Rocket Pharmaceuticals, Inc. (RCKT) Earnings Call Transcript & Summary

Good day, and welcome to the Rocket Pharmaceuticals Investor Program Update on Danon Disease and the RP-A501 Pivotal Phase II Trial. As a reminder, today's program is being recorded. I will now turn the program over to Meg Dodge, Senior Vice President and Head of External Affairs. Meg, please begin.

Thank you, and welcome to everyone joining us for today's Danon Disease Program update. Today, we will share new Phase I findings in preliminary Phase II clinical observations for RP-A501, including the initial safety experience that recalibrated dose. We will also review the pivotal study's definition of efficacy success and our plans to complete dosing, followed by an update on the Danon population and potential commercialization opportunity. You'll hear from Chief Executive Officer, Dr. Gaurav Shah; our Chief Medical Officer, Dr. Syed Rizvi; and our Chief Commercial Officer, Sarbani Chaudhuri. We are also pleased to include perspectives from Dr. Eric Adler and Dr. Barry Greenberg, whose work has helped advance the understanding of Danon Disease and the clinical evaluation of RPA-A501. Following prepared remarks, we will move into Q&A with our management team, including Gaurav, Syed, Sarbani, and our Chief Science and Gene Therapy Officer, Dr. Jonathan Schwartz. Before we begin today's discussion, this discussion includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements concern our development plans, clinical and regulatory milestones, population estimates and potential commercial opportunities. They involve risks and uncertainties, and actual results may differ materially. Please review the disclaimer in today's presentation and the risk factors in our filings with the Securities and Exchange Commission. These statements speak only as of today, and Rocket undertakes no obligation to update them except as required by law. RPA-A501 is investigational and its safety and efficacy have not been established. The revenue estimates we will discuss are internal modeling scenarios, subject to clinical success, regulatory approval and commercial assumptions. And with that, I'd like to now turn the program over to Gaurav.

Thank you, Meg, and thank you to everyone for joining. Before turning to today's program update, I want to highlight the financing we just announced after market closed. Under our new Hercules facility, we received an initial $35 million, which, together with our existing resources and based on our current operating plan is expected to fund operations into the third quarter of 2028. Additional borrowings under the facility could also extend our cash way into 2029, subject to applicable borrowing conditions and depending on the timing and amount of future draws and our operating expenditures. This additional financial capacity supports our focus on completing the RP-A501 pivotal program and advancing toward a potential BLA submission. Let's start with the bottom line upfront. First, Today, we are sharing additional Phase I data both longer-term clinical observations and biopsy findings, which show evidence of disease reversal or stabilization through 36 months and up to 7 years post treatment with RP-A501. Second, and completely new preliminary clinical data from the initial 4 Phase II patients who were treated before the recalibrated dose an immune regimen and did not receive C3 inhibitors further support the efficacy of RP-A501. These findings build on evidence of restored myocardial [ LAMP-2 ] expression and changes in cardiac structure while extending our understanding of patients' clinical courses over several years. The original Phase II experience included serious safety events, including the tragic loss of the patient in the cohort evaluating an immunomodulatory regimen containing a C3 inhibitor. Together with input from global external experts, we responded by recalibrating the dose and modifying the treatment protocol. So the third takeaway here today is that the first 3 patients treated under this final revised approach have completed the initial observation period without clinical or laboratory evidence of thrombotic microangiopathy, capillary leak syndrome or other significant toxicities. These early observations are encouraging and follow-up continues. Syed will review the safety experience and the changes we have made. Number four, we have aligned now with the FDA on the pivotal efficacy population of 12 males receiving commercial-grade RP-A501 at the recalibrated dose. New today is that the FTC target is at least 7 patients meeting both the prespecified responder criteria at 12 months. which are improvement from baseline to at least create 1 in myocardial LAMP-2 protein expression and a reduction of at least 10% from baseline in left ventricular mass index or VMI. This gives us a clearly defined responder analysis. The first 3 patients count toward that population, leaving 9 additional patients to be dosed. We expect to complete dosing by mid-2027, and I will discuss the pivotal design and our intended accelerated approval halfway later in the program. And finally, today, we will share new analyses that substantially strengthen our understanding of Danon epidemiology and the diagnosed patient population and reinforces our confidence in a potential $1 billion-plus global peak annual commercial opportunity in the initial indication in Danon males alone, and we have already engaged with FDA in expansion to females, which would increase this market much further. We conducted 2 comprehensive independent epidemiology analyses 1 genotype based and 1 phenotype based and both converge on approximately the same estimate, which is 10,000 to 11,000 people with Danon disease in the United States and more than 20,000 if you include Europe as well. Importantly, we have also identified on a cumulative basis, more than 900 U.S. patients with a confirmed Danon disease diagnosis, establishing a patient-level baseline while hiding a substantial diagnosis gap, and Sarbani will take you through this evidence beyond the findings where these patients receive care and how these insights provide a strong foundation for accelerating diagnosis as we move towards launch. Now to put both the clinical need and the opportunity in context, we first need to understand the disease itself from the underlying biology to its aggressive clinical course and importantly, the limitations of current care. And for that, I'm pleased to turn this over to Dr. Eric Adler, an internationally recognized cardiologist expert in Danon disease and academic founder of the Danon Program alongside Rocket. Eric will take us through the biology of Anin, how the disease progresses, why patients remain under diagnosed, the burden and limitations of heart transplant, and finally, why LAMP2B gene edition is so directly aligned with the underlying disease mechanism.

Well, thank you, Gaurav. As you know, I'm a heart failure cardiologist who has cared for Danon patients and study Danon in the clinic and laboratory for many years. I still remember the first Danon case I saw nearly 20 years ago and the hopeless feeling I felt staring at that hypertrophy heart and knowing there's a little I had to offer. How far we've come. Danon [indiscernible] inherited cardiomyopathies for its near complete lifetime penetrants and males, early and aggressive cardiac course, multisystem involvement and the potential to affect multiple members of the same family. Danon is caused by pathologic variance in LAMP-2, which includes lysosome-associated membrane protein 2. It is eXelate and can affect successive generations, but de novo variants also occur and absent family history do not rule it out. A hallmark is severe thickening of the heart muscle. Ejection fracture can remain relatively preserved despite substantial hypertrophy, myocardial injury and electrical abnormalities. By the time it falls, the cardiomyopathy may already be advanced. Importantly, hypertrophy and specifically cardiac mass measured by MRI is a very important tool we have for prognosticating patients. We know that when the estimated LV mass is abnormal in patients with cardiomyopathy, their prognosis is worse than those with normal LV mass. The clinical course differs for Danon males and females, my focus that it will be primarily on the males. In males, cardiomyopathy often begins in child or adolescent and progresses rapidly. By the time many inherited cardiomyopathies are only beginning to manifest, a young man with Danon may already have progressed to advanced heart failure, transplantation or death by his early 20s. Females generally develop cardiac involvement later at a more heterogeneous course, emerging natural history data shows that the majority are clinically affected by the their 30s, while subset developed life-threatening heart failure at a younger age. Despite its severity, Danon remains significantly underdiagnosed. We know the clinical signals such as rate suspicion, a young patient, particularly in male with ununal-severe cardiac [indiscernible] hypertrophy. EKG abnormalities including ventricular preexcitation, elevated muscle or liver enzymes or manifestations outside the heart are sometimes put out always present. In my opinion, any explained cardiac hypertrophy or dilation in a young person should warn a genetic test. You may be saving their lives as well as their family members. This is the best way to diagnose Danon as well as other genetic cardiac disorders. Unfortunately, genetic testing remains low in the broader community and finding the cross-organ systems may not be connected. Essentially any young person with cardiac hypertonic get an evaluation this can stabilize for the patient, but their family members as well. In short, in my opinion, any unexplain cardiac hypertrophy or dilation in a young person should warn a genetic test. You may be saving their life as well as their family members. This is the best way to diagnose Danon as well as other car genetic cardiac disorders. Unfortunately, genetic test remains low in the broader community, and finding across other organ systems may not be connected. Earlier diagnosis supports disease-specific cardiac care, timely planning for advanced heart failure and transplantation and evaluation of potentially affected family members, in Danon time matters because progression of heart failure can be remarkably rate. Today, there is no approved disease-modifying therapy for Danon. Currently, current care is largely supportive cardiac surveillance, arrhythmia treatment, including ICD, management of heart failure complications and as disease advances, [indiscernible] support and transplant evaluation. When our patients progress to end-stage heart failure, heart transplant is the only rescue we can offer from eminent death. But getting a patient in transplant becomes a race against both the disease clock and donor availability. A donor heart at scares. It's not something that can simply prescribe when my patient needs it. Patients us be referred, evaluated and listed that remain alive and clinically suitable into the right donor becomes available, across published among cohorts only about 20% to 25% ultimately receive a transplant. As a heart failure transplant cardiologist, I think it's important to put these outcomes in context. Transplantation could be life-saving. But keep in mind that the average survival post-transplant is roughly 8 to 10 years and in a young person, like gets a heart transplant, the lifespan is still significantly reduced after transplant. And for those who survived transplantation carries a substantial lifeline medical burden, patients require lifelong immunosuppression and rejection surveillance with ongoing risk of serious infection, organ toxicity, [indiscernible] failure and potentially another transplant even in best case scenarios. That's why transit figures of free survival is such a meaningful outcome in debt and more time aligned with their own functioning heart without dependence on a scare toner and without the mortality risk line of transplantation. That is why transplant-free survival is such a meaningful outcome in Danon, more aligned with their own functioning heart without dependence on a scarce donor and without the mortality risk and lifelong burden of transplantation. From gene therapy, the opportunities to change that trajectory to preserve their own hard for a longer delay or potentially avoid the need for transplantation. Data and biology provides a direct rationale for LAM2BG edition. Pathogenic LAMB2 variants can leave cells with absent or mark reduce LAMP-2B, a lysosomal membrane protein needed for normal cellular clearance. When that recycling process is impaired, material accumulates contributing to heart muscle injury hypertrophy and advanced remodeling, essentially [indiscernible] builds up on these hearts. The result is thick in an abnormally functioning heart muscle. We know from stem cell mouse and more recently, a clinical trial that when you replete LAMB02, you improve clearance of this garbage as well as size and function of the heart muscle cells. RP-A501 is an investigational gene therapy designed to deliver a functional LAMP2B coding sequence to heart muscle cells through a single infusion with a of restoring protein expression and addressing the underlying cellular defect. What makes this approach compelling is the direct connection between the genetic defect, the protein we aim to restore and the cellular process we aim to improve. We can test hypothesis by measuring myocardial LAMP2B expression, cardiac mass and remodeling, markers of heart muscle injury and clinical status. With that, I'll turn it over to Rocket team for the program update.

Thank you, Eric. This is Gaurav again. So that clinical context explains the urgency of developing a treatment that addresses the underlying cause of Danon disease. So let's now turn to clinical evidence supporting our development strategy. Before reviewing the findings as shown on this slide, I want to extinguish the different patient populations. 7 males received RP-A501 in Phase I across 2 nominal dose levels. 6 patients received the original Phase II dose of commercial-grade product, 4 in the initial cohorts and 2 in a subsequent cohort that included a C3 inhibitor. Finally, 3 additional patients have received the recalibrated dose under the modified protocol. So together, these groups represent 16 treated patients. The 3 patients treated at the recalibrated dose are the first members of the 12-patient pivotal efficacy population as noted on this slide, this would be Cohort 4 and is the final pivotal cohort. The Phase I principal efficacy analysis includes 6 patients, a seventh patient entered the trial, but had advanced systolic dysfunction and underwent heart transplant approximately 5 months after treatment. The Phase II -- sorry, the Phase I biopsies provide evidence of myocardial LAMP-2 expression in all 6 patients in the principal efficacy analysis at the assessments summarized around the 12-month time point. So today, we share additional biopsy findings that extend that evidence. As the box shows on this slide, both low-dose pediatric patients demonstrated robust LAMP-2 expression at their 36-month assessments. Patient #2 also demonstrated robust expression at a 60-month assessment in long-term follow-up, and these findings provide additional evidence that myocardial lamp to expression can persist for years after a single administration of RP-A501, the updated Phase I analysis used a July 31, 2026 data cutoff and includes follow-up extending the 7 years with assessment timing varying by patients and parameter. The red outline columns here highlight LV mass index reductions. One of the 2 co-primary efficacy measures in the pivotal Phase II trial and troponin reduction, which is a key secondary measure. As summarized all 6 evaluable Phase I patients met the numerical thresholds for both pivotal responder criteria at approximately 12 months. which are at least grade 1 myocardia LAMP-2 protein expression and at least a 10% reduction in LVMI. At the latest available imaging assessments LV mass index remained below baseline in 5 of the 6 patients with reductions of at least 10% in 4 of them. The magnitude of these reductions observed is notable in the context of other cardiomyopathy therapies, while stabilization over multiple years also differs from the progressive increase in cardiac mass observed in Danon natural history. While that's true, NT-proBNP, which is a marketer of heart failure and troponin, which is a marker of cardiac injury were reduced from baseline in all 6 patients at their latest follow-up. We also continue to see encouraging findings in how patients feel and function. Significantly, 5 of the 6 patients are now asymptomatic from heart failure symptoms, having improved from NYHA Class II to Class I, while 1 remains Class 2. All 6 patients reported an improvement of at least 5 points, and in most cases, much more on the Kansas City Cardiomyopathy Questionnaire, a measure of patient-reported health status. Patient 6 completed the Phase I study and demonstrated fotypic improvement in the years after infusion. After the last data cutoff for this presentation, we have learned that the patient underwent cardiac transplantation approximately 4.8 years after the RP-A501 infusion. This patient had been lost to long-term follow-up and efforts are ongoing to obtain additional information and evaluate the explanted heart for transgene expression. Across the 6 evaluable Phase I patients, 5 remain transplant-free, Kaplan-Meier estimated transplant-free surreal was 80% at 58.05 months. Median transplant-free survival was not reached and median follow-up was 5.7 years with a range of 4.3 to 7.1 years. Now turning to long-term biomarker observations. The analyses performed from data from the International Danon Disease Registry indicate that LV mass and BNP levels increase with age in untreated malls due to disease progression. In contrast, patients in the Phase I study demonstrated reduction or stabilization in BNP and LV mass following RP- A501 treatment. And of note, the prospective natural history study has now enrolled 58 patients and counting. The Phase I findings support the rationale for the pivotal endpoints as they demonstrate a clear association between cardiac protein expression and improvements in hypertrophy. All 6 patients in the principal efficacy analysis demonstrated myocardial LAMP-2 expression of at least grade 1 and an LV mass index reduction of at least 10% on the assessments in this summary. These assessments were predominantly at 12 months with some LV mass index measurements extrapolated from staggered visits due to COVID-19. At approximately the 12-month assessment, as summarized here, all 6 patients in the Phase I efficacy analysis met the numerical thresholds used for the pivotal responder definition in the Phase II trial, longer-term follow-up now extends from 4.3 to 7.1 years, thus providing additional context on the durability of myocardial LAMP-2 expression, cardiac structure, biomarkers and clinical status after treatment. These longer-term observations add evidence regarding the course of these responses over time. And together, they give us confidence in the biological and clinical rationale for the pivotal study which will evaluate response at the recalibrated dose at the prespecified 12-month assessment and beyond. Now turning to Phase 2. 6 patients received original dose of 6.7x either the 13 genome copies or GC per kilogram. The preliminary clinical findings we will focus on today come from the initial 4 patients treated in cohorts 1 and 2 who received an immunomodulatory regimen of rituximab, sirolimus and steroids. -- and then Syed will review the safety experience and how it informed the modified treatment approach. So today, I'm excited to share these preliminary observations that extend from approximately 18 to 36 months after treatment in the initial 4 Phase II patients. At the latest available assessments, 3 of the 4 patients in Cohort 1 and 2 had LV mass index reductions of at least 10% from baseline, ranging from approximately 30% to 36%, and in those 3 patients, other measures of cardiac structure, biomarkers and clinical status showed a mix of improvement and stabilization. The third patient had an approximately 9% increase in LV mass index but reductions in posterior wall thickness and NT-proBNP reductions and an improvement from NYHA Class III to Class I, these preliminary findings show variable cardiac responses and should be interpreted in the context of each patient's age, growth and disease stage. Symptoms and patient-reported health improved or remained stable across all 4 of these initially treated patients. So these findings provide encouraging evidence of clinical activity in the early Phase II trial. The pivotal efficacy analysis will be based on 12 patients treated in cohort 4 at the recalibrated dose of 3.8 [ e13 ] GC per kilogram. So now I will ask Syed to review the safety findings and how they inform the modified treatment approach.

Thank you, Gaurav. The safety experience has directly informed the current treatment approach. CMA, kidney injury and other complement-mediated complications are recognized risks of this systemic AAV gene therapy. This is why the trial includes 3 specified monitoring and management protocols. In our study, TMA occurred in 2 of the initial 4 Phase II patients. Given the frequency and clinical significance of these events, we revised the protocol to include a C3 inhibitor as a component of the immunomodulatory regimen in Cohort 3 to mitigate the risk of complement mediated toxicities such as TMA. C3 inhibitor is the type of targeted medication that blocks the complement system protein C3 to potentially stop immune reactions and inflammation, although this appears to have other uncovered consequences when combined with other trial-related treatment. Following RP-A501 infusion, both patients who received a C3 inhibitor containing immuno moderation experienced severe adverse events, including capellary leak syndrome, resulting in the death of 1 of the patients. The death is a profound loss. Following these events, treatment was paused, a comprehensive root cause analysis was performed. It is likely possible that the C3 inhibition resulted in decreased optimization of AAV and increased uptake by vascular and [indiscernible] cells with resultant vascular injury. In conjunction with global immunology and gene therapy experts, we reassess the dose, immunomodulatory regimen, eligibility criteria and monitoring plan. In agreement with the FDA and IDS, the C3 inhibitor was removed from the immunomodulate regimen and the dose was recalibrated. These changes were intended to reduce the observed risk while retaining a dose supported by the biological and clinical evidence. We resumed treatment in the pivotal cohort 4 at 3.8x stem to the 13 genome copies per kilogram compared with 6.7x 13 in the original Phase II cohort. The Phase II study uses in-house commission grade products with a higher proportion of full capsids carrying the therapeutic genetic material, because empty capsids add to total viral exposure without delivering the intended cargo to a better full to empty capsid ratio allows a lower total dose to deliver a biologically comparable amount of functional sector. We, therefore, recalibrated the Phase II dose to 3.8x, 10i to the 13 noncore per kilogram with the goal of preserving the therapeutic profile seen at the effective Phase 1/2 while reducing total capsid exposure. Ultimately, the recalibration incorporated analytical characterization of the commercial-grade products, including full particle content, together with the earlier clinical experience and nonclinical bridging work. The overall body of evidence, including updated Phase I clinical efficacy data as well as the nonclinical data supports the potential of RP-A501 as this precalibrated dose to modify the underlying disease process in Danon disease. Furthermore, today, we are also reporting new data from a Danon disease mouse model. as they recalibrated 3.13, commercial-grade Phase I material produced robust cardiac LAMP-2 expression mitigation of disease-related enzyme abnormalities and showed vector by distribution, comparable to the same at a higher [indiscernible] dose. These findings considered alongside the Phase I experience support to selection. In addition to dose recalibration and removal of C3 inhibitor, the protocol modifications include rituximab given over 3 doses versus and enhance monitoring for TMA and capillary leak syndrome. The protocol specifies threshold for intervention, including the use of eculizumab eligibility screening includes a comprehensive evaluation for underlying predisposition to TMA, including genetic testing. The first 3 enrolled patients in Cohort 4 under the modified protocol were treated sequentially with at least 4 weeks between infusion. Each of these patients completed the required initial observation period. As of the September 4, 20, 2026 the [indiscernible] shown on this slide the platelet and complement market it extend to approximately 3 months after treatment. Over this period, there was no clinical or lab evidence of TMA, CLS or other severe complement-mediated toxicities, consistent with the objectives of the protocol amendment. The platelet and complement market assessment as part of the enhanced monitoring plan remained largely within normal limits. One patient had a transient decrease in platelets count at approximately 8 weeks 8 to 9 without symptoms or signs of platter dysfunction. The investigator and once did not consider a clinical significance. Subsequently, it's fully resolved. Reported SC5B9 values should be described only in relation to the assay range and the absence of associated chemical findings. These initial observations are encouraging. Follow-up is ongoing and additional patients and longer observation will be important to characterize safety under the modified protocol. After reviewing the initial safety data from these 3 patients both the independent data monitoring committee for the trial, and the FDA confirms that enrollment and dosing could continue under the modified protocol. I will now turn to Dr. [ Derek Greenberg ] to discuss the clinical significance of the findings and what he will be looking for as the pivotal study progresses. Terry? Thank you for joining us.

What stands out to me as a clinician is the findings that we had from the initial patients that we treated in the changes in lab IB protein, the deficient protein in [indiscernible] disease in the heart and the changes that we saw in cardiac structure, we performed endomyocardial biopsies over the first 3 years that patients had been treated with gene therapy, and what we were able to show was really remarkable because we could demonstrate that we were getting an adequate number of genes to the heart that is the deficient gene in Danon disease. And even more importantly, that this gene was functional and producing protein, we provided evidence that the gene was producing this protein for at least 3 years. That's the duration of time that we did these endomyocardial biopsies for -- and then we paired up this finding, this observation that we're now getting the deficient protein in the heart, along with measures of cardiac structure in particular, the amount of thickening of the muscle mass or cardiac harpertrophy that's a home part of Danon disease and we were able to show that virtually hand-in-hand with the production of the LAMP-2 protein, we were able to see a reduction in cardiac hypertrophy. This is particularly important because we know that Danon disease is a rapidly progressive disease for which there are no curative treatments available at present only cardiac transplantation is available for patients with end-stage cardiomyopathy, but that's associated with significant morbidity and mortality as a treatment gene therapy with RP-A501 has the potential to eliminate or delay the need for a cardiac transplant. And it represents a significant benefit to these patients if that could be accomplished especially when the therapy can be administered with limited or manageable toxicities under the modified treatment protocol, we've treated now 3 patients. These are in Phase II cohort 4, and they were all treated safely without any evidence of TMA or complement mediated adverse events taken together the longer-term Phase I clinical data that I described and the most recent safety profile that we're now seeing in Phase II cohort 4 indicates that the value of gene therapy as a potential for dining disease is considerable. We're looking forward to continuing this study and seeing the final outcome in these patients. At this point, I'm going to turn the floor over to Gaurav, who's going to explain new pivotal analysis and the plan to complete the study.

Thank you, Barry. Throughout the development of RP-A501, we have remained in close collaboration with the FDA to align on the regulatory path toward a potential BLA for this important therapy. Most recently, we received FDA agreement to complete enrollment in our updated pivotal Phase II study with a total of 12 patients treated at the recalibrated dose. To provide a brief overview, this is a global single-arm open-label registrational study with an efficacy population consisting of 12 male patients receiving commercial-grade RP-A501 at the recalibrated dose. The clinical efficacy target is defined as at least 7 out of 12 patients meeting both prespecified responder criteria at 12 months. Those criteria are: one, myocardial Lamptprotein expression of at least Grade 1; and two, improvement from baseline and LDMI reduction of at least 10%. A responder must meet both. We intend to use these 12-month pivotal results as the primary efficacy basis for a BLA seeking accelerated approval with prior to review and upon approval, eligibility for a pediatric rare disease priority review voucher. Any FDA approval would be based on the agency's comprehensive benefit risk assessment of the totality of the clinical evidence and overall data package, which includes safety, efficacy and manufacturing quality. The first 3 patients mentioned earlier count toward the pivotal efficacy population, thus leaving 9 more patients to enroll and treat. We have 6 sites prepared to dose with the potential to add more, and we expect to complete dosing by mid-2027. Each patient will contribute a primary assessment at 12 months after treatment. Our immediate priority is completing enrollment and dosing these patients safely. Our natural history study combines retrospective clinical history with prospective follow-up, which now has 58 patients enrolled, collecting cardiac imaging biomarkers, heart rhythm, major clinical events and quality of life information through a common approach across centers. Following both males and females helps us characterize the broader disease and can inform future development in additional Danon populations. As I mentioned earlier, in parallel with this clinical work we have substantially strengthened our understanding of the Danon population itself, both the underlying epidemiology and the real world diagnosed patient population. Sarbani will now take us through the comprehensive analysis behind our epidemiology estimates. What we have learned about where diagnosed patients are receiving care and how these insights are informing our strategy to accelerate diagnosis as we move towards launch.

Thank you, Gaurav. Danon disease represents a meaningful initial opportunity in malls with HCM. A broader opportunity is across mills who are earlier in the disease course. Beyond males, it is a female patient population with high unmet need. To size that population rigorously, we approach the question from 2 independent directions, 1 starting with genotype and the other with clinical phenotype. Both approaches converged on approximately 10,000 to 11,000 people living [indiscernible] disease in the U.S., about 4,000 males and 6,000 to 7,000 females. Let me start with the genotype analysis. We have conducted the most comprehensive molecular characterization of Danon disease to date, integrating more than 450 patient records with pathogenic or likely pathogenic LAMP-2 variants across 6 complementary data sets. This provides the foundation for a genotype based prevalence estimate. We started with classic loss-of-function variants, which are commonly reported in Danon disease. These variants are well represented among approximately 315,000 individuals in genome, giving us a strong population genetics anchor. But they account for only 62% of pathogenic or likely pathogenic LAMP-2 variants identified and confirmed Danon cases. We, therefore, use our molecular characterization to scale from this anchor and estimate the full Dan and genotype positive population. We then approach the same question independently from the phenotype. Here, we built a comprehensive sex-specific natural history model, informed by more than 700 Danon patients as well as analysis of real-world Danon disease patient data. We select HCM as a population anchor because it is the predominant cardiac phenotype in Danon disease and robust population level HCM data are available. We applied 8 adjusted estimates of Danon prevalence within HCM from published studies separately for males and females to estimate the Danon population with an HCM phenotype history. But HCM has not captured the full tenant population. A significant proportion of patients have not yet developed cardiomyopathy while others may have progress to dilated cardiomyopathy phenotype. We therefore use real-world Danon patient data and our natural history model to estimate these additional patients and scale from the HCM anchor to the full Danon population across all stages of disease. So to independent approaches, 1 anchored in population genetics and 1 in clinical phenotype convert on approximately 10,000 to 11,000 people living with Danon disease in the U.S., applying the analysis to the United States and EU supports an estimated population of more than 20,000 people. These are model estimates that we will continue to refine. Our initial commercial focus in narrower Danon [indiscernible] with HCM and consistent with the population being studied in our pivotal program. Treatment eligibility within that population will depend on clinical evidence and approved label. Nowlet me move from estimated prevalence to patients we can already see in the real world. On a cumulative basis, we have identified more than 900 patients with confirmed Danon diagnosis across approximately 300 U.S. institutions. This is a deduplicated unique patient count compiled across multiple sources, including claims and electronic health records, genetic testing data, HCP reporting and our field intelligence. Most were captured over the last 5 years as a cumulative count of diagnosed patients, it includes those who have undergone heart transplantation as well as those who may have subsequently died. Importantly, we know not only how many patients have been identified but where they receive care. The top 100 institutions account for approximately of identified patients. Yet these 900 patients represent less than 10% of our estimated U.S. Danon population. The significant diagnosis gap is consistent with the lower rates of genetic testing in cardiomyopathy today, ranging from only 1.6% in adult HCM to approximately 14% in pediatric cardiomyopathy. We also see evidence that underdiagnosis is greater among females, females represent 55% of identified patients, a lower proportion than we estimate in the underlying Danon population. So the patients are there. We already see a meaningful diagnosed base and a clearer understanding of where they have been treated. The opportunity now is to build from the foundation, expanding into the broader cardiology community to identify the many patients who remain undiagnosed. To narrow the diagnosis gap, our strategy directly addresses the barriers that doctor Adler described earlier. First, patients are dispersed across the broader cardiology community, with genetic evaluation is not yet systematic. We need to educate and activate cardiologist to increase testing in young HCM patients and to recognize the Danon signature as a trigger for heightened urgency. Second, genetic counselor capacity and payer requirements can create barriers to testing. Rocket's Mission genome program helped simplify the path to genetic transformation through no-cost testing and counseling. Third, we want to empower young patients with unexplained cardiomyopathy and the families to ask, could they have a genetic cause and advocate for valuation. And fourth, cascade testing can be a force multiplier with each diagnosis creating an opportunity to identify additional affected family members. I'm encouraged by the broader environment, HCM same guidelines increasingly support genetic testing, while targeted therapies and genotype driven trials are making genetic diagnosis increasingly important. Our strategy is designed to build on the momentum and identify patients earlier and more systematically. Our initial focus is mailed with HCM with U.S. as our first commercial priority. We estimate this initial indication could support more than $1 billion in global peak annual revenue, reflecting both the addressable patient opportunity and the potential for premium value in a catastrophic rare disease with no approved disease-modifying therapy. That estimate incorporates diagnosis treatment eligibility, access and achievable annual treatment volume. This also indicates targeted expansion into priority international markets with long sequencing informed by access and market opportunity. Beyond the initial indication, there is potential to reach additional Danon populations over time, including females with earlier onset HCM, males before HCM develops and females with later onset cardiomarkers. Any expansion into these populations will be guided by supporting clinical evidence and regulatory alignment. We are already laying important groundwork for these potential opportunities. Our natural history work is deepening our understanding of disease trajectory and helping inform patient selection and future clinical development. The epidemiology and patient identification work that we've done to date allows us to understand where the currently diagnosed patients are or have been managed. We also have an understanding of the broader HCP community who are likely to manage Danon patients not yet diagnosed. Together, these potential populations could expand the global peak annual opportunity to more than $2 billion. With that, I'll turn it back to Gaurav

The long-term clinical data from the Phase I study demonstrating sustained LAMP-2 protein expression and improvement or stabilization of cardiac hypertrophy biomarkers of cardiac injury and stress and heart failure symptoms are indicative of RP-A501's potential to transform the natural history of denim disease. The early efficacy data from the Phase II study further corroborates RP-A501's therapeutic potential. The initial experience in the first 3 Cohort 4 patients treated under the modified protocol is encouraging, no DMA, no capillary leak syndrome and no other severe toxicities through the current follow-up period. These findings are consistent with the intended effect of the safety optimizations, although additional patients and longer follow-up are needed to characterize the safety profile fully. Most recently, we aligned with the FDA on the updated pivotal Phase II study, which will include a total of 12 patients treated at the recalibrated dose. As mentioned, the efficacy target is at least 7 responders at 12 months. with each responder required to meet both criteria of protein and LV mass index reduction. We plan to complete treatment of the remaining 9 patients by mid-2027. That is our immediate priority at Rocket as we work toward the pivotal analysis and the potential submission seeking accelerated approval. Our commercial work has always so advanced. We have a clear understanding of the Danon population the institutions caring for patients and the steps needed to connect diagnosis with potential treatment. That work provides a focused basis for commercial preparation as development progresses. So the evidence shared today reinforces our belief that RP-A501 has the potential to alter the course of Danon disease. Phase I results show sustained myocardial LAMP-2 expression and improvement or stabilization across measures of cardiac hypertrophy injury stress and heart failure syndromes preliminary Phase II finding support continued clinical activity and the initial Cohort 4 safety experience supports continued enrollment under the [ MODIFY ] protocol. . As announced today, based on our current operating plan, our existing resources, together with the initial $35 million funded under the Hercules facility are expected to fund operations into the third quarter of 2028, with additional borrowings under the facility extending our cash run rate into 2029. Thank you, especially to the patients and families participating in these studies to the investigators and study teams and Dr. Adler and Greenberg for their prospectus today. And we can now open the call to Q&A. Thank you very much.

[Operator Instructions] Your first question is coming from Andrew Sai from Jefferies.

This is [ Matt Barkes ] calling in for Andrew Tai. Congrats on the Danon update. Just a couple of questions for me. It's pretty clear that with this new efficacy target of only needing 7 of the 12 patients to respond. I'm just curious if there's a chance for you to provide a rolling update to the top line. For instance, like if the next 7 patients achieve the targets? Are you able to announce 3 test early? Or are you going to have to continue to wait for all 12 patients to have the 12 months of follow-up? And then also, if you can just talk a little bit about your natural history study. Is this going to be a formal external competitor to the filing? Or is this just a supporting context?

Thank you, Matt. For the rolling update, I can tell you what we've done in the past, certainly in former trials like with Fenconeanemia when we hit 5 out of 12, we did announce the top line. However, that's a discussion that we will have with the FDA as to exactly what top line means. So we will wait on answering that until further conversations and as the trial progresses. . And regarding the natural history study, yes, the external natural history study is important to verify and authenticate the assumptions that form the statistical basis for this pivotal design. In other words, do patients get worse with left ventricular mass index and troponin and other markers, just as we've seen in the first 2 patients, we're going to confirm this with the larger group of patients. But it is not an external comparator the comparator for these patients' outcome is the patient's pretreatment baseline of LV mass index, protein, troponin, et cetera, right? So the natural history study is the fortifier but not an external comparator.

Your next question is coming from Roanna Ruiz from Leerink Partners.

A couple for me. I was wondering if looking at the -- I think you were talking about Phase I patient parameters for up to 7 years. Could you elaborate a bit about the 1 patient that underwent cardiac transplantation. I think it was around 4.8 years after treatment. I know it might have been lost to follow-up, but any additional color there? What do you think might have happened and any implications on durability there?

I'll pass this over to Jonathan.

Thanks for the question. We are still gathering information regarding the clinical deterioration. So it's very premature to state anything conclusively. We do know that this patient had a significant arrhythmic component to his Danon presentation, which may have exacerbated some aspects of arrhythmia track or heart failure that were not necessarily reversible by the gene therapy, although that's quite speculative. We do know that this patient had improvement in a range of parameters and very extensive symptom resolution during the initial years following therapy. We do intend to update this more significantly. I think this emphasizes that there is likely to be a spectrum for the duration of benefit. And this patient in all likelihood represents the short end of that spectrum. Obviously, we have the majority of patients who continue to do well multiple years after therapy, and we will obviously have much greater information with respect to the overall bell curve for durability, which is likely 5 years at the low end, and we still are awaiting the remainder median progression-free survival, median transplant-free survival, it has not been reached, and that's really about all we can state at this juncture.

Okay. That helps. And I want to dig into the -- I think you mentioned the 900 patients diagnosed across 300 U.S. institutions, any thoughts on what proportion of them may have already had heart transplants or might be too far along in disease to potentially receive gene therapy?

As I mentioned, this includes those who have already undergrown had transplant as well as those who may have substantially died. These have been cumulatively diagnosed over the past 5 years. We only, at this point, know the mall versus female breakdown as I mentioned. We don't have the full status of the heart transplantation. I think what we can say from this analysis is there are real data patients that are being diagnosed on an ongoing basis. We know where these patients are being treated or have been treated. We're also building the foundation for sustainable long-term patient finding efforts. Considering the rapid disease progression, some of the patients identified today may deteriorate to advanced heart failure, unfortunately, [indiscernible] to the disease and some may be transplanted in the future. So our main focus as we ramp up our efforts is to educate on Danon accelerate diagnosis. So we see rents patient numbers grow up, grow and leading up to the approval and then sustaining the growth from initial launch to peak.

Your next question is coming from Josh Schimmer from Cantor.

Congrats with all the progress on those both clinically and commercially [indiscernible]. A couple of questions. First for the efforts in the female Danon patient population? What are the gating steps before you're able to start a clinical trial. In that population, do you have to have a certain safety experience from, from the trial in the boys? Or is it on a different trajectory? And then if you're projecting peak sales of north of $1 billion for the Danon program, I just want to clarify, first, that's just in boys, number one. And number two, given the cadence at which you've been identifying patients thus far, it would seem like you'd have to have quite a significant step up to be able to treat, say, 400 to 500 patients in any given year. So maybe you can talk a little bit towards those efforts? And what gives you the confidence that you'll be able to really ramp up the patient identification efforts as substantially as you've indicated.

Thank you, Josh. So I'll answer the first question. and then hand it to Sarbani. So for the female Danon population, we know that there is a very high unmet need. We have a lot of inbound interest from the community I will say that the FDA has already been engaging with us on developing a female trial. We'll probably start in a more severe population that mimics men or boys really with Danon disease. And in fact, the FDA in their correspondent has indicated proactively that we should start a female trial as soon as possible and even look at presymptomatic mail. So I think for this disease, the FDA is super supportive of the development as fast as possible. Regarding how we get to the opportunity, I'll turn it over to Sarbani.

Let me just also clarify about what we mean by peak and how we get there. So first of all, the RP-A501 revenue model is based on a sizable prevalent patient pool with the treatment window of several years. It's not a birth incidence mass model, nor will it be dependent on any type of newborn screening. We estimate the revenue curve to be a gradual time to be with the steady adoption curve, a flatter trajectory at peak over multiple years before a gradual ramp down to diagnose incident patients. So when we think of the gene therapy treatable pool over the next several years after launch, with a steady adoption curve, it's going to come from 3 places, existing prevalent Danon males with HCM who have preserved azetifraction and the disease is not yet at end state, which, as I mentioned, gives us a treatment wind of several years. fresh pool of Danon males transitioning from 3 HCM stage each year. And third is increasing diagnosis rates that enable identification of the above patients in addition to those who are already diagnosed. A Rocket plans to intensify the efforts on Danon education and genetic testing to drive an order of magnitude increase in Danon diagnosis rates. We have had external industry benchmarks as well as cardiac ecosystem, till such as what we've seen with ATTR as well as other analogs that will act as a catalyst on our Danon diagnosis mission. In addition, potential regulatory approval of disease-modifying treatment will also meaningfully accelerate Danon diagnosis. And we have already started the efforts because we know where current diagnosed patients are, we have a very good idea about where future patients could lie mainly in a very select group of pediatric cardiologists and that's the work that we plan to take on over the next couple of years leading up to the launch. So we can sustain not only an initial bolus, but also over time.

Your next question is coming from Patrick Dolezal from LifeSci Capital.

Is it your expectation that manufacturing is the primary driver of the meaningful safety improvements we're seeing in Cohort 4? And can you help quantify the magnitude of those improvements with respect to full capsid proportion? And then second question, what are the biologic drivers behind the improved manufacturing process at the go-forward dose level driving similar transduction and biodistribution as at the prior dose level, which was higher on an absolute basis. I think you commented on that in some of the preclinical studies.

Yes. So I would say that the improvements in safety are a combination -- well, first of all, removing the C3 inhibitor, which was together with the torrential rain of AAV9 is problematic really for endothelial cell injury, in removing that, we certainly were able to remove the capilary leak issues that we saw earlier. Now with regard to the TMA that we saw in the earliest part of the Phase II trial, I would say that the recalibration to account for higher potency in the Phase II product versus Phase I that was predicted is really the recalibration that did the trick. Our ratio of full empty improved from less than 50% to over 70% consistently and reliably. And I would say also, Patrick, that the conviction that we have that the recalibrated dose is truly a recalibrated dose and not just a dose reduction is threefold. One, based on the clinical data that we saw in the treated patients, the 3 patients treated safely, a mimics and mirrors the Phase I data in their patient population that had a 100% response rate as we indicated earlier. Secondly, Syed mentioned some preclinical evidence in a mouse model that compared the 3.8 E13 new dose with the older low-dose and that comparison confirmed equal impact in mice at those 2 different levels of 2 different products. And finally, manufacturing enhancements increased the proportion of eculizumab, as we mentioned, resulting in greater biological activity in laboratory testing compared with the earlier clinical material in Phase I, especially at higher dosing levels. And while these potency assays are not designed to predict clinical effectiveness, the findings are consistent with the improved quality profile of the Phase II product. And that last point I made is based on new information that has emerged in our internal analysis recently. And I think that should address both of your questions, correct, Patrick.

Yes. Super helpful.

Your next question is coming from Tara Bancroft from TD Cowen.