All right, thanks everyone for joining us for the next half-hour session. Again, my name is Dae Gon Ha, one of the biotech analysts here at Stifel. For the next half hour, it is my pleasure to host Rocket Pharma. And from Rocket, we've got Kinnari Patel, President and COO, and we have Jonathan Schwartz, who has this very fancy title, Chief Gene Therapy Officer. So thanks to both of you for showing up today. Let's start off with a brief overview. I know a lot of us know your story, but for those of us that are not familiar, give us a brief intro, and we'll dive right in. Sure. So Rocket Pharmaceuticals, we've been in this industry, in the business of selling gene therapy for about eight years now, and we really started as a lentiviral company that focused on developing first and only curative gene therapy for diseases that are severe, unmet medical need, only treatment option is bone marrow transplant. So we started as a company that focused on Fanconi anemia, PKD, LAD-I. These are really a lentiviral portfolio. About five years back, we said, "You know, we're not a platform company. We're really drug developers at the heart of it." So when we came across great programs like Danon disease, we said, "You know, let's use the AAV technology to see if we can make something happen for our heart disease using AAV platform." So now we have a portfolio of therapies that are publicly known, ranging from a BLA that's under review with FDA for the lentiviral portfolio, and the second one being submitted next year, to our Danon program, starting our phase II pivotal study in U.S. and Europe. And we have two other cardiac, monogenic diseases, PKP2 and BAG3. One's in the clinic, and the other one's going to the clinic next year. So there's a portfolio of AAV and lentiviral programs ranging from hopefully commercialization next year to pre-IND, and that is just the tip of the iceberg. So those are our disclosed programs. We have quite a bit of programs being worked on. Our goal is to have really one new IND come to the clinic every year. So we think, we're here for the long run, and, and we wanna do things better and better and learn from each program and add to it. Okay, let's just going by the interactions I've had with the investors. I'm gonna start with Jonathan. Danon. So you've recently had that update on the phase II trial design, which was met with great enthusiasm. Remind us of that trial design that you were able to reach an alignment on, and if I could just tack on, is that alignment just with the FDA, or how does the communication look like with the ex-U.S. regulators? Sure. So the alignment with the FDA for the pivotal phase II Danon study is that this is a single-arm study with 12 patients, supported by ongoing external control, including prospective natural history, with a primary endpoint which is a composite at 12 months of myocardial LAMP2 expression, protein expression, as well as a reduction or stabilization in left ventricular hypertrophy, specifically at least 10% decrease at one year from baseline in left ventricular mass index. And obviously, though the co-primary endpoint is supported by additional secondary endpoints, including a key secondary endpoint which is troponin, specifically high-sensitivity Troponin I. Other biomarkers including natriuretic peptides, NYHA class, multiple quality of life parameters, including the KCCQ, and others. Mm-hmm. And I'll ask Kinnari to join this response with respect to, with respect to the status of EMA and the, and the specifically renewed dialogue between the agencies. So the great thing is, over the last two years, FDA and EMA have really started collaborating. So any products that are PRIME or RMAT designated, they started doing discussions on a routine basis, and because Danon program has both the RMAT and the PRIME designations, we've been having these discussions not just with FDA, but FDA is having it directly with EMA, and we've had conversations with EMA. So this phase II study that has been aligned with FDA was recently submitted in the EU for CT application through a centralized process. So that has been agreed, so it's the single phase II study that's gonna serve both U.S., Europe, and of course, MHRA. Mm-hmm. Is it the expectation then, the N = 12, which we'll dig into a little bit, will be all conducted in the U.S. then, but still satisfactory to the worldwide regulatory agencies, or will you open a new center? So we will have both U.S. and European centers, a total of five to six centers across the U.S. and Europe, to have the N= 12 patients enrolled, and that data will be used across both regions. So how we think about having the distribution is, given the U.S. is up and running already, majority of our patients, so 60% of our patients of 12, at a minimum, we want to treat in the U.S. We wanna have a few patients treated in the EU for things like... In Germany, if you treat a patient there, it's easier for payer and, and commercialization purposes, right? Mm-hmm. If you have a patient treated in the U.K., you can have a representation for MHRA approval along with the MAA and EMA. So that's how we're thinking about the European sites being brought in. So it's gonna be a handful of patients in the EU of the N = 12. Got it. I think the specifics necessitate a little bit of an explanation. N = 12- Mm-hmm. But you also are starting with the two pediatrics before you go into the 10 adults. So walk us through sort of that cadence of N= 2. I think we've previously talked about sort of activating the pediatric sites earlier. Mm-hmm. Recognizing the adults will happen sequentially. Have you identified and/or dosed those pediatrics? And also talk about the N = 10 adults. So I can certainly get started and hand it off to Jonathan. We've identified more than enough patients to have beyond 12 patients be identified for the study across Europe and the U.S. and Europe. The two pediatric patients, what happened is for our phase II study to be pivotal and to avoid future comparability or commercialization issues, we brought in manufacturing in-house. And when we brought the manufacturing in-house, our product was purer, better full to empty ratios, and some other optimizations we had done led to the FDA saying: "Hey, for the pediatric, which is considered vulnerable population, can you do a safety run-in?" So we're doing one patient, waiting a minimum of 30 days, second patient, waiting three months before we can have the pediatric cohort be full, fully enrolled as needed. Adult, so patients 15 and older, so the adolescents, older pediatrics can be enrolled simultaneously. Mm-hmm. So those activities have been initiated in the U.S. Okay. And just to be perfectly clear, Dae Gon, the total study of 12 will be a combination of pediatric and older patients. The restriction is just that the first two patients who are younger than age 15, who are eight to 14, need to be enrolled sequentially with 30 days interval between them and need to be followed each for 90 days- Mm-hmm ... before additional pediatric patients can enroll. Mm-hmm. We anticipate that the study will be a mix of older and younger patients. Mm-hmm. Likely, the majority of patients will be between the ages of 10 and 14. Mm-hmm. There will be potentially some as young as eight, and potentially some in the older teenage or young adult years as well, as long as they meet eligibility criteria. Okay. But it's not like there's a split between two peds and 10 older, or for that matter, at this point, even any other hard divider between the younger and older patients. Gotcha. Just to clarify, though, for the first two, I guess we would label them run-in rather than just phases. Mm-hmm. First one dosed 30 days before the second one gets dosed, but then at what point can you start going into the N = 10 expansion? N= 10 could start in parallel for 15 and older. Just the peds population, we would have to wait three months after the second ped is treated, so we can have additional pediatrics be involved with that staggering. Got it. Okay. Yes. We had a number of discussions around the composite endpoint. Jonathan, you and I previously chatted about this as well. The confidence seems to be around the LAMP2 expression, given that you're directly delivering it with the gene therapy, therefore, you should see it. But the hesitation is more on the left ventricular mass reduction. Mm-hmm. Specifically, when we think about the phase I experience and what you've seen there, because of COVID and various timing issues, not every patient has had the 12-month data point there. Can you maybe remind us what you've collected, what you've seen in phase I, and how you kinda got around the confidence in that 12-month for the left ventricular mass data? Sure. So I think, very importantly, every patient, every patient who on phase I, six of seven- six of six, who would have been eligible for phase II, had at least 20% reduction in left ventricular mass or left ventricular mass index. In the two pediatric patients who were most recently treated, they had more than 20% increase at 12 months. In the adult patients, the trajectory was a little bit different, but again, all patients would have met that criteria. In the adult cohort, we saw ongoing remodeling and evidence of reduced left ventricular mass beyond 12 months. And that is probably indicative of, in part, because cardiac remodeling occurs over time, in part because the pediatric patients received the immunomodulatory regimen that had less steroid and a faster steroid taper. And it's quite likely that the steroids do contribute to some degree of edema in the weeks and months after therapy, and that includes potentially myocardial edema. In the phase II study, all patients will receive that enhanced immunomodulatory regimen. It utilizes sirolimus and rituximab, and a lower dose of steroid with a faster taper, such that almost all the patients are likely to be off of steroids by three months after therapy, and on low doses of steroids by two months after steroid therapy. Got it. Kinnari, you earlier mentioned, you have way more than the N = 12 that you're aiming for. What's your flexibility in terms of enrolling this 12 versus maybe broadening it out to overpower it, if you will? It's a great question. I think what we're trying to do is just understand the disease as a whole from male and female population. So the patients we've identified, ideally, from a regulatory perspective, I'd like to keep it as N = 12, right? But if there's a significant unmet medical need, a patient comes and cannot wait till it's commercially a viable product, then we're gonna make an exception of having one or two additional patients be treated, more because they really need the therapy, and it could help with the overpowering. But at this point, we're really focused on the initial 12-patient treatment. Mm-hmm. And yes, Jonathan. Yeah, we can always make it larger. And remember that it is open label, so we do have an opportunity to review data, and make decisions about enrollment, and questions like this, you know, really at a number of different junctures throughout the course of this study. Okay, that's interesting. So in addition to the open label nature of the study, I would imagine there is some DSMB between the run-in patients and then the N = 10. Mm-hmm. What additional monitoring is there in between or aside from N = 2 and N = 10? The first two weeks of monitoring, if you mean? So, in addition to the Data Safety Monitoring Board, there's also a clinical monitoring team that includes not only investigators and sponsor medical representatives, but independent experts in hematology and immunology, who are reviewing lab values during the initial two weeks and even sometimes longer, specifically with emphasis on complement activation and other early safety signals, and helping make recommendations about safety monitoring. The independent data monitoring committee obviously will review data from the first two pediatric patients, and then we'll continue to review data, you know, likely no less frequently than twice per year, more frequently if there are any events that warrant their input. Mm-hmm. Mm-hmm. Is there any flexibility on the 12-month measure of the LVMI as well as the expression? There's always flexibility. I think it's all gonna be based on data, right? So if we see great signal earlier on, and we see a clear benefit-risk differentiation, I think it warrants a conversation with health authority to share that- Mm-hmm ... along with our IDMC members. But 12 months is how we're projecting it at this point. Okay. Yeah. Yeah. And certainly, you know, if in the initial patients who are on the study, we see what we see at 6 months is highly indicative of what we see at 12 months, then for some of the later enrolling patients, we may be able to take things forward. But again, at this point, we're anticipating that we'll need to follow the 12 patients for 12 months. Right. Base case, 12 months. How should we think about the demographic for the N = 10? You mentioned it could be younger, it could be older, but I think with the phase I and the higher dose, one patient unfortunately had been so far gone- Mm-hmm ... that the gene therapy didn't really benefit them. So what are some key learnings there, and how are you thinking about sort of putting that bracket on the age group? Yeah. So I think, I mean, obviously, the age is something we continue to pay attention to. It is very conceivable that you will have some patients who maybe are in the, you know, later teenage years, who still meet eligibility. And I think the most critical eligibility restrictions to make sure that we're not treating patients who have, extensively advanced fibrosis- Mm-hmm ... and who have end-stage cardiomyopathy, or are likely to be a year away from transplant or death, is really the restriction on left ventricular ejection fraction. After that high dose, older patient was treated and had progressive cardiomyopathy, we recognized that, okay, this was the only patient on the phase I who had a left ventricular ejection fraction of less than 40%. So we implemented that as an additional criteria for the pediatric cohort. For the phase II, that criteria is that patients are excluded if they have a left ventricular ejection fraction less than 50%. Mm-hmm. And remember that in hypertrophic cardiomyopathy, such as Danon disease in males, LVEF is generally preserved through until patients have much more advanced fibrosis and are at end-stage cardiomyopathy. And that's true not only for Danon, but for most HCMs. It's really. It's similar to what's known as heart failure with preserved ejection fraction, HFpEF, if you will. And so we don't anticipate that restricting enrollment to patients with at least a 50% LVEF is going to exclude otherwise eligible patients. It will exclude patients whose cardiomyopathy is so severe that the transduction is unlikely to rescue them. Mm-hmm. I don't think we've heard much about the full approval. We've heard about the composite biomarker-driven changes at 12 months. What can you speak to in terms of agreements there, and what are you leaning towards? Yeah. So FDA was very collaborative in our discussions, so actually, we ended up changing our core study to a five-year study instead of a two-year study. Why? Because they said, you know, if you follow these patients long enough in the core study, you can use the same N = 12 patients with a longer follow-up to convert it to a full approval. So we won't need additional phase III or post-marketing study as a confirmatory. These patients are going to be followed, and in addition to the primary endpoints that we talked about, we're also going to be collecting key parameters like BNP, troponin, KCCQ, quality of life measures, as well as NYHA classification. So totality of that evidence over a duration of three to five years would convert this to a full approval. Got it. Right. And obviously, FDA will also pay attention to incidents of end-stage heart failure events. In other words, heart failure hospitalization- Mm-hmm. requirement for mechanical circulatory support, like an LVAD, transplant, or death. Yeah. And especially as one gets out to two or three years- Mm-hmm. or, certainly to five years, one would anticipate a specific incidence of those events. Mm-hmm. And we'll obviously have a specific incidence of those events for natural history patients who are not treated. Mm-hmm. And I think with that data collectively, that gives the FDA. Mm-hmm. a lot of confidence for, for full approval. You mentioned the prospective natural history study. Mm-hmm. Will you present that at a certain point, the full extent, so we can start to appreciate the overall disease course of these subjects? Yeah. So the prospective study, we started about four to five years ago with N = 10 patients. That is ongoing, but we've actually started a second study. I think it's getting posted this week on ct.gov, and it's going to be both U.S. and European-based. And so that prospective study will have 36 patients with Danon disease, both males and females. Mm-hmm. That information, as we have substantial data being collected, will be presented publicly. Okay. Okay. Any questions from the audience before we pivot? Okay, 601, you guys initiate that, that study. That's wave two. Mm-hmm. Talk to us about sort of the read-through that Danon is providing for this particular program, what the nuances are between Danon disease versus PKP2. Sure. So, I mean, I think that the big Danon read-through is that the tropism of many of these AAV serotypes for the heart is not just something that you see in a research lab- Mm-hmm. that it applies to patients, to... In the clinic. And that's true for, I think, AAV8, AAV9, AAV10, and rh74, which is an AAV10 variant. And you know, remember, when we started the Danon phase I, there were a lot of people, including some reasonably smart people, who did not believe that it was going to be feasible to meaningfully transduce cardiomyocytes with AAV9. And I think a lot of that was based on much older work that had been done with AAV1 targeting SERCA2a, those Celladon studies that you know, were initially promising and then subsequently rather disappointing. We were basing our findings really more on the serotypes, like AAV9, that had a fair amount of animal experience in mouse, in dog, in primate studies that showed a really stronger propensity to transduce heart muscle as opposed to skeletal muscle- Mm-hmm. anywhere from three to five-fold greater, to 10-fold greater, to even more than 10-fold greater propensity. And I think that that's really what the RP-A501 Danon study demonstrated. For RP-A601 in PKP2- ACM, we opted for rh74, largely because our preclinical experiments in a very meaningful murine knockout model demonstrated an overall greater benefit risk, higher efficacy, and more consistent safety relative to an AAV9 construct that was also evaluated. So we really went with the vector that seemed most appropriate for this specific condition, and also basing the overall clinical safety profile of rh74 across programs, including in Duchenne, where it's been given at very high doses, with a reasonable safety profile to date. Mm-hmm. So all of that contributed into the decision to go with A 601 for PKP2-ACM. When we think about the clinical pathogenesis of PKP2-ACM versus Danon, for example, are we thinking a similar trajectory of small phase I and then maybe a phase II biomarker-driven AA accelerated approval? I think that that's certainly something that's on the table. Mm-hmm. It's hard to commit right now. I think we'll need to see some efficacy and safety data in phase I. Okay. Mm-hmm. Obviously, the good thing is that PKP2-ACM is a very well-characterized disease. This is a disease for which many patients are identified and are followed in and participating in different cohort studies at Johns Hopkins and elsewhere, so that a lot of different disease features have been characterized. There's a risk prediction model that makes use of any number of disease features, including some very straightforward electrocardiographic findings and things that you can measure on Holter monitor. So there's a lot of natural history information available. What's different from Danon disease is that it's, although it is a life-threatening condition that does cause a lot of sudden cardiac death in young, you know, teenagers and young adults, it's not as uniformly and rapidly fatal across the board as Danon. So those are some of the features that will factor into what the phase II study design is. Whether or not we'll be able to do a single arm for a pivotal or not is, I think, to be determined. But fortunately, there is a lot of really strong natural history data and risk prediction data existing already in the community. That was something we did not have for Danon disease when we started the program. I see. Did you guys guide to when that phase I, 601 data could be expected at all? We have not. Okay. Okay. But it is an open-label study, so, you know. Yeah ... as we have cohorts of patients that are treated and have meaningful- Yeah ... benefit risk information, we'll make it available at medical conferences. Got it. Okay. Not a sell-side conference in early January? No. Okay. All right, Wait, there's a sell- side conference in early January? It's a good location out there. Let's briefly talk about 201 and your broader lenti ambitions. So congrats on the BLA acceptance, and now we have the PDUFA date. Any inclination or communication on an advisory committee, and any other, like, things or you're hearing communication-wise? Right now, we're based on a clear benefit risk, having a commercial product from patient one onwards be given to each patient. So the benefit risk, unmet medical need, and the high quality of CMC product, we don't think there'll be an advisory committee, but at this point, you know, FDA could change their mind. If we know there's an advisory committee, we'll absolutely let the street know. Mm-hmm. But at this point, we're not planning for one. Mid-cycle review has come and gone. It's gonna be coming. Coming. Okay. Around... Are you able to disclose around when or- Usually, it's. I think we did disclose when we submitted, so around December. Okay. Okay. All right, so sounds good. What about in terms of your pre-commercial activities, given that this is a very small, rare orphan condition, what are you guys putting your efforts on right now? We strategically focused on making this product available in the U.S. and not submit the MA at this point. So our commercial colleagues, we have a great commercial team with our Chief Commercial Officer, Carlos Martin, and he has a team of experts that worked on AAV, ex vivo l enti, and CAR T commercial launch activities prior to joining Rocket. So they're really putting together centers of excellence and having that set up in the U.S. What our plan is really for LAD, when we make that available and go through the payer's perspective, all of that experience will be actually added to Fanconi anemia, which is our bigger lenti program, and that's going to be filed next year in U.S. and Europe. So our plan is really do something small, learn, de-risk, get the experience, and add to it. It's gonna be a systematic improvement in our commercial launch strategy. By the time we get to Danon, we'll have plenty of experience with at least two products commercially viable in the U.S. and Europe. I'm gonna go a little bit over time. Hope you can bear with me. Fanconi 102, I think the prior guidance is BLA by year-end. The latest update is first half 2024. Mm-hmm. Walk us through sort of the, the behind the scenes, what happened there, and sort of additional work that needs to get done before the submission. Not exactly additional work, just pen to paper, and trying to get all of the CMC, the data, and all of that put together. I think being a biotech company with such a great portfolio, we're always trying to just resource manage our prioritizations. So it's pure execution at this point, getting the submissions to the health authorities and fine-tuning some sections of what we learned from LAD into the FA filings. Gotcha. Okay, and the boilerplate question, cash, cash runway, milestones. Cash runway end of 2025 into 2026. So, with the last financial raise we did, we're pretty comfortable for the next 2 years or so. This also does not include the PRV we're expecting to get for LAD-I. Mm-hmm ... and upon Fanconi when it's submitted and getting that, which is great, about a $100 million each non-dilutive funding. Yeah. So this is without that. In terms of milestones, we are feeling a little bit more grown up now with the Danon behind us first BLA in. So our milestones really gonna be, our focus is just executing on our six programs that we have publicly disclosed. When we have meaningful PDUFA dates available, we will make it public. When we have substantial number of patients on the end of phase II study treated, and all of these systems, we'll have that data be publicly available in medical conference. It's like the no real guidance beyond Fanconi being filed next year. Hopefully, second half of next year, we'll have some Danon update coming out. Mm-hmm. Maybe PK, PD, but no formal guidance. Got it. Okay, well, with that, I guess we can we can wrap it up. Kinnari and Jonathan, thank you very much. Thank you so much.