Welcome to day two of the Bank of America Healthcare Conference. I'm Greg Harrison, one of the biotech analysts here at B of A. This afternoon we have Rocket Pharma here with us, with Gaurav Shah, the Chief Executive Officer. Gaurav is gonna make a couple opening remarks, and we'll jump into Q&A. Thanks, Greg, for having us here. It's a wonderful conference each time. This is a year where I believe we're gonna see a lot of progress with gene therapy in general, certainly at Rocket, but across both AAV and Lenti with other companies. We're very excited. Rocket specifically is poised on becoming commercial soon, in 2024. We're in transition period from being an R&D company into being a full-on commercial company with integrated manufacturing. We're very excited about that. We have some key inflection points, I would say, in the next 12 months around Danon, Fanconi, LAD, PKD, and now our new program, PKP2-arrhythmogenic cardiomyopathy. We're very excited. I always feel like we're just getting started with this company. Great. Yeah. Let's talk about the transition to becoming a commercial company. Should have INDs this year for LAD one and Fanconi. How are those preparations going as you. Mm-hmm. to commercial from a clinical company? The LAD is a great starting point because it's a devastating disease. It's not a common disease, so it's not gonna be so much effort on establishing a global commercial footprint. There's already a lot of inbound interest to certain sites and centers of excellence that we're gonna rely upon quite a bit as we move into the commercial phase. We do need to set up the supply chain and have adequate manufacturing and other variables in place before we launch LAD. Fanconi is a bigger market. We've now discovered and identified thousands of patients with Fanconi anemia. For that program, I would say that there's 3 approaches, three pillars or three legs of the stool. One is it's a value-based story. We have to start talking about pricing, so we're engaging payers, and we're thinking deeply about that as we move forward. Number two, the second leg is driving demand, right? You have to create the market here. It has a couple of components. One is patient finding, patient identification. Another is education of HCPs and KOLs. All of those patient finding as well as driving demand measures are already coming into place now for Fanconi. We're already seeing sort of early signs that there's a lot of excitement in the market about using a gene therapy with no conditioning. I would say the question is why not try, right? Before you have a transplant. The third component here is supply. We have to ensure that there's enough manufacturing supply. We don't wanna be in a situation where we've driven demand, but we have to have a lottery system or something, right? All three of those legs of the stool are coming together. The key here is to start early, to prepare early. We're fortunately not the first to launch in either Lenti or AAV, so we can learn from the successes and challenges of many of our colleagues here as we move both into the U.S. and European launches. Okay, great. Yeah. How should investors think about pricing? you know, there's some analogs out there of, you know, previously approved gene therapies. When you look at the indications, you're going into LAD-I one, ultra rare. Yeah. And Fanconi is still very rare, but not as rare. Does the prevalence of the patient population play a big role in pricing? How should we think about that, especially when people look forward to Danon, which is, you know, much larger population? The more rare a disease, in some ways it's easier to justify higher prices because you're drawing down less total funds from the market, right? That's gonna be an inverse correlation that holds true regardless of what therapies or what diseases we target. I would say that the analogs that are already out there are appropriate. It's not just about the price, it's actually about the uptake in the market, right? Because having a high price but having very little uptake is not gonna either help patients or it's certainly not gonna help the company. I think selection of assets, again, is critical here, right? Being first, hopefully best and only in class, so there's no one else going after the same indication is important. Number two, having a clear mechanism of action where we can target an area of high unmet need is important. Thirdly, the disease itself needs to be one where it is so obvious that a gene therapy approach that could be curative is the best path forward, right? You wanna select diseases where potentially, unfortunately, there's fatality early in life, where there's a high demand naturally existing amongst those patients and physicians to seek something like gene therapy. You can't pursue gene therapy in a nice to have indication. It has to be sort of a devastating illness. I think all the ones that we've selected, you know, meet all those criteria. I believe that as we move into commercial phase, those fundamental principles are gonna come to play again when we discuss both pricing and uptake. With these first two indications, LAD-I and Fanconi anemia, how is the current state of diagnosis and patient identification, and what sort of work lies ahead there? Fanconi anemia is a pretty well-characterized disease. The true prevalence, our estimates of Fanconi anemia, if you include all the complement types, are between 6,000 and 8,000. I would say that about half of those patients have already been identified. There is a global organization called FARF, Fanconi Anemia Research Fund or Foundation. FARF has been working on Fanconi anemia for about 30+ years now, and created a really, a global community around diagnosis as well as treatment. There is another 50% still to be identified, and we do that through again, education, through screening, and that effort is starting. It's already started at Rocket in conjunction with FARF, so we collaborate very closely with them as well. Okay, great. Talking about larger indications, let's change gears and talk a little bit about Danon disease. You know, for those who are new to the story, maybe can you just give a little recap of what you've shown today, and what impact your gene therapy has been able to have for these patients? Yeah. Danon disease is one of the most devastating forms of cardiomyopathy out there. The largest heart on record is a Danon heart, especially in boys who invariably pass away, if not in their late teenage years, early twenties, without a heart transplant. Even with a heart transplant, the median mortality survival is around 19 or 20 years old. It's a disease of autophagy. These patients are missing a protein that's essential to clean out debris within the cell. The patients get diagnosed relatively early in life, 8 to 10 years of age or so, but they're not always first presenting with heart failure. They present with neurological issues and muscle weakness, so it's hard to diagnose and identify these patients in the real world. That's something that we're working on as we identify more and more patients. What we've seen in our phase I trial so far, seven patients were treated, six of those were selected appropriately and treated appropriately. All six of those have had either stabilization or in most cases, improvements across every measure that we looked at or every biomarker or clinical endpoint that we looked at. Number one, protein expression. They all had protein expression. Number two, a reduction in vacuoles. You actually see these vacuoles that represent debris buildup in the cells decreasing on heart biopsy. Number three, BNP, which either normalized or decreased remarkably in every single patient. Troponin, which normalized and decreased in every single patient. LV mass, which is the best measure of progressive left ventricular hypertrophy, LV thickness, which is another corollary, NYHA class, and quality of life scores as measured by KCCQ. It's rare in treating anything that you see improvements in every single parameter you measure. I also wanna say that it unequivocally has correlated. Those outcomes have correlated unequivocally with positive protein expression. Yeah, I feel like we've cracked open the door to cardiac gene therapy with this disease, and there are many more to come. That's fantastic. Yeah. You talked about some of these endpoints. Which do you think are most important when it comes to a pivotal trial here? Yeah. What do you think are the appropriate endpoints that you would like to look at in order to get a trial that, you know, would be of a manageable duration? The good news is that you could select any of them, right? We wanna focus on the ones that we think are most likely to reasonably predict clinical benefit and can support an accelerated approval pathway. Our current thinking is protein expression is completely relevant here. First of all, it's a full length wild-type transgene that we're inserting. It's not truncated. We think that the other biomarkers that might form a composite endpoint need to be as objective as possible. What is the most objective measure here? It's lab values. We know that BNP is correlated with worsening heart failure and, you know, lowering BNP with improving heart failure. Troponin is a marker of cardiac injury. Some combination of those three, we feel could justify an accelerated approval pathway where these markers reasonably correlate with clinical outcomes and can justify a, you know, a manageable trial size. Okay. Now, I know there's, you know, discussions with FDA happening this year on what the trial could be. What other aspects of the trial do you think would be an appropriate design, you know, as far as size, patient population, duration, those sorts of things? Yeah. Our guidance has not changed really in, I would say since we had the end of phase I meeting with the FDA at the end of last year. We think that the trial would be less than 50 patients, single arm with a, an external natural history as a comparator, a 12- 18-month time to endpoint, and, you know, the biomarker composites that I mentioned. We will have some key secondary clinical outcomes here, including NYHA class, quality of life scores, that are gonna be relevant, especially as we follow these patients longer, potentially for a full approval. Okay. Got it. This is a, you know, a key point for investors, in the stock is, you know, what's the trial gonna look like? How long it's going to take? Of course. When could we expect some sort of update, on the, whatever agreement comes into being with the FDA? As soon as possible. I mean, the one thing we can control is to get the trial ready, to get the patients lined up, and the other thing that we can't control is the FDA, right? As soon as possible. You know, trial activities are, already underway now, so. Gotcha. Now since you've been, you know, running the current phase I, what differences have you noticed, if any, in diagnosis of Danon in general awareness, just as a result of there being a potential treatment out there? Yeah. Within the Danon community, there has been, I would say, an unbelievable interest in this gene therapy approach. Their lives have really been transformed. The example that we talk about in the company and outside the company frequently is one of the pediatric patients who was treated recently. In the couple of years prior to gene therapy, when he went trick-or-treating, he had to be pulled around in a wagon. A year after this, almost a year after this gene therapy, the last Halloween, it's Halloween, right? For trick-or-treating with. He was running from door to door, it was a remarkable change. Even after two hours, he couldn't be pulled back to go home. From wagon to running around like a kid should, it was something that we didn't expect, the family didn't expect. Some of these stories are getting out there in the community. We're not putting them out there publicly or formally, but they're just sort of, you know, being socialized. I think there's a lot of interest, not just for males, but a lot of females also have early devastating disease. That's also translated into a lot of interest in the phase 2 trial. We have more than enough patients already lined up to fill the whole trial plus quite a bit. I just wanna get this started, you know, get going as soon as possible. Definitely. With all those patients lined up, how should we think about timing then? You know, once you have agreement on the trial, enrollment, I would assume, would be pretty quick. Yeah. You know, getting to data. Yeah. We haven't provided official timeline. We need to know the size of the trial and the endpoints and all of that, of course, before we can say exactly how long it'll take to enroll. We'll come back with that specific point with some clarity. Okay. Maybe we can talk a little bit about the PKD program. Where are you at there with PKD and where would you see it fitting into the treatment landscape? This being, I think, your only indication where there's really another approved treatment. Yeah. No, great point. PKD, first of all, is the largest Lenti opportunity. It's up to 80,000 patients in the U.S. and Europe who have PKD. On the larger end or larger than Fanconi. We have shown data in two adult patients. We've enrolled all the patients in the phase I now, as we've disclosed. We'll have an update at ASGCT next week on that. We're starting with the severe population, which is very different from the Agios compound, which is targeting a little bit of a mild to moderate population. I think that, you know, without comparing directly, for severe patients, certainly, we've seen six or seven-point increases in the hemoglobin that have been sustained for more than a year. Again, when gene therapy works, it really works. I think certainly patients with severe and even severe to moderate disease or moderate to severe disease are gonna be open-minded about a one and done treatment that can normalize their hemoglobin versus something that you have to take the rest of your life with more modest improvements that aren't even 100%. I think we'll be able to focus on 50% or more of patients who meet those severe to moderate criteria, certainly as we develop the drug in the market. Mm-hmm. What's the path to, the market here in terms of clinical progress? You know, every time we finish a phase I'm thinking, "Why can't we just file based on the phase I?" Because the data are so remarkable. We will need to do a pivotal phase II trial that we hope will start by the end of the year. We're gonna target by the end of the year to start it up. In PKD, the path is clearer than in Fanconi even, where now it's clear, but we have to figure out that mitomycin C resistance in Fanconi anemia was a good surrogate biomarker. PKD is like other hemoglobin disorders or hemolytic anemia disorders, where you can measure improvements in hemoglobin, as well as transfusion independence as accepted endpoint. I think it's gonna be a little bit more straightforward to negotiate with the FDA. Great. Okay. Looking at the next wave of Rocket Pharma, you've talked about that and we'll get into the other program maybe after. You know, what should we be thinking about in terms of what's next for you guys? Yeah. I always say this, and it remains truer than ever. The iceberg under the surface is larger than what you see above the surface. We have more programs that are in the pipeline. We're very excited about them. I think tackling monogenic disorders with either AAV or Lenti, but mostly AAV as we move forward, is still an open field. There's a lot out there, and there's a lot out there where we can still be first best-in-only in class. That's coming up. Do I wanna say one IND a year? Well, next year, certainly, we're focused on BAG3 dilated cardiomyopathy, which is, I think, as exciting as both Danon and PKP2, which we call Pegasus. There are more beyond that as well. Yeah, we have an integrated company where now we can take an idea, create the vector design from scratch with our scientists, turn it into a produced vector in our research lab, put it into preclinical studies, tox studies, and now we can create the clinical vector in-house as well, turn it into a clinical trial, and now we have a commercial team. It really is fully integrated from discovery to commercial, discovery to manufacturing to commercial, in a way that I could never have dreamed of. That's great. Now you mentioned the preference for AAV going forward, versus lenti. What's the strategic rationale there and what are your expectations just around in general around durability of AAV? Yeah. We are agnostic, modality agnostic. We really wanna focus on unmet need, like I said, where there are devastating diseases where gene therapy is the obvious solution, clear mechanism of action, targeting the cell of interest and the protein of interest. Both Lenti and AAV can do that. There are programs that come up that have Lenti focus, and we're open to them, and we're evaluating them. The reason to focus on AAV is because you can target more organs. Cardiac is certainly our current focus, but there could be other therapeutic areas, and there's a lot out there. AAV is also, now that we have a manufacturing facility, we can plug and play pretty easily. The cost of goods tend to be somewhat easier, especially if you can scale up and produce in large quantities. That's sort of the direction we're going in at the moment, but, you know, we're evolving as a company. There's a second part to your question. Yeah. Maybe just... Oh, the durability of- Oh, yeah. of AAV. AAV. In the heart cells don't turn over. Most of us have the same heart cells that we were born with. Once it's expressed there, we think, and the evidence suggests that it should stay there forever. You don't need redosing. That's the current thought, one and done for life is the thinking, certainly for heart. Other organs, there is increased cell turnover, we'll see what happens there. Got it. Now can you maybe just talk us through a little bit your decision-making process when you're evaluating new opportunities, and how you land on the programs that you decide to move forward? Yeah. Sometimes we read about them and start the discovery work in-house. The selection criteria haven't changed in seven years. We wanna try to be first, best and only in class, number one. Number two, we want, like I said, a clear mechanism of action. You hit the cell of interest and the protein of interest, not a chaperone protein, not a chaperone cell, not two cells removed, right? Three, we wanna address diseases with bigger and bigger market opportunities. I think Danon-esque or Danon plus, right, is our focus area so that we have an increased business case to make as we move forward. Those three tenets of philosophy have not changed one bit. I think they'll remain whether we're with AAV or Lenti or in the future, another gene therapy modality, which we're gonna be open to. Okay. You recently announced that you got IND clearance for PKP2 arrhythmogenic cardiomyopathy. It's a mouthful. What do you see as the potential for this program? Yeah. The prevalence of this program is double Danon. Not only that Danon is a relatively newly identified area of interest, the combination of the gene mutation or the gene that's mutated with the clinical triad was only made in the last 20 years or so. The LAMP2 mutation wasn't even a part of the cardiomyopathy panel until a few years ago. It's a newly identified disease that's gonna take time for us to find all the patients. ACM, which used to be called ARVC, is different. It's been around and known for a long time. PKP2-ACM, which we call Pegasus, just to start using that term a little bit. That is the one of the most common, if not the most common reason for sudden cardiac death that's monogenic in nature. It's been identified. People know about it. There's a lot more diagnosed cases, even in databases that exist and are accessible to the public. That's one real exciting development that differentiates and helps us quite a bit as we move and think about commercialization. In general, the reason it's a compelling opportunity is because the arrhythmias that kill people are predictable. Patients with premature ventricular complexes or PVCs and increasing PVCs and other EKG findings like T-wave inversions are at highly increased risk of life-threatening ventricular arrhythmia. We can predict who these patients are. We're gonna start the phase I trial in a population of patients who have ICDs in place for safety issues, right? Even in those patients, we'll be able to measure PVCs and other arrhythmias, even if the ICDs don't fire. We'll be able to establish, hopefully safety and potential efficacy in an early biomarker, which it took us time in Danon to identify. We were starting from scratch. For that reason, it was very exciting. rh-74, the capsid here, I will say is important to highlight. First of all, in our preclinical studies, which we'll be able to talk more about at ASGCT next week, we compared AAV9 with rh-74 head-to-head, and we did see better safety with rh-74. We also know from Duchenne, obviously, with rh-74 that we can push the dose into the E14 range more comfortably than AAV9. It might be that for Pegasus PKP2, that we have to go into the E14 range to get the level of protein expression that these patients need to really make a difference. For all those reasons, we're very excited about that IND clearance this week. Great. How should we think about timing of data updates here? I guess just more generally, I know in the past, I always tell people, "Rocket's like clockwork every 6 months, every program gets updated and it's always positive." Should we expect that sort of a pace of updates from this program and future programs going forward? Yeah. Most of our programs and trials are open label, and we see the data real time. You know, when we do data cuts, we see the data and we share the data. That will continue for all of our programs, you know, unless they're gonna be randomized blinded trials, which at the moment we don't have any. In terms of functioning like clockwork, I don't know. I don't wanna say when we're gonna see the data, but when we do to say when we're gonna see the data, we'll function like clockwork. Great. We're not there yet. Like to hear that. Next week you have a number of presentations and posters at ASGCT. You know, what should we be focusing on, you know, when we're looking at the updates that you're gonna provide? ASGCT has traditionally, for us, been a place to update the Lenti program. You'll see some updates for each of those programs. Our cardiology programs, real clinical updates and data cuts, we want the cardiologist to present to cardiologists, so usually it's not ASGCT. You know, we may have some general update there as well. PKP2 Pegasus, I think is gonna be the big one where, we're publicly in an academic setting gonna talk about the preclinical data, which I think, pretty exciting. Okay, great. Just one last question, as we're about to wrap up. How should we think about the overall commercial strategy ex-U.S.? You talked about global commercialization, you know, in these initial indications. Does that hold for, you know, as you get into larger diseases? The U.S. and Europe, at some point Japan, because there's a lot of Fanconi anemia and Danon patients in Japan. I think those three regions, we feel and are confident that we're equipped to tackle those. I think for rare diseases, it's a hands-on approach where we know the centers, we know the physicians, you know, the treating physicians. We know the patients' families. In many cases, we know the organizations and the advocacy groups in a very hands-on way. I think if we try to make this too complex structurally, you lose the secret sauce of how to launch a rare disease in the U.S., Europe, and Japan. I think beyond that, you know, it's probably not set up for a biotech company. I've been at bigger companies where individual country pharma organizations can do a lot of great work outside of U.S. and, you know, the big countries in Europe and Japan. At that point, we'll be open-minded about how to get the therapies to the most number of patients possible. In the near term, for all these programs, even medium term, there's a lot of value we can create just by executing as we are. Yep. Okay, great. Well, with that, I think we'll wrap up. Thanks so much, Gaurav. Yes. Thanks everyone out there for listening. Thank you. Great. As always.