2, and LV mass reduction? Just, sort of give the rationale for that. Danon disease is a disease of big hearts in the sense that the largest heart ever on record in a human being was a Danon heart. So these are massive hearts where autophagy is impaired, and these patients have vacuoles build up. The hearts become thick, heavy, and eventually fibrosed, and eventually lead to these patients' death. So it only makes sense that an endpoint like LV mass index makes sense for Danon specifically, combined with protein expression. So the combination shows that you're getting protein expression, and the protein expression is responsible for the shrinkage of the heart at a time when it's usually increasing in size. We showed that over the course of male patients' growth, the Danon heart increases in size by a certain percentage every year. Showing a difference from there is pretty meaningful, especially when combined with protein expression and other secondary endpoints like troponin, NYHA class, etc. We've set up the trial, very thoughtfully and with a lot of dialogue with the FDA. It took a while, but I think we got to the right endpoint. It's a 12-month endpoint in 12 patients total. That trial is now fully enrolled. We're in the process of dosing, and we are dosing patients. We haven't given exact guidance on when the readout is, but, you know, we'll start seeing some incremental data internally, certainly in 2025. I think we wait for the final disclosure, until the whole data set is done because it is a pivotal trial design and just to respect the confidentiality of the FDA dialogues there. Now, I do want to point out also that next Monday, we are gonna have a late-breaking abstract, or presentation at AHA that's accompanied also with an investor call. We just announced that earlier today. So we're very excited about that. That's in the long-term phase 1 data, and some of those patients are out almost five years. The last update was in 2022. So this is the first meaningful data update in Danon in a long time, and we're very excited about it. That's good. So how many patients is that? And just like, what is it, like, similar endpoint, like, LV mass reduction that we will be able to take a look at? It's six patients that are followed long-term. There was a seventh patient who was treated, but that patient was too far gone, too far progressed in their heart failure with low ejection fraction. That patient would not be eligible and was not evaluated long-term because they got a transplant early. Six of these patients have been followed for a few years. The endpoints there, of course, is phase 1. Safety was the endpoint. But we looked at all of these efficacy endpoints, including protein, including LV mass, including troponin, BNP, NYHA class, and other parameters. Two years ago, when we presented the update then, those were trending favorably. I think it's interesting to see how gene therapy works in the heart long-term, and to see whether or not we see continued expression and improved biomarkers over time. That's an important question that's outstanding in the field, and we'll have data on that next week. Got it. That's great, and then I guess that the, you know, in this type of a setting, I think patient age has a big meaningful impact on, sort of like the magnitude and the rapidity of how quickly you can start to see the benefit on LV mass, improvement. I mean, if you can talk about, like, so what was sort of those metrics? What have you seen in, like, phase 1 and for phase 2? Like, if there is any difference in terms of, like, the baseline age or, all those type of nuances to think about. Historically, I would have said that pediatric and younger patients tend to do better with gene therapy. I think what we've seen in our trials, at least, is that if it's the right therapy for the right disease, it's age-agnostic. Some of the patients who benefit in Danon disease, for example, were older, and they're around the age 20 or so. We've even seen that in PKD, so I think that that was an assumption for a long time, but the right therapy for the right disease should be age-agnostic. Got it. So going back to the status of the study, so you mentioned that, so you've completed the enrollment of these 12 patients by September, and then, so you have dosed some of them, not all of them. Right. Just like, what's the cadence of, like, how long does it take to get to that dosing? Yeah. So there's a three-month run-in for troponin that the FDA mandated so we can have sort of a more longitudinal comparison of pre versus post. So, not all those patients would have gone through that. There's other, you know, pre-treatment workup, like cardiac biopsy. So, we haven't given exact guidance, but, you know, it's ongoing, and we're gonna get it done as rapidly as possible. Okay, but when did you start? When did you initiate? When did you, sorry, enroll the first patient, or when did you dose the first patient? Have you talked about that at all? We haven't, but the enrollment basically happened between July and September. I see. Okay. Before the post-pediatric follow-up. Two patients were treated earlier. Right. Followed for a certain time, discussed with FDA and IDMC, and then we started the broader trial, really from July to September. So, enrollment would have been done then. So, there's getting everyone dosed just takes some time. These are, like, new patients versus what you had in phase 1, sort of like no. Yeah. No, sort of reusing of patients, I'm assuming New patients, similar demographics and disease characteristics as the phase 1, but new patients, yes. Sites-wise, like, same, similar, or? Yeah. I mean, I think the phase 2 has more pediatric patients, right, because we've opened it to the pediatrics now. So. Okay. That's the difference. All right. So yeah, I guess one question that I get from investors on this is that I think in the last one year, sort of people have been expecting some sort of, like, an interim update on the study. And this is really, sort of, like, you're looking at an instant or a delayed gratification on a story, right? Like, that's what it comes down to. So when you think about that, like, is there like a single data update that you would get for like the 12-month endpoint, or is there some breadcrumbs along the way that you might drop, which might be useful? Best things come to those who wait. There's an old commercial, right? I think that we feel good about what we've seen in the phase 1 that we've disclosed to date, and we wanna make sure that we get this right and that we do all the analyses at the same time consistently and not in a piecemeal fashion. So that we can present a cohesive data set that's BLA ready. So I would rather wait until we have that, but obviously, we'll see how the trial progresses. Yeah. I'm sure you get a lot of questions on sort of, like, the curve of enrollment, as well, and when does that start to, Yeah. Like, you know, the sort of, like, 12 months out is, like, is it most of the 12-month out is gonna happen in, like, second half 2025, or? We don't have exact guidance, but I would say a couple of things, which is that top line in this trial, it's an analysis of a certain number of patients have to reach the endpoint, not necessarily all 12. So when we're ready to announce the top line, we'll announce it. Now, even if everyone is dosed in a relatively short amount of time, they may all read out at the same time anyway, right? So I think the guidance here is really to get the whole trial read out at 12 months, and, you know, which would coincide hopefully with the top line data set. Right. And so this is for, sort of, like, accelerated approval, right? Like, for the full approval, what level of understanding do you have with the FDA? Yeah, like, how much of a follow-up would that require? Is it the same endpoint? Any focus on, like, LAMP2 versus the LV mass reduction? So we deliberately took some time to work out the accelerated approval path because the FDA gave us a carrot to also discuss the full approval package at the same time with the same trials. It's the same 12 patients followed for longer, up to five years. And the endpoints here are more clinical, and we're capturing all of them, which includes NYHA class, includes quality of life scores, even some six-minute walk test results, etc. So all that is already part of the trial. And those then become the primary endpoints for the full approval. Got it. Is there a scenario in which, like, let's say if the data coming out from this phase 1 is really good on certain aspects that you might not need to show like a longer follow-up on your pivotal study? Yeah. I think the phase 1. Full approval. Right. The long-term follow-up for phase 1 hopefully is definitely supportive for the actual phase 3 pivotal trial as well. The whole data set would include efficacy and safety in phase 1 plus phase 2 with all the years of follow-up. So yes, I think that that's accurate. Okay. It is the same dose and same process. Yeah. So, that's helpful. These trials are, like, have you disclosed how these trials are powered, like, from an endpoint? Like, what is effectively the delta that you're trying to show? So they're well-powered. We haven't disclosed the SAP yet. We will. But it's well-powered, greater than 90% powered. And it's engineered to show a difference in treated patients versus the same patient pre-treatment. Right. Right? So you wanna show on protein expression an improvement to grade one or more. It means just there was no protein, and now there's protein. And in the LV mass, you wanna show an improvement of 10% or greater versus the natural history where it's actually getting 10% approximately or worse year over year. So you wanna that's the delta that we're showing. And because it's a big delta, nothing versus one and plus 10 versus minus 10, we were able to design a small trial, that's still pretty well-powered. Is the natural history, the data here, like, fairly tight, or is there, like, a lot of noise there that it would be, like, well-accepted? Great question. It is, it's not completely homogeneous, but it's directionally consistent, and consistent enough that, you know, when the FDA looked at it, that they agreed that, look, these patients don't get a big heart 'cause they're born with a big heart. They get a big heart because it grows in size. And if you shrink it, it's almost common sense that something is happening. Yeah. And, like, does that sort of relationship stay within a tight range as the age of the patient? What I'm trying to get at is, like, is the patient age demographic that you have in your trial like well-comparable to the natural history cohort? It is. First of all, it's comparable overall. And then also, we're trying to enroll patients in natural history that are matched for age and disease characteristics with treated patients, right? So we're gonna get a reasonably good comparison. Now, everyone's heart grows faster when the body is growing faster, right? So between age eight and 15 or 16, there's a great increase in heart size, even if you don't have Danon disease. And that's why we used LV mass index, which corrects for that body mass and weight and height, instead of just LV mass. So that's all corrected for. So the natural history data, like, when can we see that, you know, like, is it gonna be before or after the phase 2? I think. Probably same time, I would say. Got it. Okay. So we'll have a clarity on that. All right. So anything else on Danon before we, you know, talk about, like, a couple of other things on your pipeline? No. I think we're excited about the, you know, taking a look at the long-term phase 1 data. The trial is enrolled. We're dosing. And, yeah, we've never been more excited. Yeah. That's great. Yeah. Looking forward to it. So maybe just, like, switching gears, and, like, talking about some of the, like, the ACM program, right? This, the PKP2, like, that you were talking about earlier. Yeah. Mm-hmm. 601. Y eah, just if you can quickly give some thoughts around like the market opportunity, like where do you expect the phase 1 update? Like what should we look forward to that? And just in terms of like a clinical development path. Like, how can that look like in this program? Yeah. So PKP2 ACM, first of all, I should say, is double Danon in terms of epidemiology. It's at least 50,000 patients in the U.S. and Europe. We're very happy to state in our recent Q that the low-dose cohort is fully enrolled. And, so we're also happy to state that we'll have a first look at that in the first half of 2025. Now, the clinical development plan here is contingent on what that first look is. What are the endpoints that are meaningful? I think that it's gonna be a combination of protein expression and a biomarker, just like we have in Danon disease. What is that biomarker? I can't predict now, just like I couldn't predict in early Danon disease, that LV mass index would be that biomarker. But we have a range of buckets to lift from. One is labs, like we did for Danon, Troponin, BNP, others. A second one is Arrhythmias. We know that Arrhythmias, like PVCs, NSVTs, T-wave inversions can, well, T-wave inversions is an EKG finding, but Arrhythmias like PVCs and NSVTs can predict fatal arrhythmias. That's another option. Another bucket is imaging and looking at right ventricular size and thickness. Of course, the last bucket is how a patient is doing clinically and how a patient is feeling, function and quality of life, right? All of those are possible second buckets in addition to protein expression. Within protein expressions, there's nuances there because this is the disease of intracardiac junctions and desmosomes. We're also developing some tools to look at those more closely mechanistically. So we're gonna look at all of this as a first look. I wouldn't expect major remodeling and complete change of the heart arrhythmia-wise in the first three to six months. I think that takes a little bit longer. Just like in Danon disease, it takes about nine to 12 months to see meaningful shrinkage in heart size. I think in all the cardiac gene therapies, it's gonna take around that long to see meaningful clinical biomarkers and clinical benefit. But the first look will give us a sneak peek at what to expect. Yeah. I mean, as you think about, like, these indications, right, like, this is pretty uncharted waters that we are in. And, not a lot of work has been done in this. So, like, great opportunity. But I guess, like, when you think about, like, sort of these, like, biomarkers and what actually, like, makes a difference, what gives you conviction that you have some sort of, like, a unique insight into this, that the hypothesis that you're working with is actually, like, the right way versus, you know, trying to, how do you get there faster, basically? Yeah. I mean, I would say that casting a wide net, right, spending the time in the phase 1 to look at everything you thought about, and it does make for an onerous trial sometimes. You know, there's a burden of testing on patients and physicians and hospitals, but we have to go through this for the greater good long-term. The second thing is just voraciously understanding the disease by reading literature, talking to patients and their families, understanding their perspective, getting advice from physicians and those who treat patients, healthcare providers, and really being curious and humble enough to know that where you end up might not be where you started. And eventually, I think that replacing a faulty gene with a correct gene in a fatal disease is gonna do something, right? And it's just a question of finding out how to identify the marker that predicts that. Got it. Great. Excellent. So yeah, I mean, I guess for PKP2, is there any sort of, like, a read across you see to Danon or vice versa? Like, if one approach works, what implication does it have for the other? I think what Danon taught us is that the agency and treating physicians are open to a biomarker-based approach because these are Danon's is a fatal disease of childhood. Now, PKP2 patients are tend to be a little bit older, but it's also a fatal disease if untreated, and I think we can rest assured that there's gonna be openness to a biomarker-based approach for these sort of cardiac gene therapies, and then also understanding how to process cells to look at DNA, look at RNA, look at protein, and how to sort of hone in on those markers so that we really understand what's going on mechanistically. That's important. The other important piece is, just knowing where natural history makes sense and how to really dig deep on what happens if you don't treat a disease so then you can understand the difference from the treated patients, right? The natural history piece is also applicable across all cardiac gene therapies. So doing the natural history study right is just as important as doing the trial right. And I think developing a company where we're looking at one, two, three, and now there's a couple of other diseases that are following on after VAC-3 and applying both the biomarker, the agency, and then thirdly, also the natural history knowledge across them creates a platform, right? So. That's great. So just, as we look at, like, the phase 1 update for, for this in first half 2025, just, yeah, curious, anything that you would outline in terms of specifics, like how much follow-up, how many patients, what, what sort of, like, endpoint to, just, like, look at more objectively than the others? I would go out on a limb if I gave any particular endpoint or highlighted any particular endpoint just because I don't know. I don't know what the data look like. I won't know until right before the release, but we'll be curious and we're gonna approach this with voracious curiosity to figure out what the endpoints are. Now, in terms of how many patients and how long we're following up, it's a low-dose cohort. We haven't disclosed the number of patients, but it's between three and six, right, 'cause that's the cohort size that's defined. You know, obviously, those patients, we've been processed for some time, but I would not expect, like, a nine- to 12-month endpoint because they just haven't been followed that long. But you know, before that. Got it. Okay. All right. That's great. So I guess, so we talked about, sort of, like, four programs, right? LAD1, Fanconi, Danon, and ACM. Just if you can, like, talk about the remaining two. Yeah. Just to see, like, where they are. To complete the Lenti portfolio, pyruvate kinase deficiency, we're starting a phase 2 there. It's agreed upon between the U.S. and EMA to be a single 10-patient single-arm trial, versus natural history. We're going after severe disease, meaning transfusion-dependent patients who are post-splenectomy and still need transfusion. Really an area of severe unmet need. More to come on that in the next year as far as the progress of that phase 2. That is a Lenti opportunity that's about the size, if not bigger, than Fanconi anemia. We're very excited about it. We've shown in phase 1 that all these patients improve the hemoglobin and, in some cases, double it, and that's sustainable over time. That's to come. The third cardiac program is VAC-3 dilated cardiomyopathy. That's the program that we inherited through our acquisition of Renovacor. DCM is actually a bigger patient population than even HCM. It's more common. These are patients who, over time, develop dilation of their heart, and they reduce their ejection fraction. Ejection fraction is commonly seen as a biomarker of efficacy there. It could be a potential biomarker along with protein there as well. VAC-3, like PKP2, is bigger than Danon, probably double the Danon market. Again, going toward that thesis of increasing disease size as we move forward. VAC-3, we'll be submitting an IND in the first half of 2025 as well. Good. It's a big year next year. Yeah. That's lots of progress on the pipeline. Looking forward to the updates. I mean, I guess, like, just to close it off, right, like, I'll ask a question to you about, like, regulatory landscape. I know, there's been lots said and discussed on this. And I get the impression, like, across my coverage as well, I see that a lot of, like, actions by the FDA in the last, like, one or two years seem to suggest that the agency was getting more and more flexible, like, more adopting, like, this natural history cohort, like, endpoints that are, sort of, like, biomarker-driven. Do you anticipate any kind of, like, a meaningful change? Like, You're running a business which is very sort of, like, tied to what the agency thinks and does, right? So what is your underlying assumption in terms of, what might happen in the next administration? Yeah. I mean, that's a late question. But I think that with Dr. Peter Marks and Dr. Nicole Verdun running CBER now, we have seen significant progress in flexibility around trial design, relying more on natural history, more openness to single-arm trials, and really being thoughtful about endpoints that don't take years but take maybe one to two years because I think they recognize that part of safety is preventing fatal diseases, right? Safety is not just about keeping therapy safe, but it's about keeping people safe, right? And if there is a therapy out there that's curative for a fatal disease, well, that's part of safety. Safety and efficacy get integrated in that sense. And I think that mindset is really making its way through the agency and also influencing the EMA as well. How that changes next year, I don't know. But I would also say that with Peter Marks, who's been there for, through a couple of administrations, through the changed administration, there's been some consistency in how they approach rare diseases. So I don't expect it to change that much. Good. Good. That's, that's a good positive note to end our session in. Thank you so much for taking the time. Thanks for joining at our conference. Yeah. And, Awesome. Good luck with all these programs. You have a lot going on. So, good luck with 2025. Thanks for having us here. Yeah. Thanks. All right. Take care.