I'm Josh Schimmer from the Cantor Biotech Equity Research Team. Very pleased to introduce from Rocket Pharmaceuticals, Gaurav Shah, Chief Executive Officer. Gaurav, welcome. Great to see you as always. Why don't you start by setting the stage for Rocket, where the company is now and where we're headed? Josh, thanks for having me, having us. Rocket is a gene therapy company. We are focused on rare genetic cardiomyopathies. We have three in the clinic, one representing each of the big buckets of genetic cardiomyopathies, which are hypertrophic, represented by Danon disease, arrhythmogenic, demonstrated by PKP2, and dilated, demonstrated by BAG3. We try to find assets that have a very clear mechanism of action, where we target the protein of interest in the cell of interest, and in which there's a high unmet need, and where we believe that we can see clinical results in a timeframe that makes sense for regulatory reasons. That's been our philosophy since day one. We actually started the company as an ex vivo lenti company, and we still have those programs, including the recently approved KRESLADI for severe LAD-I, a Fanconi anemia program, and a PKD program. We've shifted our focus to cardiomyopathies in the last few years to really be able to prioritize and use our resources most wisely, but we continue to seek opportunities to partner out the LV assets. We will be launching KRESLADI in the fourth quarter of this year for those patients who want access to it. In general, we have a pipeline underneath these six programs that's deep and equally exciting. We're very excited about the next 9 to 12 months, as there are numerous catalysts coming up. And then quickly on KRESLADI with the upcoming launch, how are you contemplating price? Well, we don't want to be the most expensive out there. But the reality, the truth is that the cost of non-therapy is pretty vast and pretty large, and even the numbers that are out there for other approved gene therapy products are lower than the actual cost of treating an LAD-I patient over the course of a lifetime. So we'll be announcing that at some point in the coming months, but in expected line with other gene therapies. Okay On the lenti side. On the cardiology franchise, as we think about the unmet need between Danon, PKP2, and BAG3, how might you rank order? Because we certainly when we talk to specialists, hear about the really devastating prognosis for Danon in particular, perhaps a little less so for the other indications. Yeah. There's almost an inverse correlation between the number of patients out there and the devastating-ness of a disease, right? So yes, Danon is very devastating. It's probably one of the most aggressive cardiomyopathies out there. Also the one where we can demonstrate clean, clear benefit in the single-arm trial, which we're working on right now for a pivotal trial. Danon, I would say we continue to say at least 15,000 patients in the U.S. and Europe. The next most devastating is likely BAG3, which is a dilated cardiomyopathy. It's a bigger market. We haven't come out with the actual numbers or epidemiology in that. And PKP2 is, of course, can be fatal with sudden cardiac deaths. There are more than 50,000 patients with PKP2 in the U.S. and Europe, but that's a disease that's heterogeneous and where we need to be very smart about trial design so we can win if it works. Okay. I guess one of the key investor active debates is your ability to really get the right balance of safety and efficacy with AAV gene therapy, recognizing that there can be some safety concerns with it. What gives you now the confidence that you've been able to hone in on the right dose, not just for Danon, but the general portfolio? Yeah. Unfortunately for AAV, there are no preclinical models that mimic the safety we see in humans. There's just no TMA model, there's no even platelets in the LFTs, and mice and NHPs and pigs tend to not fluctuate too much with AAV. We have to learn this in the real world and sometimes the hard way. In terms of the dose, we have now treated three patients with the revised regimen and the recalibrated dose of 3.8 E13 vector genomes per kilogram successfully, safely. These patients tolerate the therapy well. It's been a journey, right? Last several years, you learn so much from each patient. Even in phase I when we'd begun, when we first started with patient 1001, he got some steroids but nothing else, and he wouldn't take his steroids, and it took a while to sort of stabilize him. He did not have TMA. But I can say even that patient who is seven years out is working full time, and he's living a normal life in his mid-20s, which would be unexpected with anything else, right? So wherever we are in Danon, I think that the long-term path to success is about the positive benefit risk. I think on the safety side, I feel we've solved it with this recalibrated dose and this regimen. Obviously, we'll need to treat more patients to see for sure. I think that with AAVs for heart, this mid to low upper E13 range seems like the Goldilocks zone. We're in the same place with PKP2. We have not announced our BAG3 dose, but you can understand it's in that range as well. And that gets around some of the more common TMA and liver issues that are seen in the E14. What kind of a or maybe frame the totality of data that gives you that confidence, that kind of low mid E13 dosing can avoid some of the safety pitfalls that, I mean, obviously there's going to be a dose-effect dynamic, but specifically for this dose, how do you aggregate data and information and apply it here to say, "3.8, we're good. Yeah. The only time we have seen TMA in the setting of Danon disease was in phase I, where we were well above 1 E14 in one patient. In Danon at this dose, in a couple of patients, one of them had another complement activating mutation called CUL4B, so we don't know exactly what happened there. Another patient got sort of the higher end of the dose, and also had recent prior infections. It could be that all three of those patients had issues that we're going to screen out anyway with new patients. Having said that, the dose range in which we saw clear efficacy in phase I was anywhere between around 4 E13 up to 1.1 E14. This dose, around 4 E13, is at the lower end of the range of demonstrated efficacy, has a great safety profile both in phase I and in so far in our phase II. Also in our phase I patients who got around this dose, at least out to three years, which is as long as we've been able to follow them in the trial, they've had the most profound reductions in LV mass index and some of the most florid staining for LAMP2. That gives us a lot of confidence. Obviously, we'll see what happens with how the trial resumes and how those patients do on efficacy-wise, but on the safety, I feel pretty good about it. One nuance here is that you don't want to see nothing after you treat these patients, right? Just from a scientific side. You don't want to see no changes in labs. You want to see something because that gives us confidence that we're actually transducing cells, whether in the heart or liver or wherever. The fingerprint of the labs in the days following the most recent patient's treatment are highly reassuring. Is the risk of TMA with various AAV subtypes dependent on the underlying disease in any way? Are certain diseases more prone to complication, or is that not even a factor? I mean. Because we will have to extrapolate and aggregate information across disease settings as we think about each dose and vector. I would say that we have seen TMA for the most part with AAV9, perhaps with AAV8. And it is not always dependent on the dose also. Sometimes it is idiosyncratic. I think there are predisposing factors. One has to be very careful about screening those sorts of patients out, anyone with a complement activating mutation or recent infections. We have seen TMA across several disease types, and you also see it in the transplant setting, solid organ transplant setting. The body is primed to activate complement, especially when you get a torrential rain of virus in the body. I do not think it is disease specific. I also do not think, by the way, Josh, that there is going to be a long-term zero risk of TMA. I think that is not reasonable to expect. However, even the patients in our trial, and we hope there's zero long-term, obviously, and certainly in this trial, I don't know until it happens, but even the patients who had TMA in our trials early on, they've recovered fully from TMA, and I'm hoping that they also benefit from the gene therapy itself in the heart. I'm surprised this many years into AAV, recognizing some of the challenges of the administration, that we've not really made progress with non-viral vector type administration. Do you see anything in the field that's encouraging or promising? If not, why do you think that is? There are some pockets of encouragement, without naming companies. I used to sit on the board of a non-viral gene therapy company. It's hard to get around the early NHP toxicity that the field is seeing. I think that there will be room for growth in non-viral. I would say it's at least five years away to really see something impact on the clinic. Meanwhile, if we have a safe therapy with AAV, traditional in vivo gene therapy, traditional gene replacement, in addition to these three programs, we have at least three others that are equally exciting that we can apply this technology pretty rapidly. What I found really interesting is talking to cardiology specialists around Danon and their enthusiasm for your program, despite some of the safety considerations you've had to navigate through, is exceptionally high. I thought we might have heard a little bit of caution. "Well, let's kind of see how." But I guess perhaps reflecting just the dire nature of the condition and not necessarily feeling like there is time to wait and see how it goes. Your sense from the broader community, is that an accurate reflection of what you're hearing as well. Meg? Yeah, that's an accurate description. What we know anecdotally from the patient community is just that there's overwhelming excitement and enthusiasm for us to continue to develop this. We've had a number of community calls co-hosted with the Danon Foundation, by which patients, caregivers, and these families can come forward and demonstrate their support. In addition to the patient community coming forward, we have a number of HCPs that have participated as well. Your sentiment that you captured is extraordinarily accurate. That's what has us exciting and motivated when we're out in the field, and we're encouraging folks to actively use the ICD-10 code that's been in place for 29 months now. When we're talking to geneticists as well, to actively encourage use of genetic testing to genetically confirm these Danon patients. Rocket has stood up Mission: Genome, which is a no-cost genetic testing effort, and that is a way for these patients and HCPs to partner and sort of take the administrative burden off getting an accurate genetic diagnosis sooner. We're encouraged by this, and the HCP community certainly seems to understand that. Let's come back to that because that's really important. Maybe first, though, three patients dosed successfully. What happens now on your path to continuing enrollment and ultimately to potential BLA filing? We're in discussions with FDA, with this new data set of three patients, tolerable, good safety profiles, and we will announce when we know what the rest of the trial looks like. There's been no indication that there's going to be a change to study design. I don't know if FDA asks us to treat more patients than the 12 total they've agreed to, given the safety issue. But if they do, that's not necessarily a bad thing, because as we have more payer discussions, even for LAD-I, I'm personally realizing that the bigger the data set, the better for the commercial launch. So a few more patients is totally fine as long as the study design remains intact. We're in those active discussions now. When can we expect data updates from the patients treated? Before we move on to data expectations, it is also important to note that what we put out in our earnings in August, a couple of weeks ago, is that in addition to dosing safely these three patients at this recalibrated dose, we have enrolled over 50 patients in the natural history study. As Gaurav was mentioning, having a more robust data package with perhaps a few additional Danon patients treated in this pivotal study can be a positive thing. We have been working very actively behind the scenes, trying to look graceful like a duck on top, but pedaling very actively underneath to make sure that we have a robust patient population that we can tap into. Of the patients that were previously enrolled in the pivotal phase II study, to our knowledge, none of those patients have dropped out. We are in the process of screening those to ensure that all of those remaining patients are eligible to participate in the pivotal study. We have identified even more than that. In the event that there is a greater number of patients that the agency wants to see, we can tap into that. We also have the ability to tap into this patient population through this natural history study in the event that even more patients are needed. We have been hard at work to make sure from an operations and execution standpoint, we are ready to go. As we are thinking about the profile of the program and the risk we are trying to rule out by adding more patients, is there a sense of we are trying to rule out events that could occur north of 1% of patients, north of 5%? Again, recognizing because you have to put it in the context of the severity of the disease. Do you have a sense of where we are trying to aim for to rule out a risk? I think that, look, if we saw 50%, 70% TMA, that's a different product. We saw 10%, 20%, and those TMAs recover, and those patients never need a heart transplant, that's different, right? It's sort of like CRS in CAR T, which I participated in at Novartis. CRS was pretty common, yet the drug got approved because otherwise it's a fatal disease and there's no alternatives, right? Similar for Danon. I think in the oncology world, people are willing to take risks like CRS or TMA, and in the gene therapy world, they're just not. I think people should be ready to take risks because ultimately you'd rather have TMA, stay in the hospital for a month or two, recover, but then live a normal life. Just to go back to the data question, I don't think we've provided guidance on that just yet, but we will as soon as we can. Okay. Let's come back then to the patient identification efforts, because it sounds like you've been very busy. Beyond the 50 patients you've enrolled in the natural history study, what are you able to comment on beyond that for patient identification efforts, and. Yeah When are we likely to learn more? Last year, we had said that we would be providing a comprehensive program update for Danon. Unfortunately, we had the safety issues, so it is basically delayed a year. Now we are going to do it this year, both a top-down analysis that will give a lot more light and color onto what the true prevalence of Danon is, and we have done a much more sophisticated analysis of those numbers. Also a bottom-up analysis of patients that are reported in the field. We have not obviously put a lot of commercial efforts into patient finding, but informal efforts have led to some pretty good results there. We will be able to share both the top-down and bottom-up alongside a program update in the second half of this year. Maybe elaborate a little bit on introducing an ICD code. What? How does that translate from, "Okay, there is a code," to now we have a better sense of where patients are? Takes time. The code has been in place for 29 months, which means you have to be actively in the field with your geneticists, your MSLs, and talking to the HCP community as to why to use it, when to implement it, and that an accurate diagnosis matters. It is not just the ICD-10 code, it is also about encouraging an accurate genetic testing confirmation so that we can verify that these are Danon patients. It is in partnership. We have been tracking the usage and uptake of the ICD-10 code over the last 29 months, which has been positive, in line with other rare diseases by which an ICD-10 code has been recently introduced. From that front, it is fine, but it is not just pursuing that. You have to be in the community talking to these HCPs, because don't forget, Danon is an indication where there are multiple forms of symptoms that emerge, and sometimes the cardiovascular symptoms are the last to emerge or the last to get identified in these young boys. You actively have to be out there in the community educating on the healthcare benefits of looking at all of the symptoms involved. These are patients who I imagine will primarily be followed by pediatric cardiologists? It's interesting because it depends on how they present. A lot of times there's a subtle learning disability, there are some psychocognitive issues, even in the single-digit years. Later, patients might have muscle pain or muscle weakness. It's not really a cardiology issue early on. They often present to neurologists, to pediatricians, to psychiatrists, to musculoskeletal experts, and by the time they have a heart symptom, a lot of them get written off as something else that's not heart. Once the symptoms of heart come on, it's pretty rapid, and it's fatal in two or three years. Unfortunately, pediatric cardiologists are not seeing Danon patients as much as they should. Our educational campaigns between now and launch focus on getting not just the pediatric cardiologists, but the other contributors there as well. Got it. Roughly how many pediatric cardiologists are there in the U.S.? Do you have any rough estimate? I don't, but I know the three or four I trust for Danon disease. I'm guessing that that's probably a fairly straightforward effort to go into those clinics and get testing done. But the challenge is going to be- It's the community effort. All that other outreach. How do you even think about approaching that type of a dynamic where it's very spread thin, you're looking for a needle in all these different haystacks that may or may not be there? And especially when you're describing symptoms that don't scream Danon. Correct. A lot of times that is when the genetic testing component comes into play. The more that we can encourage accurate genetic confirmations of these diseases, so you are not just testing for Danon disease when a genetic panel is being ordered, you are testing for a whole suite of cardiovascular indications. That encouragement to have these HCPs do this genetic testing is really how you are going to get a sweeping effect and a scan for these diseases. How ultimately do you get this test into perinatal or screening at birth? Time. It is a multi-year process to get placed on the suggested national screening panel, and then you have to fight on a state-by-state basis. It takes a lot of time. We have studied intimately the journeys that some other rare disease companies have gone through in order to be able to be added to the infant genetic testing panel when their heels are pricked, and it is a multi-year journey. We have started that work, and we know we are in for you develop a couple of pilot programs, show those results to the national screening board, and then you move forward. Okay. Are there certain criteria that you need to achieve either in the pilot program or from a drug development program to have it added, or? There is no indication on these panels for which there is not an approved product. So there needs to be an approved product in order for these pilot programs to succeed. So that is step one. Yeah. If there is any company that could change the system to the advantage of patients, Rocket would seem to be one to have the passion and persistence and compass, right, to make sure that patients can be identified, especially in this condition. Yes. Where it seems like early diagnosis is really important. It is a hard diagnosis to make unless you have a high index of suspicion or are testing broadly in the perinatal setting. 1,000%. And I think that is where we put our Superman capes on. Yes. And we rely on the KOLs who are experts in the field to help get the message out there with us, and we look forward to talking more about that with our program update. And that's also reflected in. Okay. We'll talk about that more. Yeah. Yeah, that's also reflected in how we're building our commercial and medical affairs teams. There's more than sort of the account managers. We have genetic diagnostics liaisons and MSLs who are very well educated and cognizant of the genetic testing part of things, not just the physician relationships. That's how we're building our commercial team a couple of years in advance. So one very common point of discussion amongst investors is where are the patients, right? And obviously a lot of work and preparation going in to advancing the program, but if there's not a degree of confidence that there are going to be patients to treat, not just a little bolus in the first year, but something maybe more proximal to the numbers that you've laid out. But it's hard for us to find the patients and probably in the same way it's hard for you to find the patients. How do you address that concern now or at the event that you're going to host later this year? So it has been less and less difficult to find patients over each year that goes by. I think there's just greater awareness. Even in the time that I've worked on Danon, I've seen that it's easier to find, identify patients, screen for them, which is how we got really rapidly to the 50 + number of the natural history. So the patients are out there. They're not always in the big adult centers of excellence. They're often in the community. And as awareness of Danon grows, we're seeing more and more referrals. So I personally am not finding it hard to find patients. Secondly, each patient who's in the natural history or on the trial, the index case, we look at the rest of the family. And surprisingly or not surprisingly, there's always two or three or four other family members who we find have Danon and who didn't know they had Danon, or someone died at an earlier age of a particular reason, which is obviously Danon. So patients are there. They're just not being identified as Danon, largely because even in the U.S. today, only 10%-20% of centers actually do genetic testing. Even now. Europe, it's a lot more frequent. In the U.S., it's still very low, but that's the mindset and practice that we aim to change. And yes, Rocket is going to be relentless. Okay. It feels like at least for the time being, we've put aside the female Danon population. I'm guessing they come back into play as you've established the safety profile because they may have a little less severe phenotype, and so a more robust safety data package would be warranted. How do we think about timelines and potential to address that part of the market? The female program is a very important part of the Danon life cycle. There is a lot of inbound interest from the Danon female community. There are certain Danon females who have devastating severe disease, not unlike the male population. Those are probably the patients that we will look at first. The FDA has themselves volunteered or asked us to start developing a female trial, so the only thing stopping us is just getting the male trial up and running and far enough to get some traction before we shift focus. As we think about the Danon population, you have estimated 15,000+ U.S. and Europe. How should we be slicing and dicing to those who would be suitable candidates for. Yeah. For therapy? For males, almost all males invariably progress to heart failure on average by the age of 20 or pass away. So there is really a homogeneous population within the male subgroup. There is going to be obviously several who already got transplanted, so they cannot get gene therapy. There are some who are going to have antibodies. I think the rest of them who are currently eight years or older, but in the future, maybe even less than eight years old, are all going to be eligible. We will address the addressable population as part of this program update, but that gives you a rough ballpark. Females. Yeah, I'm sorry. On the female side, it is more heterogeneous, but females also progress invariably and almost always die of heart failure. It might not be the same penetrance as males, but it is not going to be trivial. In our checks, I routinely come across docs who at least claim to have adult male Danon patients, maybe a female as well. Is that those anomalies, or is there something there that you may be able to pursue? I do not think I have run across more than a couple of male patients who are older than 40 or 50. They are out there. I do know they are out there, but they are not a lot. There are 85 to 90 types of mutations that could constitute Danon disease. If you include some variants of unknown significance, it could be over 100, and they are not all made the same. There are splice variants, there are truncations, and it could be that some of the splice variants are a little bit less aggressive and those patients live longer. Regardless, they are going to have symptoms of the lack of LAMP2 over time. Even those milder phenotypes are going to be eligible for the gene therapy. Maybe we can turn to PKP2, which is two problems in one. There's the arrhythmia, then there's the cardiomyopathy component. As you think about advancing this program, recognizing that some patients may have more of an arrhythmia, some may have more of a cardiomyopathy, and there are two endpoints to consider, how do you advance this towards a pivotal? Yeah, I think arrhythmogenic used to be called ARVC, it's now ACM, arrhythmogenic cardiomyopathy. The key problem is in the name, arrhythmia. One of our advisors and someone I really respect and trust is Barry Greenberg, who's working with us on some of these trials. It makes sense that if you can shift the profile of arrhythmias, then you can shift the nature of the disease over long term. So arrhythmias have to be part of whatever trial we design, including potentially primary or secondary endpoints. The RV dysfunction tends to come a little bit later in life. In our trial, we've actually seen someone with RV dysfunction convert from abnormal to normal, which was very reassuring. I think we're going to target the moderate to severe population, but not so severe that they can't benefit from gene therapy. So I think that's the Goldilocks for PKP2. The trial design discussions are ongoing with FDA, and we hope to have something as soon as possible. Got it. For BAG3 as a dilated cardiomyopathy, especially maybe in light of some of the FDA questions around Capricor's own program and echo measures and the reliability in a dilated cardiomyopathy setting, what do you think are approvable endpoints that you can explore and characterize early on? Ways to look at LV function, whether it's EF or strain, or a clinical exercise output, are all valid. I think there are learnings from the Capricor review, including ensuring that we don't have a lot of missing data points, ensuring 100% agreement on the SAP before we embark on the trial. I think the Capricor experience does not negate LV outcomes as viable outcomes with FDA. It's just how we get there that we need to be careful and thoughtful about, and we are. I guess the potential to show a benefit in a single-arm trial may depend on your ability to actually reverse the dilated cardiomyopathy. Yeah. Is that feasible? I actually don't have a good sense as to the ability to remodel a dilated cardiomyopathy to improve ejection out. Yeah. Mice and humans are not the same, but we've seen complete reversals in the mouse for sure. We don't know if we're going to see it in humans. My sense is that gene therapy is the most profound type of therapy out there. If anything's going to reverse it's going to be gene therapy replacing DNA at the core. All right. Eager to see more updates from Rocket across these programs. Gaurav, Meg, thank you so much for joining. Thanks for having us. Thank you, Josh. Thank you.