From the Cantor Fitzgerald Equity Research Team, pleased to introduce from Rocket Pharmaceuticals, we have Gaurav Shah, Chief Executive Officer, and Kinnari Patel joining us, President, Head of R&D, and Chief Operating Officer. Welcome. Thank you so much for timing the announcement of the completion of enrollment of the Danon trial with our healthcare conference. That was a great news update. Maybe just give us first a quick snapshot of where Rocket is across the programs and what we should be looking forward to over the next 12-18 months. Yeah, across the program, so we are a gene therapy company. We focus on indications with high unmet need, where there is a clear mechanism of action, a clear target, where the protein of interest is in the cell of interest, and we can get to that cell of interest and protein relatively easy, where there's a clinical path to development that doesn't take too long from a regulatory viewpoint. So we put together a pipeline of more than five programs, but five are disclosed and in the clinic, and there's a sixth one that will be in the clinic. Those six programs are starting with the ones we started it with years ago, Fanconi anemia, pyruvate kinase deficiency, leukocyte adhesion deficiency one, LAD-I. Those are the lentiviral programs. And then we have the in vivo AAV programs, Danon disease, PKP2 arrhythmogenic cardiomyopathy, both of those are in the clinic now, and the third one, BAG3 dilated cardiomyopathy, to be in the clinic next year. Excellent. Well, so you completed enrollment of the Danon program, maybe a quick snapshot of the trial design and when we should be looking for clinical data readouts. Yeah. So we're not providing guidance on when the data readouts will be, but I can tell you the general design of this trial. It's a twelve-patient, single-arm trial with the patient's own pretreatment parameters as the comparator. We also. It's gonna be fortified by an external natural history, which is not a comparator, but it helps fortify some of the assumptions. So twelve-patient trial, single arm, twelve-month endpoint of a combination of protein expression, as well as improvements in LV mass index, also fortified by other secondary endpoints, such as troponin and quality-of-life measures. Got it. And so is this a responder analysis, and if so, what counts as a response on LAMP-2 expression and then LV thickness? Yeah, so, the absolute values per patient for a patient to count as a responder are that they have to have an increase in protein expression from baseline to at least one, grade one or greater, right? So in other words, a little protein expression on top of the baseline is all we're looking for, because in the Phase I, even patients who had minimal protein expression had long-term benefit. And also, the patients have to meet the criterion of LV mass index improvement of 10% or greater, given that in the natural history, untreated patients have an increase in LV mass index of 8% versus a decrease of 10% or greater that we're looking for. Both of those parameters have to hit, and we haven't really specified how many patients have to meet that endpoint to be a positive trial, but we'll have more updates on that as we go. Are both of those endpoints measured at one year? Do they have to... So there'll be a biopsy to check that box in a year as well as the- Correct. Okay, got it. So, so in conversations with investors, I think a lot of the focus for this program has shifted from, you know, how well does it work, is it gonna work, to now thinking about the unmet need and the patients. I think you've said 20,000 to 40,000, if I'm not mistaken, US and Europe, but then we kinda have to start carving the market up, right? Mm. Males, females, age appropriate, etcetera. So maybe you can talk a little bit about some of those nuances of the addressable market for when the program does launch commercially. Yeah. So it's 15-30 thousand- Okay ... is the guidance that we've given, and it's an X-linked disease, so at birth, it's half/half males, females. However, females tend to live twice as long. So in the real world, the prevalence is likely more frequent. It's more prevalent in females in a two to one ratio to males, right? So that makes common sense. In terms of how many patients are actually there that we can find with Danon, we're finding it's about half/half right now, just because males are the ones presenting earlier, and females are a little bit more heterogeneous in their presentation. But we do continue to make efforts, both top-down and bottom-up, in identifying patients and fortifying that 15-30 thousand number, and we feel confident that that is the right true prevalence of Danon disease, although only a proportion of those are actually diagnosed that we can find right now. Do you have an estimate of what% are diagnosed, and how do you go out and find those that aren't? Yeah, so about 20%, but maybe Kinnari can help us think about ways to find the other 80%. Yeah, a couple of things we're putting in place is really genetic testing. So we're doing a lot of educational workshop with the, first and foremost, the Danon Foundation, family and friends group that they have, to provide linkage of how to get genetic testing done across the world. Usually, when we find an index patient, a kid usually, what we realize is when we do the family testing, mom has it, other siblings have it, so we tend to find index case that has anywhere from three to 15 patients in a family. That's another way. The third component we're putting into is we have a team of GDLs, Genetic Diagnostic Liaisons, that we've put into place. They actually go center by center in the U.S. right now in order to just help the cardiac centers become better affinity with the genetic testing, so patients can actually get through that system of requesting a test, getting the results, and getting the right diagnosis. So those are a couple of things we're working on right now. Our timeline is, really, by the time we launch, we wanna have a significant number of patients identified and ready for access to therapy. ... In terms of kind of that 20% diagnosed, estimate, where do you want that to be at the time of launch? That's a good question. I think to get to the true peak of Danon, we have to chip into the other 80%, obviously, right? And the sooner, the better. I don't think we have a target of what% we want to chip away by launch, but, you know, as much as possible. Yeah. So what have you started to do in terms of the female population? Yeah - and evaluating them, just given how important they'll be for the, for the product over the long term? It's a great question. Actually, this weekend, the Danon Foundation people reached out to me because one of the boys that got treated with gene therapy, his mom passed away with Danon disease. So there is a huge demand for the female population. And even FDA and EMA have said, "We're very supportive of you starting a study." So our goal is in the next six months, have those discussions with health authority to figure out what's an efficient path to design a clinical study for the females, and hopefully next year sometime, we can get that study across US and Europe health authorities. Why, why were females not included in the original development? We always think about our drug development in the narrowest, most unmet medical need population. So when we looked at the boys, if they homogeneously passed away by the age of nineteen or twenty, we said, "Let's start there to understand the benefit risk. Yeah. Once we understand that population better, let's try to understand the female population, where there are females that pass away in their teens and twenties, but there are some that live into their thirties. So we really wanted to understand the disease heterogeneity that exists, to figure out what is the right endpoint, how do we design a study, how do we understand what's meaningful for the female population, which may not be apples to apples to male population? Got it. Are you looking at all for Danon in older males? 'Cause when we had- Yeah ... checked around with cardiologists, kind of happened to stumble, I don't know how, not, not verified, but stumbled on anecdotes of older males still living with Danon disease. Yeah. We have encountered a couple of cases. There are very few number of males who have lived beyond forty. There's maybe a handful that at least we know. Yeah. What happens as the males get older is that they start having other involvement, CNS and especially muscle. So there is a point of no return, even if their heart somehow remains intact, and I'm talking about non-transplanted males, right? So the trial is open to it, right? It's age eight or older, and the label ultimately would not exclude the older males, but they tend to be progressed a little bit too much. Got it. So I guess there, there's the prevalence consideration, there's the incidence consideration, which obviously is gonna be substantially lower. How long do you think it'll take to really work through the prevalence? Yeah. When you get through that, what do you think of maybe a steady state? Yeah ... penetration into the incidence might look like? Yeah, so the median survival in this population is probably in thirty-ish, males and females combined, right? And so 15 to 30 thousand is the prevalence of the incidence one can calculate ultimately. Obviously, in the early days, it's not gonna be the incident population. We'll draw down from the prevalence pool, we'll reach a peak, and there will be a tail. I don't know what that looks like yet. I will say, though, that there's about a 20-25% de novo mutation rate in Danon, so it's not always inherited, and that definitely provides for a long tail. Okay, got it. Maybe kind of coming back to the assay and LAMP-2 expression. I guess the category one expression levels- Yeah ... is, I think, is it 0% to 25% or 1% to 25%? It just means it's present, but it's less than 25%. Yeah. So I would- Okay ... I would say now, quantifying protein expression is a very complicated task, and I think companies other than Rocket have also found it difficult to exactly quantify. That's why we've stuck with grades, and FDA seems to like that as well. So what is less than 25%, but still present? Well, maybe 5%-25%, but we've seen that even patient 1001 from the phase 1 trial, who was probably closer to the 5%-10% range, if you look at it technically, has had prolonged benefit, you know, troponin drops and feeling well, et cetera. We will have a long-term phase 1 data update at a conference where, you know, haven't announced when or where, but that will provide information out to five years, including that patient 101 at some point, so. Would you expect patients to just continue to improve over that period of time, or do you expect that they ultimately hit some plateau? Yeah. If so, at what point? Yeah. It's kind of interesting because getting the direct patient perspective through parents, and them coming back to Rocket, talking about it, their labs sometimes go up and down, but what we see is clinically, they're functioning like a normal kid, right? We have patient that are four years out, that are holding a job, no transplantation requirement, able to go to college, have their own place they bought. So all of those stories, kind of holistically what we see is the benefit is sustained and durable- Yeah ... which is great to see. Yeah, and I think they continue to improve, I would say, over a year or so, which is why we have a one-year endpoint. And I think the data that we'll present will sort of show how that plays out over time. Yeah. It- ... The product seems to, quote, kind of punch above its weight, meaning, you know, even a small amount of expression- Yeah. -can lead to very, you know, by the sounds of it, quite transformational clinical outcomes. As we think about toggling outside of Danon and into PKP2 or- Yeah ... or BAG3, are these settings where you would kind of expect a similar phenomenon? Yeah ... where even a small level of expression can deliver strong results? Or do you think that threshold is gonna be higher in these other indications? Yeah, it's hard to know. Yeah. Both PKP2 and BAG3 tend to have patients that are heterozygotes, right? So they're probably starting out with, I don't know, grade two expression. So how much do we have to improve to show a clinical benefit and a biomarker benefit? We just don't know. I think we'll find out with the trial. Got it. Okay. When would you be in a position to give us some timelines for data readout for the PKP2 program? Yeah. Unlike Danon, PKP2 is in Phase I, so we have, you know, we're working to figure out safety, obviously, but what are the right endpoints to measure for a pivotal Phase II? And I think we can be a little bit more, you know, take the world on the journey together with us, unlike Danon, where we're just gonna get the final endpoints and- Yeah ... sort of a registrational trial, so it's a little bit more locked up. Is there anything you're looking for from the Lexeo data update in PKP2 with their gene therapy approach that may inform some of the decisions you make? It's hard to comment on other companies, obviously. Yeah. But I will say that for us, we're enrolling well. The rh74 capsid is one with a lot of experience in humans, obviously, with a pretty good safety profile, especially into the E14 range. And to take that back to your question on protein expression, we don't know if we need to get into the E14 range or not. Depends on how much protein expression you need to see. So we think with this capsid- Mm-hmm ... we're well positioned, you know, to do well there. Yeah. What are the endpoints that you're looking for in PKP2 to, again, kind of guide you to the amount of protein expression that you do need to? Yeah. So the predictors of fatal, or fatality in PKP tend to be certain types of arrhythmias, PVCs, NSVT, non-sustained VTach, also certain T-wave inversions. They tend to predict fatal arrhythmias, so we're gonna be looking at EKGs and Holter monitors, obviously. Troponin and BNP are also correlated with progression. Mm-hmm. Also, this is a disease of right ventricular enlargement. In our preclinical models, we saw improvements in both arrhythmias and right ventricular size, so we're gonna be looking at echoes as well. Then ultimately, it's about how a patient functions and feels. I will say that these patients, they have a lot of them have ICDs. Everyone enrolled in our trial will have an ICD, but having an ICD go off, some patients describe it as dying and coming back to life. It's really a big deal, and the anxiety leading up to that, especially if you have a couple of times a year or every couple of months, is really debilitating and can cause a lot of depression. So first of all, potentially, we may change the trajectory of the heart failure, which ultimately kills people even with ICDs. Second, if we can reduce the number of ICD shocks, that would be transformative for these patients. And third, we wanna eventually get this to patients before they have ICDs, right? So that's the real ultimate population that we wanna get it to. Do you have a sense how often they experience a defibrillation event? Yeah, it varies. In some cases, it's for advanced patients, it's monthly. Yeah. In some cases, it's once or every year or two years, but it is. Yeah ... it's not a fun event. So I guess the ECG and the Holter would be, like, the first strong indication- Yeah. Mm-hmm ... correct of portending the clinical benefit. Yeah. Maybe we can talk about the Fanconi program. It seems to get forgotten, I guess, by investors. Yeah ... who really focus on Danon, and I think part of that mind frame is because there are questions whether there is a meaningful number of Fanconi patients to treat. We've seen challenges with lentivirus- Mm-hmm ... commercialization in terms of, like, really- Mm-hmm ... gaining traction, and so just naturally, the focus shifts to Danon. Yeah. What do you think about that? Is there a path to execute in the Fanconi setting that maybe we have not yet seen or learned about from the other lentivirus launches? Actually, I'm glad you're asking about Fanconi, 'cause Fanconi community, on annual basis, have a meeting with scientists, patients from around the world, clinicians, and Rocket is always invited to be a part of the table, so that's actually starting this week on Thursday. Fanconi, they changed their name from Fanconi Anemia Research Foundation to Fanconi Cancer Foundation because so many kids that got transplanted are now dying through cancers, secondary cancers, so gene therapy and the promise of gene therapy, especially with no conditioning regimen, it's a big, welcomed treatment option for these patients and almost a first-line therapy. They'd rather try a gene therapy that, even if it doesn't work, they can always go to transplant, but if they develop cancer, they have treatment options available because of their DNA fragility, and not having conditioning, they preserve that optionality for treatment. So it's a very welcomed component, and I believe it's already public, or it's coming out. The Phase I data, Fanconi one, which was the promising data out of CIEMAT, the NIH of Spain, they've had these patients on treatment over five plus years, and they actually just got recognized by Lancet. So their long-term data is gonna be published in Lancet, talking about durability of the therapy and how valuable and transformative it has been for the patients. So I think that's coming shortly, if it's not already out this week. So we think Fanconi has a huge promise. At this point, I know there's a lot of focus on AAV, but we're keeping execution plans on lentiviral, including Fanconi anemia, going because the patients are there, waiting. And what we realized in the last eighteen months or so, even the hardcore transplanters are saying, "Hey, we wanna be a center for your gene therapy commercial optionality," because these patients really want it because the benefit-risk profile is so clean cut. Yeah. If a patient is diagnosed with Fanconi anemia well ahead of their bone marrow transplant, and they have this gene therapy off-the-shelf option with the high response rate, the question that families and patients are asking is, "Why not? Why not do the gene therapy? Yeah. Right? So there's almost no downside, and the upside is that you're averting bone marrow failure the same way you do with allogeneic transplant, and we're not incurring that high risk of head and neck cancer that ultimately kills these patients. So why not? So we can talk a little bit about the unmet need dynamics, again, the prevalence and the incidence, you know, especially with there being a current gold standard of bone marrow transplants. How many patients are there that haven't been transplanted? What's the new rate? And I guess by the sounds of it, you think there should essentially be no transplants, even matched transplants. Yeah. I mean, obviously, we haven't started with label negotiations at all, but we obviously think that the label ultimately should be broad, and even sibling match transplants have high risks of head and neck cancer. So that's our view. Obviously, we'll see where it goes. In terms of how many patients have or haven't been transplanted, that's something that we're working up as part of our commercial model. Maybe can you review some of the incidence and prevalence estimates? Yeah. So all of FANC, which is 26 complement types, A to Z, is likely 8,000 patients or so in the US and Europe. We're looking at FANC A, C, and G, which is probably up to 7,000 or so. Like Danon, the median survival here is in the thirties, so you know, that's... you can get your incidence from that. Like Danon, we'll draw down from the prevalence pool in the same way, so. Do you have an estimate for what percent do have a suitable match to even consider? We don't necessarily have modern data, but there was a 10-year study published by the NIH that showed that of Fanconi anemia patients, only one in three actually get transplanted, right? So I think in their database, they were showing 250 a year, and only 70-80 were being transplanted in the U.S. and Europe. So that's some sense of where things stood at least a few years ago. We don't have the modern update just yet. Got it. Maybe you can talk a little bit about the work that you're doing to kind of identify and then prepare and maybe characterize the market for some of these considerations that we're talking about now. Yeah. So, for Fanconi anemia specifically, we're working with the patient advocacy group, but more than that, the experts in Europe and U.S. Fortunately, Fanconi anemia, because of the presentation that a child has even as early as birth, they're more readily diagnosed. That's the good news, and we did last year put in an ICD-10 code, so we can track the Fanconi anemia patients a lot better and know which centers are centers of excellence. So, we're working with them from bottom up to get the coding correctly, but also top down to get the centers to be comfortable with the gene therapy, having a qualified treatment centers be educated, and have them more than just centers that we have in clinical trials. I think that alone, those discussions are going to some of the hospitals where maybe an expert or two may know about gene therapy and treatment options, rather than just a transplant. We're learning that a lot more PIs are getting interested in not just diagnosing, but also trying to see if the kid can qualify as early as the age of one for this treatment. Got it. What... Do you have a sense of what some of the factors were? You know, obviously, preconditioning is a- Yeah ... consideration for, like, Skysona, Zynteglo, Lyfgenia. You're not gonna have that consideration, or are there other gating factors to a lentivirus launch that might have held back those products in a way that wouldn't for Fanconi? Yeah, I think their one concern has been sort of this oncogenic virus issues, and I think those have been mostly put to rest for the later generation vectors like- Mm-hmm ... like Fanconi's vector. I think that gene therapy works in rare, devastating diseases, and you can easily justify the benefit-risk. It is not good as a nice-to-have, right? So it's just not gonna be ever. There's not gonna be uptake. I mean, look at SMA one, right? It's a clear benefit, and there's huge uptake. So you have to go after indications that are similar to that, that are fatal and devastating, especially early in life, for gene therapy to. Mm-hmm. Really have legs. I think Fanconi and LAD, which are currently on track for potential approvals, both fit that, as does Danon and the other programs. What is the status of the Fanconi filing, and when do you expect to have a PDUFA date? Yeah, so we typically don't announce the filing itself. We typically announce when we have a path toward PDUFA, and we'll be doing that, and generally it's on track. Got it. 'Cause you had previously, I think, guided to filing in the first half of 2024. I don't think you revised that. We didn't revise that, and, you know, there's timeline, regulatory timelines in this day- Yeah. and age are shifty, as you know. Do you, do you expect there to be an ad com, and if so, to discuss what? Mm. Um- We might have different views on this, but... I don't predict it, but, you know, I think the beautiful thing about Fanconi anemia is, without conditioning, the side effect profile is relatively clean. So between the side effect profile being relatively clean, the commercial grade manufacturing CMC in the same process being used for most of the patients in the Phase II pivotal study, it shouldn't be a CMC issue or a safety issue. So efficacy is the part that confuses people initially, right? But I think what we've seen, working with experts in Fanconi anemia and the gene therapy, is we have come up with a predictor analysis of how many cells do you need, what kind of bone marrow status does a patient have to have in order to predict, higher probability of success for benefit? So I think because of that package, I'm less concerned about an ad com, but it's not a shared view. No, it's not, not that I'm concerned. I have no view except that if it comes, we'll be ready for it. I think the clinical package is fabulous. If part of the perceived differentiation is gonna be on the risk of head and neck cancer, I mean, you're not gonna have a data set that proves that. Yeah. But are there kind of supportive data points you can provide that does say that the risk of head and neck cancer with a transplant is driven by that, the chemo dynamic that you're not gonna have? Mm-hmm. Like, what gives you the confidence that that is a- Yeah ... treatment dynamic as opposed to just a disease burden effect? In general, Fanconi patients have increased rates of solid tumors, right? It's a DNA fragility issue, and just like they get bone marrow failure and leukemias, they also get solid tumors. But what we found, and we've characterized this in the literature as well as with our communications with FDA, is that patients who get transplanted have a three- to five X increased risk of solid tumors, and if they have GVHD, it's almost certain that they will get a solid tumor. So that's published work, and also some internal work that we know of and we've shared with the FDA. So it's not that gene therapy patients won't get head and neck cancer, but it's just much less likely versus transplanted patients, I guess. Maybe a quick snapshot of the LAD-I and the pyruvate kinase deficiency programs, and what we should be looking for from those. Yeah. LAD-I, we anticipate, if all goes well, an approval hopefully by year-end. We- Mm-hmm ... submitting some final questions on, you know, validation of assays and stability and things like that, so that should be- Mm-hmm ... ready to go. And LAD-I is, in some ways, a project of love from us, from Kinnari and others. It's not a big patient population, but it defines what gene therapy can do. When gene therapy works, it really works, and it's unequivocal, with nine of nine patients surviving 100%, 100% to date, being infection-free. It's really been remarkable, so we're very excited about this, that program. PKD is moving toward Phase II, but, you know, we, you know, we're a small biotech. We can do what we can do at one time, so. The last priority review voucher we saw sold for $150 million, which is, like, a 50% increase. Yeah ... versus previous, coinciding with possible sunsetting of the pediatric priority review voucher. Do you think we're gonna see that trend consist? Have we reset the value of these PRVs? Do you have any insight into that? So my ideal hope is it gets extended again, the PRV, but I think momentarily there is a spike, as you say. The good thing is for Rocket, at least our programs are already designated, and so they should qualify, even if it expires, to get the PRV vouchers for both, not just LAD, but for Fanconi and Danon program coming up. So I think that's the good news, but we're working with the policymakers and the rare disease community to see if we can extend this, further, because I think it's really valuable for the biotech world and also for rare disease patient population as a whole. Probably its own separate conversation topic, but we are out of time for now. So, Gaurav and Kinnari, thanks so much for joining. Thank you. Thanks. Looking forward to more updates from Rocket in the months and years to come. Thank you. Thank you. Thanks, everyone.