Rocket Pharmaceuticals, Inc. Aktie

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.

This is Ikenna on for Tara. I had a couple of questions. You guys mentioned that the pivotal study will use left expression and a 10% reduction in LVMi as the key endpoints. What data or clinical rationale support that selection of the 10% LVMi reduction threshold? And will the assessment for LVMi be evaluated by a central imaging core? And then I'll follow up after that.

Let me ask Jonathan to answer this one.

So I'll start with the -- I'll start with the last part of the question, all of the imaging as well as [indiscernible] to chemistry will be evaluated at a central facility in a blinded fashion by independent readers. And that's true both for echocardiogram and MR on the on the imaging side as well as, obviously, the LAMP-2 histology. I think our Phase I data in which really all of the 6 patients who did not have reduced left ventricular ejection fraction and stage cardiomyopathy at baseline, really met those endpoints at 12 months and that those 12 months milestones were then indicative of sustained improvements in most cases, patients continued to improve beyond 12 months for most parameters. So we believe that these thresholds really are indicative of improvements that are sustained and likely to continue Additionally, we also have accumulating natural history data that the progression of hypertrophy in males continues. It doesn't -- it really -- these hearts thicken at a demonstrable rate per year, and so any degree of stabilization or even modest improvement represents a substantial deviation from the relentless progression of the hypertrophy that has been well documented and will continue to further document in male individuals with Danon disease.

All right. And I had a really quick follow-up on the rolling disclosure. You guys noted that the timing and definition of the top line are under discussion with FDA? Could You share any more color on what the specific options are that are being discussed and what would need to be true to report results before also patients reached that 12-month assessment.

So what we described today was a protocol-defined efficacy target of 7 patients out of 12. We are in the process of finalizing a statistical analysis plan, which will mimic that, but a lot of these definitions are in discussion, so I can't really answer further. I will note that based on recent FDA feedback, we're going to be very thoughtful about how we roll that answer out given that the [indiscernible] is so critical to the final outcome with the FDA. So right now, the protocol-defined efficacy output is 7 out of 12, but further information once we finalize the efficacy and other details of top line, et cetera.

Your next question is coming from Tessa Romero from JPMorgan.

I wanted to double-click here on just what the feedback is that you're receiving from the Danon community on RP-A501, their interest in receiving gene therapy and specifically their comfort around the safety profile. How do they think about what would be an acceptable level of risk here? And how do you think about it?

The Danon disease community has been very courageous and very patient as we go through this development plan. I would say that, in fact, the support level from the Danon Foundation and parents and other caregivers has been unprecedented in our programs. I think that Danon disease is such a rapidly progressing disease with guaranteed fatality if these boys are not transplanted. And the community is willing to take more risk than they would otherwise if it weren't such a devastating fatal disease. So even with the safety events we saw last year, we saw the community rally around continuing the trial. Today, even though we only need to enroll 9 more patients that should use this opportunity to explain that there are way, way more patients at a rating. So we need to get this done as soon as possible. In general, they've been enormously supportive of the trial because the alternatives are bleak.

Your next question is coming from Richard Law from Goldman Sachs.

This is Jean for Rich. So my first question is for the KOL, and then I have 2 questions for the management team. Dr. Adler. Do you believe there's a threshold in LAMP-2 expression that is needed to have clinical benefit. And for patients who flat expression decrease over time to low levels back to baseline, how durable could the initial clinical effects last?

Yes. So the -- Dr. Adler is not on the Q&A here. So this is Gaurav, I'll answer. So for the LAMP-2 expression what we call a Grade 1 increase, in other words, a visual increase by Grade 1 or more is not an exact percentage, but in general, for the patients who have responded at the Grade 1 level, it's been about 10% to 25% protein expression. Grade 2 is approximately 25% to 50%. Grade 3 is 50% to 75% and Grade 4 would be up to 100%. So in terms of how durable this effect should be, I would say -- divide it up between protein expression, LE mass index and other lab biomarkers, protein expression should remain intact for many years to come. We see it intact for at least 5 years as we showed earlier in 2 patients, the second patient being new information. The cardiomyocytes that we all are bored with are mostly the cardiomyocytes that we keep the rest of our lives. We don't recycle them. So the episomal expression should remain for long term in the heart and it has, and I was happy to report that today. For LV mass index, remember that these hearts grow, and on average, we've shown that they grow about 8% per year. So we expect reductions in the first year. But over time, even if we just see stabilization over 2, 3, 4, 5 years, that's much better than the expected increase we would see 1.08, x 1.0x, 1.08 year after year can be additive and/or multiplicative, right? So versus that, even stabilization alone is a big win. And I think the FDA has recognized that in how we're thinking about the long-term follow-up and the full approval path.

For the troponins and the BNP to lower the BNP, the better the heart failure symptoms and the lower the troponin, the less cardiac injury, and we've seen both of those sustained 3 to 5-plus years as we showed in the tables today.

For the second question, I want to follow up on earlier discussions on how many patients qualify for treatment. Let's use the 900 patients that have been identified. Can you please walk us through like how many of these patients would be qualified for treatment and the qualifiers you will use like gender, age within treatment window?

And then also, like how many patients do you believe will require C5 complement therapy in the commercial setting?

Thanks for the question. So to be clear, the 900 patient is record. It's a recorded count in an internal database. We don't have all the information there. This is done nearly to find patients for the clinical trial and know where the sites are where patients can be found. So it wasn't a big commercial endeavor to find these patients who was pretty straightforward and simple. And the reason I say that is the answer to your question is something that will provide a little bit closer to the launch. We're not quite ready. But as Sarbani has said earlier, there is slightly less than half male, slightly higher than half females, and we don't have the transplant status yet. So addressable market, et cetera, is something that we will talk through as we get closer to BLA. The goal today was merely to identify the patients out there and basically to reiterate that while Danon diagnosis truly diagnosed rates are rare to find. They're out there, and they're quite prevalent in the U.S. more than folks might have thought.

My last question is like why did you set the efficacy target of 7 out of 12 responders? Is there any reason to believe there are subpopulations not able to benefit?

Based on the Phase I, we saw all patients respond. I think that this gives us some room. It's just how the assumptions differ from treated patients versus natural history. If you look back at, I think, Slide 10 on the presentation, we know that LV mass increases year after year, and we've seen this in the retrospective and prospective cohorts that we've studied. And we know that LV mass index in treated patients goes down here, at least year after year, we see that sustained over time, sort of creates this alligator mouth right top versus bottom, and the 7 out of 12 target is based on what it takes to read out as a positive trial, and that's based on these assumptions.

Yes. The no hypothesis is very stark. Patients will not spontaneously express LAMP-2 and patients will not spontaneously have hypertrophy stabilized or regress. So the 7 of 12 provides us with very, very good statistical robustness. Obviously, we hope that everyone benefits and everything that we've been discussing today and everything that we've been doing up until this day is to optimize the potential for the largest possible benefit.

Your next question is coming from Jason Zemansky from Bank of America.

Great. Congrats on the program, I guess, if I could ask 1 on the patients of the original Phase II cohort whose LV mass index increased by around 9%. Have you identified anything that differentiated the patient from the 3 with a 30% reductions. I know you mentioned age might be a factor. But just in terms of trying to understand whether there may be an underlying phenotype. I know you're not ready to comment on the addressable population, but does this change what you've learned about how this could -- how broad a treatment this could ultimately be?

great question. So we have not done a full analysis of either genotypic or phenotypic differentiation of responders versus the couple who didn't respond so far. First of all, this patient at the most recent visit, which was 2 years out, it was 15 years old, which means he started at 13, a time of hard growth, rapid heart growth. So that could be part of it. We do see reductions in left posterior wall diameter, for example. So the other thing, though, I would say is that this was the earlier Phase II before the recalibrated dose and also with a different immune modulation regimen. And we believe that the new recalibrated dose plus the revised regimen is going to be that are both for safety and is going to hopefully recapitulate the efficacy that we saw in Phase I. That's why we designed it that way. So while this is preliminary, it's early Phase II data, and it's reassuring in the sense that we're continuing to see responders with gene therapy, but it's not an early read on the pivotal Phase II in any way, shape or form.

Great. And then maybe just a quick 1 on enrollment. I think you previously discussed about having identified possible candidates for the 9 remaining patients for the study. Maybe what are some of the gating factors to getting these patients into the trial? Is there a reasonable scenario where mid-2027 could be a conservative estimate?

Our official guidance is mid '27. There is a 3-month troponin running as it was previously. So we do have to do that for all patients. There's logistics, there's vaccines and there's just coordination across a limited number of sites. So we are moving as rapidly as we can, but the guidance is mid-2027.

Your next question is coming from Yun Zhong from Wedbush Securities.

Congratulations on the update. A follow-up question on the initial 4 patients. Although I understand that the dose was different from the recalibrated dose. I wanted to confirm that the material is the same commercial scale manufacturing material. So is there any way again those data from those 4 patients could potentially contribute to the final statistical analysis if for any reason you are not able to reach that 7 patients out of 12 patients to be responders?

And also, the second question is given that the Phase II study is a global study. And can you remind us, have you talked about your plan for ex U.S. and maybe your discussion with the FDA on the requirement of full approval, please?

Great. Thanks, Yun. So the official pivotal analysis is going to be based on Cohort 4. Everything else is supportive, right? So I think it's hard to extrapolate beyond that statement. The Phase II pivotal study is cohort 4 with 12 patients, the responders in both Phase I and Phase II form the larger data package for both safety and efficacy and will be considered as a totality of evidence, but is not part of the pivotal population.

For ex U.S., I would say that right now, we're focused on a U.S. launch and approval, as Sarbani outlined. We have talked to the EMA in the past, but really as a small company, our focus is strongly going to be in the U.S. We have enrolled and will enroll from Europe, but U.S. is the focus.

And our final question comes from Mike Ulz from Morgan Stanley.

Thanks for all the updates as well. Maybe just a quick follow-up on some of the safety questions. Can you just remind us when you typically saw the TMA and capillary leak syndrome from the prior cohorts and then just how that compares to the follow-up you have so far in the Cohort 4?

Yes. We -- thanks, Mike. We saw TMA and capillary, as you mentioned, this is a very different experience what we're seeing at cohort 4. It's much more similar to what we saw in Phase I. There certainly is evidence of transduction. You saw in the graph that we showed that [indiscernible] for example, does go up. So we do know that the virus is getting in. And just following some of the early cardiac and liver markers, we're not giving water. There is a torrential rate of AAV9 that the patients are experiencing, but it's a different experience from the early Phase II where we saw TMA and capilary leak, so much more reassuring, Mike.

This concludes today's program. Thank you for your participation. You may now disconnect.

All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, one of the biotech analysts here. It's my pleasure to introduce Gaurav Shah, CEO of Rocket Pharmaceuticals. Just a quick reminder, the format for today is a fireside chat. So if anyone has a question in the audience, please feel free to raise your hand, and we'll address your questions during the discussion.

But before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative. And with that, Gaurav, thanks again for joining us, and maybe I'll hand it over to you to make some intro comments before we get into Q&A.

Thanks, Mike, for having us. Great to be here.

Big picture, Rocket Pharma is a gene therapy company. Our renewed and invigorated focus is on cardiovascular genetic medicines. We have 3 programs in the clinic, one hypertrophic, mostly cardiomyopathy called Danon disease, arrhythmogenic cardiomyopathy called PKP2 and dilated cardiomyopathy called BAG3, all are progressing rapidly. We also have a legacy pipeline of hematologic conditions. We just got an approval for severe LAD-1 called Kresladi earlier this year, for which we sold the PRV for $180 million.

We're very proud of that. So at this point, we are an integrated company from discovery to commercialization from the beginning to end. Today was-- is a very important day, and I'm very happy to announce here at Morgan Stanley that the FDA has now cleared our path to dosing the rest of the Danon trial.

We were previously on hold last year due to a safety issue, and we were asked to treat 3 patients with a modified immunomodulation regimen and a recalibrated dose. We treated those 3 patients safely. The therapy was well tolerated, and the FDA has now given us a green light to move forward. And interestingly, the green light does not expand the trial at all. We will continue with the 12-patient single-arm trial. We already treated 3, so 9 more. Everyone needs to be treated at the recalibrated dose with the revised immunomodulation regimen, which is what we wanted actually. And we anticipate moving that trial forward as soon as possible. This was sort of not -- this was definitely the upside because there could have been the possibility that the FDA asked for a larger trial given the safety issues earlier. But because the safety was so pristine, I believe that they allowed us to continue the trial exactly as it is.

We expect to start treatment for the rest of the patients soon and complete dosing by mid-2027. And importantly, we will provide a comprehensive Danon disease program and general portfolio update on October 6 this year at 4:30 p.m.

The other important point, very important point that I want to make is about our current cash position and runway. We remain well capitalized. Our current runway extends into the second quarter of 2028. I also want to remind investors that Danon disease has rare pediatric disease designation. So it carries the potential of an additional PRV at approval, which is important when considering the program's overall funding in the future. We also have an active ATM with Cantor and honestly, several financing options available to us and a lot of flexibility given the cash runway to select the right capital at the right time. I wanted to make that point. Our focus in the meanwhile is really executing the Danon pivotal program and making future capital decisions at the time that they make most sense.

Great.

Thanks for that introduction and congratulations as well on the feedback from the FDA. And I know it's been a lot of work there. So great to see that. I guess maybe just give us a little bit of background on dosing for the Danon program. I know there's been some changes there, and you're seeing good safety so far, but just kind of what gives you confidence that that's the right dose?

Yes. So the original dose was 6.7e13 vector genomes per kilogram. The recalibrated dose, and I don't say new dose, I say recalibrated dose is 3.8e13 vector genomes per kilogram. Now in Danon disease, because of impaired autophagy, we have very good evidence to believe that higher full empties actually lead to a more potent product for a variety of reasons. So having 40% or so more full -- sorry, more fulls lead to more potent product. Having 40% more fulls, higher full empty ratio leads to the 6.7e13 product in Phase II having been stronger than we thought, more potent than we thought. So we had to recalibrate it down to 3.8e13. So the new 3.8 is the old 6.7. So we believe with FDA alignment and expert alignment that the new product in the Phase II is exactly the product that we treated patients in Phase I. So that's the rationale for it. Also, 2 of the pediatric patients in the Phase I trial had been treated at around 4e13 with the old product. And even if this full empty calculation doesn't hold 100% true, those 2 patients did very well. In fact, they had the most profound reductions in LV mass index for at least 3 years. So we know that this range from about 4e13 up to about 1e14 is active, and we selected a dose that we believe is on the best side of the benefit risk profile here.

Great. Can you talk a little bit about just safety and remind us changes to the immunosuppressive regimen, what you saw previously? -- that triggered those changes and then kind of what you're seeing now?

Yes. So we first had a regimen in Phase I that was a combination of pretreatment rituximab over two cycles, pretreatment sirolimus and ongoing sirolimus for about a couple of months and steroids with as rapid a taper as possible. With the more potent product, we found a higher incidence of TMA than we were comfortable with. So what we did then is that we added a C3 inhibitor from Apellis. And that C3 inhibitor was instituted about a year ago in two patients, and it worked for TMA. It did eradicate TMA, but unfortunately, it came with the paradoxical reaction of capillary leak syndrome for a variety of reasons we can talk about if you'd like.

But when we saw the capillary leak syndrome, one of which case was fatal, we had to obviously remove the C3 inhibitor. It's not the C3 inhibitor itself, by the way, it's the C3 plus AAV, the clearing rate of AAV, the combination basically opsonizes the AAV that would have been opsonized with C3b and the AAV then attacks endothelial cells. It's not something that we would have predicted, but it's what would happen in the real world in the clinic. So we pulled out the C3 inhibitor, number one. We've now extended the rituximab to be given over 3 cycles, same total dose, but we believe the extended rituximab further eradicates B cells and prevents classical complement activation. And we added eculizumab only as PRN, in other words, as needed, which we have not needed to use. You only use it if there's evidence of TMA, and we have the steroids with a rapid taper. That's the new regimen. And so far, it's working very, very well.

Can you just talk about that immunosuppressive regimen you just described and kind of like differences across the field? Is this common now, kind of the same sort of regimens you're using? Are you using some different things than others or...

Companies are -- depending on the capsid, companies are using anything from high-dose steroids alone to pretreatment and ongoing eculizumab or C5 inhibitor to some folks are doing exactly what we're doing. I think there's no right recipe. I think it depends on the disease, the specific capsid, the specific vector design, all of it matters. No 2 gene therapies are made exactly the same. No diseases are exactly the same. So I think for our programs, Danon, we also use the same regimen for PKP2 and BAG3 for our vector designs, we feel that we found the right mantra.

Yes. Makes sense. I know you have to enroll now a total of 12 patients. You have 3 enrolled, so you need to sort of find 9 more patients. Maybe just talk about have you identified those patients and then the process of getting them treated and how long that might take?

Yes. So we have identified well over 9 patients. Our funnel has actually expanded quite a bit. Most of the patients who were previously qualified, a couple have -- are no longer qualified, but most of them remain qualified. In addition, our funnel has drawn from our medical affairs group and genetic testing and the new ICD-10 code and other efforts at finding patients out in the real world. Our natural history study itself has enrolled more than 50 patients itself. So finding 9 patients is going to be exceedingly easy, I should say. Of course, patients can't all be treated on the same day, even though the ongoing trial, patients will be treated in parallel and not sequentially. There are logistics. We also want to mix it up with sites in Europe as well as the United States, 3 sites in each continent. So it's going to take a little bit of while.

Our guidance right now is mid-2027, but obviously, we're moving as fast as possible. Importantly, the October 6 webinar is going to give a lot of insight into both the top-down epidemiology and bottom up. Top down, I would say that we've looked at both phenotypic analyses, meaning finding hypertrophic cardiomyopathy patients and then finding which of those are Danon patients as well as genotypic epidemiology, which is genetic testing at birth, right? So genotypic testing maximizes diagnosis at birth, whereas phenotypic, it goes up over time, right? So where that lands in the middle, we're going to do that analysis. And we're also going to talk about patients we found in the real world in the United States over the last couple of years. So that's a very important webinar for folks interested in Danon to tune into.

Yes. Sure. Can we just go back to the 9 remaining patients? You mentioned there's a lot to choose from. Are there specific characteristics of patients that might respond better or not to your gene therapy? And can you do things to try and get those patients into the study?

In general, with this gene therapy at Rocket, all gene therapies at Rocket, and I would say all gene therapies in general, there is a point of no return, right? Any disease progresses so far that the fibrosis and other body reactions prevent gene therapy for entering and having an impact -- we believe, and we have some empirical evidence to suggest that, that point of no return is when patients have progressed beyond an ejection fraction lower than 50%. This is a hypertrophic cardiomyopathy. So the ejection fraction should remain normal. So by the time it's diminished, it means that there's fluid fibrosis. And when there's a lot of fibrosis, it's unlikely that the gene therapy will penetrate where we need. So that's probably the point of no return.

The only other patients excluded would be those who have antibodies, neutralizing antibodies to AAV9. We do exclude those as well. I would say that for the male patients, that's still provides 80% of patients that still eligible who have not progressed -- who have not been transplanted yet, right? And the thing with male Danon patients is that although it is somewhat heterogeneous population, most male patients become symptomatic with heart disease in their double-digit years, they progress rapidly and the median life expectancy for those males and/or transplant is 19 or 20 years old. So it's pretty homogeneous within a heterogeneous population.

Makes sense. I also wanted to just ask you about durability of the treatment. You've treated patients, I think, a couple of years ago. So just maybe give us an update on what you're seeing there in terms of the durable effects.

Yes. So for the patients whom we followed on long-term follow-up, as far as we have followed them, and we published this in the New England Journal of Medicine and we've given informal updates more recently out to 5 years and more for some patients. The protein expression is florid at as much as 5 years. In fact, the first patient treated 1001 was treated in 2019. He's 7 years out. He's working. He's going to school. He was a patient whom we weren't even sure got full impact of gene therapy because he wasn't taking steroids as expected. for a variety of social reasons. But even that patient who is 7 years out has strong protein expression, Troponin, BNP, LV mass index are all looking very, very good even 7 years out. That's been true of the other patients as well, at least as far as we follow them on long-term follow-up. Obviously, if they're lost that, we don't have that.

That's great. Maybe back to the registrational study. You mentioned primary endpoint is sort of consistent with your agreement with the FDA previously. So maybe just walk us through the co-primary endpoint and kind of what you've seen previously.

The co-primary endpoints are very much in guidance, following the guidance from the FDA for genetic rare diseases, which is if you can find a protein that truly defines the disease and show both preclinical models and clinical evidence that the protein expression correlates with some sort of clinical outcome, number one. So protein expression LAMP-2. And second is LV mass index. And that's something that we negotiated really face-to-face with Peter Marks when he was here and others at CBER because Danon is a disease of big hearts. So how do you show benefit, shrink the heart.

It's very much common sense. We were looking for a year for other methods like should we look at LV strain, -- should we look at cardiac output. At the end of the day, the simple solution was the right solution, combination of improvement in protein expression plus LV mass index reduction by 10% or more. And that's, in fact, been taken up by other companies as a standard of care or a standard endpoint now for these types of diseases. That has not been changed from our prior guidance. And I should say that the trial is confirmed as 12 patients total. It is a responder analysis and not necessarily all the patients need to meet those endpoints to be a positive trial. And we'll have more updates on that as well later in October.

Understood. And I wanted to get back to this idea of safety, and you've had 3 patients that have done very well. I think it's through about 4 weeks plus now.

And I guess remind us previously, when you saw these adverse events like TMA or capillary leak, like did you see them very early in the treatment? Did they show up in that 4-week window? Did some show up post 4 weeks or just.

Yes. TMA, I mean, we've -- I've myself looked at so many labs and thought of these milestones for many years. You know TMA develops by day 4. Capillary leak takes a little longer, maybe day 5 or 6. I don't think in the real world, we've seen capillary leak be on rocket maybe one case at most. So it's not something that's commonly encountered. Hopefully, it's never encountered again because people know that C3 should not be combined with gene therapy. But within a week, at most two, if there's no TMA or capillary leak, I think we're in good shape. What does creep up a little bit later across the board, which we've seen with most gene therapies is immune-mediated destruction of liver cells, which sometimes turns into transaminitis. And that's -- you want to see some transaminitis. -- otherwise, it feels like you're giving water. That usually manifests between, say, week 2.5 and week 6 or so. But certainly, for any of our programs, it hasn't been problematic at all and been pretty well controlled.

I should also add that how do we know that -- how do I feel confident that this recalibrated dose is the right dose. We've done some nonclinical bridging studies that we revealed this morning. We'll have more on that. We've done some analytical comparability between the Phase I and Phase II product. We'll talk more about that, too. And importantly, in looking at transduction of heart and liver in the days and weeks following the gene therapy, our new product seems to follow very similarly to the pediatric patients in the Phase I product. So I feel pretty good that we are transducing these cells.

Great. I also wanted to just ask about your FDA interactions a little bit. There's been a lot of leadership changes over the past year or so and more recently. So maybe just characterize your interactions there. Is the FDA have a favorable view towards gene therapies? And are you dealing sort of with the same group of people? Or over time, has that kind of changed?

So I would say the guidance for rare disease and gene therapy from the FDA has always been favorable. I think it's becoming more favorable even with the prior administration here who's now changed. I think most of my colleagues at Rocket and in the field would say that it's all about the reviewers themselves, specific reviewers. There's less impact from higher up sort of making changes. Of course, I think we saw that a couple of times. But outside of that, those things that happened late last year and earlier this year, if we have a good relationship and a dialogue with the review team with constant iterative mutual education discussion even with patients and patient groups and those sorts of initiatives, that's the right way to go. We've never really had an issue with any of our programs even when we had the prior administration, Danon and all the other programs are moving forward pretty rapidly without a lot of issues. I think the new -- I can comment on the CBER Director, I think he's very open-minded, certainly a rare disease and gene therapy. So we're very excited about working with him and the programs.

Great. You touched on this already, but October 6, you'll have kind of a very comprehensive update on the Danon program. I think you mentioned maybe epidemiology. I guess, what else might we expect or should we be looking for?

So we will have a broader portfolio update as well. I think we'll talk about -- first of all, and then Danon and we will talk about the clinical profile so far. We won't have efficacy, just to be clear, just because it's so early. As you can just calculate, the first patient would not have been treated much more than 3 months ago, right? So we don't have enough efficacy data. But we'll talk more about safety, the general experience across the Phase I and Phase II. We'll talk about the epidemiology top-down, bottom up, and we'll have some updates on the rest of the portfolio as well.

Okay. Great. Maybe we can shift gears into some of the other programs that you mentioned earlier, but I guess maybe just a big picture question. What makes gene therapy such a good approach to treating these cardiovascular or cardiometabolic disease.

Well, I think for at least the programs that we're looking at, and I think most colleagues in the cardiac gene therapy field are looking at, you can't do anything other than DNA replacement. There's no small molecules. Many of these are transmembrane proteins or cardiac junction proteins. You can't just put a small molecule there and expect it to traffic to the right place. So you have to hit them in the nucleosome at the DNA level, and there's no other way, right? So really, there's no alternatives other than transplant for most of these patients.

And I think that's what makes them compelling. I think Danon is a one-off. Danon is probably the most aggressive cardiomyopathy out there. The vacuoles build up pretty rapidly in the course of a couple of years. So reversing the cardiac modeling or cardiac remodeling you can do within a year or 2 in Danon disease in a way that I don't think we're going to see across the other older patient cardiomyopathies. So Danon is a good test case. Building on that, BAG3 is a dilated cardiomyopathy. These patients usually don't manifest until a little bit later in their life, 20s or 30s. They have a slower onset of action. But we do believe that BAG3 replacement with gene therapy is a viable approach. That trial has started, and we'll have more updates on that soon. PKP2 similarly is an ongoing trial. We've treated 3 patients. And that's an arrhythmogenic cardiomyopathy. So I think there it's a little bit more tangible to show a demonstrable benefit without waiting for RV dysfunction just with the arrhythmias themselves, and we hope to have an update on that with the regulatory agencies soon as well.

Just on those sort of Wave 2 programs you just mentioned, I guess, just given your experience with Danon, any like key learnings that you can apply to these sort of the next wave to accelerate things? Or what are some of the learnings?

I would say there's general lessons, right? There's lessons on safety. Treating patients with AAV-based gene therapy creates muscle memory in the organization. It's just like doing a commercial launch. There's a feel for it. There's a dialogue. There's experts around the table that you talk to. You just have an instinct when something happens and you know it's going to go wrong or it's not going to go wrong. So I think that learning applies across our portfolio. You mentioned Wave 2. I would call these 3 programs, Danon, PKP2 and BAG3. I would call them still Wave 1. There's a Wave 2 with at least 3 other programs -- some of them as exciting or more exciting in my opinion, but we'll be able to apply this across all 5, 6 programs over time.

The other learning, the general learning across the field is how to really interact with the FDA in a way that's collaborative, that's transparent, that's proactive so that we're not surprised at the last minute. A valuable point I can make is that the lesson from LAD-1 for Kresladi, we did have a CRL there. We made assumptions based on what we were seeing other companies do. Orchard, bluebird who had gone before us and gotten lenti-based therapies approved. We had made assumptions of what the FDA would have wanted to see. And when we got there at the last minute, they wanted us to sort of copy exactly what bluebird and Orchard had done, and that cost us a year or more, right?

So we -- in retrospect, I would have asked earlier, even if that delayed things by 6 months, I would ask early that's what I'm doing with these programs now to make sure that everything is teed up well in advance. Those are the general lessons across the program.

Yes. Makes sense. If we just focus more on PKP2 and maybe talk about the unmet need there and the market opportunity.

So PKP2, I mean, we think that there are at least 50,000 patients in the U.S. and Europe. One larger company who had pursued it in the past and dropped it that it was 140,000. So it's somewhere in that range. I think that because of that large population, there's probably room for more than one biotech or pharma to treat these patients. There's a lot of patients out there. They're easily diagnosed because -- these are patients who exercise and have palpitations, unfortunately, have sudden cardiac death.

The current treatment of ICD is employed in about 80% of patients in the U.S., but it doesn't stop progression of right ventricular dysfunction. It doesn't stop the anxiety that is debilitating for these patients, and there are also breakthrough arrhythmias that can be fatal. So there is a very high unmet need. The patient community we've interacted with is really excited about the prospects of gene therapy. And at least the 3 patients that we've treated, we still have the Phase I open, have done exceedingly well and the therapy has been life-changing for them.

Can you maybe talk about some of the earlier data you shared and what impact you've had on sort of key endpoints and your thoughts around some of those endpoints?

Yes. So I would say that the endpoints fall into 4 categories. And these are the same 4 buckets that anyone discussing with FDA is going to have to talk through, right? One is protein expression, one is arrhythmias. -- one is RV function and the fourth one is how patient functions and feels. There's only 4 buckets. We're all going to arrange the chairs in a deck in our own way, but there's only so many chairs to arrange, right?

Protein expression; we feel that we've looked at protein expression very thoroughly using not just Western blot and immunofluorescence but also looking at trafficking of chaperone proteins that should be present in the cardiac junction if PKP2 is there. We've demonstrated improvement for all 3 patients. We've looked at arrhythmias. The common arhythmias that people look at are PVCs, NSVTs and T-wave inversions. Not all patients have abnormalities in these, but we've seen improvements where abnormalities existed in our patients. We've seen one patient who had a normalization of RV dysfunction, the only one who had RV dysfunction normalized that function. And on the NYHA class and KCCQ scores, we've seen improvements across the patients we treated.

We started at a dose that we thought was the right dose to start with based on preclinical models. Therefore, we have less patients treated, but we do believe that we have the pivotal dose ready to go. The FDA has agreed with that. And now it's a question of which of those endpoints are primary or secondary and how do you design the trial.

I guess are we -- you mentioned, I think you're going to have an update later this year on this program. Will it include sort of the path forward as well in the Phase II design?

Yes.

That's the plan. Those discussions are ongoing. I don't have exact guidance on when, but they're ongoing.

Okay. Got you. And you hinted at this, too. There are some competitors here. I know data is sort of early comparing across trials, but is there any way to think about any differentiation that's emerged early across the program?

I think the programs are similar. Different patients are going to have antibodies with different capsids. I wouldn't declare a victory of any one over the other. I would say that the data that we've presented is directionally, uniformly moving in the same direction for all 3 patients with no deviations. So that makes us feel comfortable that at least we have the right dose with the right patient profile to move forward to a pivotal trial.

Understood. Maybe we can shift gears to just BAG3 and maybe give us a quick background on that condition, kind of next steps for that program.

BAG3 is super exciting. It's a program we inherited from the acquisition of RenovoRx a few years ago. It does represent the largest bucket of cardiomyopathies, which is dilated. I think if we can crack the BAG3 code, there's a lot more to come. In fact, some of the technical Wave 2 programs are looking at other programs like that. And BAG3 is a protein that has multiple functions. It's not so simple as Danon, which is just associated with autophagy. We think that a similar approach with mid-e13 dosing based on preclinical data that we've seen and demonstrated and publicized should afford some benefit. This is a dilated cardiomyopathy.

So traditional LV endpoints are going to make more sense. I don't know if it's ejection fraction or cardiac output or some sort of exercise test or LV strain or something else. But this is a playbook that's been played in the cardiac field in the past. So while Danon, we have to figure out, PKP2, we have to figure out from scratch. This is something that should have a well-trodden path.

Yes. And maybe talk about time lines for that program?

BAG3 is in the clinic, and we hope to have more updates soon.

Okay.

Got you. Maybe across the 3 programs we've been talking about, can you talk about just the capsid or key differences? Is there -- are there anything different there?

So AAV9, I felt -- we felt that AAV9 is the right vector for Danon disease because Danon disease is not just a disease of the heart, but also the CNS and muscle. -- we know AAV9, AveXis, et cetera, penetrate the CNS exceedingly well. Often, these are patients who present with learning disabilities first, even before they have any muscle pain or cardiac symptoms. So AAV9, we believe, was the right capsid for those male patients. rh74, of course, has tremendous experience in humans through Sarepta and others. At the dose that we're dosing all of our patients in PKP2,BAG3 and potentially future patients as well in the pipeline, which is mid- to mid-upper e13, the total capsid exposure is probably 1/3 that we've seen from Sarepta and others. I know that there have been safety issues, especially liver issues with some of the other companies, but we're dosing about 1/3 of the total capsid exposure because the dose is less and the full empties are a lot higher. So we do feel that at this range, rh74 is an excellent capsid to penetrate the heart.

Okay. Great. Maybe in the last few minutes, we just shift gears to your sort of LAD pipeline. You mentioned it earlier, Kresladi. -- maybe give us some background there and kind of next steps to launch there.

Yes. So I'm happy to say that yesterday, the -- we had relisted the price, the WAC for LAD-1 for Kresladi, which is $3.9 million, a little behind Zynteglo. And I think it's the third highest gene therapy at this point. That's based on health economics analysis as well as the clinical benefit that we've seen in patients. The patients who don't get gene therapy can get transplant, which is costly, has a lot of toxicities and doesn't always work. So Kresladi, we're launching it in Q4. That remains on track.

And there are not a lot of patients out there, but we do have at least one, if not more, centers that will be open to treat patients who have inbound interest. We're not putting any marketing or commercial muscle behind it other than making it available. It's a severe devastating condition. We're very close to the KOL and patient community here, and we're very proud of that launch.

Yes. Can you just talk about the estimate of patient numbers in the U.S. and how many of those roughly are identified?

So there are 25, barely, this is an ultra ultra-rare disease. There's 25 total LAD-1 patients born in the U.S., approximately 2/3 of those tend to be severe. And most of those severe patients pass away pretty fast. So there are a lot more moderate patients out there than -- because they add up over time. Within the severe population, which is where our label is and where we will treat patients, there are a small number of transplants each year. So I would expect no more than single-digit numbers per year for severe LAD-1 lot.

Got you. And I guess the latest thinking on your other hematology assets or updates there?

Yes. I mean I started -- or I was hired to start this company at RTW based on pyruvate kinase deficiency PKD. When gene therapy works, it really works. We've treated 4 patients with PKD. Most of them have doubled their hemoglobin and kept it to normal over years. Fanconi anemia is an elegant gene therapy with no conditioning whatsoever. Most patients that we've treated have remained -- in fact, all of them have remained bone marrow transplant-free over time, and most of them have corrected their bone marrow. And we have those programs. We own those programs. We look ongoing -- in an ongoing way, we're looking for partnership opportunities. However, FA is also eligible for a PRV. For now, we prioritized to the cardiac portfolio, but those are always in our heart as well.

Okay. Great. It looks like we're just about out of time. So why don't we wrap it up. Thanks so much, Gaurav, and congrats on all your progress.

Thank you, Mike.

I'm Joshua Schimmer from the Cantor Biotech Equity Research Team. I'm very pleased to introduce from Rocket Pharmaceuticals, Gaurav Shah, Chief Executive Officer.

Gaurav, welcome. Great to see you as always. Why don't you start by setting the stage for Rocket, where the company is now and where we're headed.

Josh, thanks for having me, having us. Rocket is a gene therapy company. We are focused on rare genetic cardiomyopathies. We have 3 in the clinic, one representing each of the big buckets of genetic cardiomyopathies, which are hypertrophic represented by Danon disease; arrhythmogenic demonstrated by PKP2; and dilated demonstrated by BAG3. We try to find assets that have a very clear mechanism of action, where we target the protein of interest in the cell of interest in which there's a high unmet need and where we believe that we can see clinical results in a time frame that makes sense for regulatory reasons.

That's been our philosophy since day 1, we actually started the company as an ex vivo lenti company, and we still have those programs, including the recently approved KRESLADI for severe LAD-I, Fanconi anemia program and a PKD program. We've shifted our focus to cardiomyopathies in the last few years to really be able to prioritize and use our resources most wisely, but we continue to seek opportunities to partner out the LV assets. We will be launching KRESLADI in the fourth quarter of this year for those patients who want access to it.

In general, we have a pipeline underneath these 6 programs that's deep and equally exciting. We're very excited about the next 9 to 12 months as there are numerous catalysts coming up.

And then quickly on KRESLADI with the upcoming launch, how are you contemplating price?

Well, we don't want to be the most expensive out there. But the reality, the truth is that the cost of nontherapy is pretty vast and pretty large. And even the numbers that are out there for other approved gene therapy products are lower than the actual cost of treating an LAD patient over the course of a lifetime. So we'll be announcing that at some point in the coming months, but [ inexpectant ] in line with other gene therapies on the lenti side.

Okay. On the cardiology franchise, as we think about the unmet need between Danon, PKP2 and BAG3, how might you kind of rank order? Because we certainly, when we talk to specialists, hear about really the devastating prognosis for Danon in particular, perhaps a little less so for the other indications.

Yes. There's almost an inverse correlation between the patient -- number of patients out there and the devastatingness of a disease, right? So, yes, Danon is very devastating. It's probably one of the most aggressive cardiomyopathies out there, also the one where we can demonstrate clean, clear benefit in the single-arm trial, which we're working on right now for a pivotal trial.

Danon, I would say, we continue to say at least 15,000 patients in the U.S. and Europe. The next most devastating is likely BAG3, which is dilated cardiomyopathy. It's a bigger market. We haven't come out with the actual numbers or epidemiology in that. And PKP2 is, of course -- can be fatal with sudden cardiac deaths. There are more than 50,000 patients with PKP2 in the U.S. and Europe, but that's a disease that's heterogeneous and where we need to be very smart about trial design so we can win if it works.

Okay. So, I guess, one of the key investor active debates is your ability to really get the right balance of safety and efficacy with AAV gene therapy, recognizing that there can be some safety concerns with it. What gives you now the confidence that you've been able to hone in on the right dose, not just for Danon, but the general portfolio?

Yes. So unfortunately, for AAV, there are no preclinical models that mimic the safety we see in humans. There's just no TMA model. There's not even platelets and LFTs in mice and [ HPs ] and pigs tend to not fluctuate too much with AAV. So we have to learn this in the real world and sometimes the hard way, right? In terms of the dose, we have now treated 3 patients with the revised regimen and the recalibrated dose of 3.8E13 vector genomes per kilogram, successfully, safely, these patients tolerated the therapy well.

We -- it's been a journey, right? Last several years, we learned so much from each patient. Even in Phase I when we begun -- when we first started with patient 1001, he got some steroids, but nothing else and he wouldn't take his steroids, and it took a while to sort of stabilize and he did not have TMA. But I can say even that patient who is 7 years out is working full time and he's living a normal life in his mid-20s, which would be unexpected with anything else, right?

So wherever we are in Danon, I think that the long-term path to success is about the positive benefit risk. I think on the safety side, I feel we've solved it with this recalibrated dose in this regimen. Obviously, we'll need to treat more patients to see for sure. I think that with AAVs for heart, this mid- to low upper E13 range seems like the Goldilocks zone. We're in the same place with PKP2. We have not announced our BAG3 dose, but you can understand it's in that range as well. And that gets around some of the more common TMA and liver issues that are seen in the E14 range.

What kind of -- or maybe frame the totality of data that gives you that confidence that kind of low mid-E13 dosing can avoid some of the safety pitfalls that -- and obviously, there's going to be a dose effect dynamic, but specifically for this dose, had we kind of aggregate data and information and apply it here to say 3.8, we're good.

Yes. So the only time we have seen TMA in the setting of Danon disease was in Phase I, where we were well above 1E14 in 1 patient. In Danon at this dose in a couple of patients, one of them had another complement activating mutation called CUL4B. So we don't know exactly what happened there. And another patient got sort of the higher end of the dose and also had recent prior infections. So it could be that all 3 of those patients had issues that we're not going to -- we're going to screen out anyway with new patients.

Having said that, the dose range in which we saw clear efficacy in Phase I was anywhere between around 4E13 up to 1.1E14. So this dose around 4E13 is at the lower end of the range of demonstrated efficacy, has a great safety profile, both in Phase I and in so far in our Phase II. And also in our Phase I patients who got around this dose, at least out to 3 years, which is as long as we've been able to follow them in the trial, they've had the most profound reductions in LV mass index and some of the most florid staining for LAMP2. So that gives us a lot of confidence. Obviously, we'll see what happens with how the trial resumes and how those patients do on efficacy-wise.

But on the safety, I feel pretty good about it. One nuance here is that you don't want to see nothing after you treat these patients, right, just from a scientific side. You don't want to see no changes in labs. You want to see something because that gives us confidence that we're actually transducing cells, whether in the heart or liver or wherever. And the fingerprint of the labs in the days following the most recent patient's treatment are highly reassuring.

Is the risk of TMA with various AAV subtypes dependent on the underlying disease in any way? Are certain diseases more prone to complication? Or is that not even a factor as we -- because we'll have to extrapolate and aggregate information across disease settings as we think about each dose and vector.

I think it's -- I would say that we've seen TMA for the most part with AAV9, perhaps of the AAV8. And it's not always dependent on the dose also. Sometimes it's idiosyncratic. I think there are predisposing factors. One has to be very careful about screening those sorts of patients out, anyone with a complement-activating mutation or recent infections. So I don't -- we've seen TMA across several disease types, and we also see it in the transplant setting, solid organ transplant setting.

So the body is primed to activate complement, especially when you get a torrential rain of virus in the body. So yes, I don't think it's disease specific. I also don't think, by the way, Josh, that there's going to be a long-term zero risk of TMA. I think that's not reasonable to expect. However, even the patients in our trial, and we hope there's zero long term, obviously, and certainly this trial, I don't know until it happens. But even the patients who had TMA in our trials early on, they've recovered fully from TMA, and I'm hoping that they also benefit from the gene therapy itself in the heart.

I was surprised this many years into AAV, recognizing some of the challenges of the administration and we've not really made progress with nonviral vector type administration. Do you see anything in the field that's encouraging or promising? And if not, why do you think that is?

There are some pockets of encouragement without naming companies. I used to sit on the board of a nonviral gene therapy company. It's hard to get around the early NHP toxicity that the field is seeing. I think that there will be room for growth in nonviral. I would say it's at least 5 years away to really see something impact on the clinic.

Meanwhile, if we have a safe therapy with AAV, traditional in vivo gene therapy, traditional gene replacement, in addition to these 3 programs, we have at least 3 others that are equally exciting that we can apply this technology pretty rapidly.

What I found really interesting is talking to cardiology specialists around Danon and their enthusiasm for your program despite some of the safety considerations you've had to navigate through is exceptionally high. I thought we might have heard a little bit of caution. Well, let's kind of see how -- but I guess, perhaps reflecting just the dire nature of the condition and not necessarily feeling like there is time to wait and see how it goes. Your sense from the broader community, is that an accurate reflection of what you're hearing as well?

Yes, that's an accurate description. So what we know anecdotally from the patient community is just that there's overwhelming excitement and enthusiasm for us to continue to develop this. We've had a number of community calls cohosted with the Danon Foundation by which patients, caregivers and these families can come forward and demonstrate their support. In addition to the patient community coming forward, we have a number of HCPs that have participated as well.

And so your sentiment that you captured is extraordinarily accurate. And so that's what has us exciting and motivated when we're out in the field, and we're encouraging folks to actively use the ICD-10 code that's been in place for 29 months now. And when we're talking to geneticists as well to actively encourage use of genetic testing, to genetically confirm these Danon patients. So Rocket has stood up Mission: Genome, which is a no-cost genetic testing effort, and that is a way for these patients and HCPs to partner and sort of take the administrative burden of getting an accurate genetic diagnosis sooner. And so we're encouraged by this and the HCP community certainly seems to understand that.

Let's come back to that because that's really important. Maybe first, though, 3 patients dosed successfully, what happens now on your path to continuing enrollment and ultimately to a potential BLA filing?

We're in discussions with FDA with this new data set of patients tolerable, good safety profiles, and we will announce when we know what the rest of the trial looks like. There's been no indication that there's going to be a change to study design. I don't know if FDA asks us to treat more patients than the 12 total they've agreed to given the safety issue.

But if they do, that's not necessarily a bad thing because as we had more payer discussions even for LAD-I, I'm personally realizing that the bigger the data set, the better for the commercial launch. So a few more patients is totally fine as long as the study design remains intact and we're in those active discussions now.

And when can we expect data updates from the patients treated?

Sure. Before we move on to data expectations, it's also important to note that what we put out in our earnings in August, a couple of weeks ago, is that in addition to dosing safely these 3 patients at this recalibrated dose, we've enrolled over 50 patients in the natural history study. And so as Gaurav was mentioning, having a more robust data package with perhaps a few additional Danon patients treated in this pivotal study can be a positive thing.

We've been working very actively behind the scenes. So trying to look graceful like a duck on top but pedaling very actively underneath to make sure that we have a robust patient population that we can tap into. So of the patients that were previously enrolled in the pivotal Phase II study, to our knowledge, none of those patients have dropped out.

So we're in the process of screening those to ensure that all of those remaining patients are eligible to participate in the pivotal study. We've identified even more than that. So in the event that there's a greater number of patients that the agency wants to see, we can tap into that. But we also have the ability to tap into this patient population through this natural history study in the event that even more patients are needed. So we've been hard at work to make sure from an operations and execution standpoint, we're ready to go.

As we're thinking about the profile of the program and the risk we're trying to rule out by adding more patients, is there a sense of like we're trying to rule out events that could occur north of 1% of patients, north of 5%, again, like recognizing because you have to put it in the context of the severity of the disease, do you have a sense of where we're trying to aim for to rule out a risk?

I think that -- look, if we saw 50%, 70% TMA, that's a different product. We saw 10%, 20% and those TMAs recover and those patients never need a heart transplant, that's a different, right? So it's sort of like CRS in CAR-T, which I participated in at Novartis. CRS was pretty common, yet the drug got approved because otherwise, it's a fatal disease and there's no alternatives, right?

Similar for Danon. I think in the oncology world, people are willing to take risks like CRS or TMA in the gene therapy world, they're just not. And I think people should be ready to take risk because ultimately, you'd rather have TMA stay in the hospital for a month or 2, recover but then live a normal life. And just to go back to the data question, I don't think we've provided guidance on that just yet, but we will as soon as we can.

Okay. Let's come back then to the patient identification efforts because it sounds like you've been very busy. Beyond the 50 patients you've enrolled in the natural history study, what are you able to comment on kind of beyond that for patient identification efforts? And when are we likely to learn more?

So last year, we had said that we'd be providing a comprehensive program update for Danon. Unfortunately, we had the safety issues. So it's basically delayed a year. Now we're going to do it this year, both a top-down analysis that will give a lot more light and color on to what the true prevalence of Danon is, and we've done a much more sophisticated analysis of those numbers.

And also a bottom-up analysis of patients that are reported in the field. We haven't obviously put a lot of commercial efforts into patient finding, but informal efforts have been -- have led to some pretty good results there. So we'll be able to share both the top-down and bottom-up alongside a program update in the second half of this year.

Maybe elaborate a little bit on introducing an ICD code. So what -- like, how does that translate from, okay, there's a code to now we have a better sense of where patients are?

Takes time. So the code has been in place for 29 months, which means you have to be actively in the field with your geneticists, your MSLs and talking to the HCP community as to why you use it, when to implement it and then an accurate diagnosis matters. So it's not just the ICD-10 code, it's also about encouraging an accurate genetic testing confirmation so that we can verify that these are Danon patients. So it's in partnership.

So we've been tracking the usage and uptake of the ICD-10 code over the last 29 months, which has been positive and in line with other rare diseases by which an ICD-10 code has been recently introduced. So from that front, it's fine. But it's not just pursuing that. You have to be in the community talking to these HCPs because don't forget, Danon is an indication where there are multiple forms of symptoms that emerge.

And sometimes the cardiovascular symptoms are the last to emerge or the last to get identified in these young boys. So you actively have to be out there in the community, educating on the health care benefits of looking at all of the symptoms involved.

So these are patients who I imagine will primarily be followed by pediatric cardiologists.

It's interesting because it depends on how they present. A lot of times, there's a subtle learning disability. There are some psychocognitive issues even in the single-digit years. Later, patients might have muscle pain or muscle weakness. So it's not really a cardiology issue, right, early on. They often present to neurologists, to pediatricians, to psychiatrists, to musculoskeletal experts. And by the time they have a heart symptom, a lot of them get written off as something else, that's not heart.

And once the symptoms of heart come on, it's pretty rapid and it's fatal in 2 or 3 years. So unfortunately, pediatric cardiologists are not seeing them in patients as much as they should. So our educational campaigns between now and launch focus on getting not just the pediatric cardiologists, but the other contributors there as well.

Roughly, how many pediatric cardiologists are there in the U.S.? Do you have any rough estimate?

I don't, but I know the 3 or 4 I trust for Danon disease.

I'm guessing that that's probably a fairly straightforward effort to go into those clinics and get testing done and then -- but the challenge is going to be...

It's a community effort.

All that other outreach. How do you even think about approaching that type of a dynamic where it's very spread thin and you're looking for a needle in all these different haystacks that may or may not be there. And especially when you're describing symptoms that don't screen Danon.

Correct. A lot of times, that's when the genetic testing component comes into play. So the more that we can encourage accurate genetic confirmations of these diseases. So you're not just testing for Danon disease when a genetic panel is being ordered, you're testing for a whole suite of cardiovascular indications. So that encouragement to have these HCPs do this genetic testing is really kind of how you're going to get a sweeping effect and a scan for these diseases.

How ultimately do you get this test into perinatal or screening at birth?

It's a multiyear process to get placed on the suggested national screening panel and then you have to fight on a state-by-state basis. So it takes a lot of time. We've studied intimately the journeys that some other rare disease companies have gone through in order to be able to be added to the infant genetic testing panel when their heels are pricked, and it's a multiyear journey. So we started that work, and we know we're in for. You develop a couple of pilot programs, show those results to the National Screening Board and then you move forward.

Okay. And are there certain criteria like that you need to achieve either in the pilot program or from a drug development program to have it added or...

There's no program -- excuse me, there's no indication on these panels for which there's -- for which there is not an approved product. So there needs to be an approved product in order for these pilot programs to succeed. So that's step one.

If there's any company that could change the system to the advantage of patients, Rocket would seem to be one to have the passion and persistence and compass, right, to make sure that patients can be -- I mean, especially in this condition, where it seems like early diagnosis is really important. It's a hard diagnosis to make unless you have a high index of suspicion or are testing broadly in the perinatal setting.

1000%. And I think that's where we put our superman capes on, and we rely on the KOLs who are experts in the field to help get the message out there with us, and we look forward to talking more about that with our program update.

And that's also reflected in how we're building our commercial and medical affairs teams. There's more than sort of the account managers. We have genetic diagnostics liaisons and MSLs who are very well educated and cognizant of the genetic testing part of things, not just the physician relationships. That's how we're building our commercial team a couple of years in advance.

So one very common point of discussion amongst investors is where are the patients, right? And obviously, a lot of work in preparation going into advancing the program. But if there's not a degree of confidence that there are going to be patients to treat, not just a little bolus in the first year, but something maybe more proximal to the numbers that you've laid out.

But it's hard for us to find the patients and probably in the same way, it's hard for you to find the patients. How do you address that concern like now or at the event that you're going to host later this year?

So it has been less and less difficult to find patients over the -- each year that goes by. I think there's just greater awareness even in the time that I've worked on Danon, I've seen that it's easier to find, identify patients, screen for them, which is how we got really rapidly to the 50-plus number of the natural history. So the patients who are out there, they're not always in the big adult centers of excellence. They're often in the community. And as awareness of Danon grows, we're seeing more and more referrals. So personally I'm not finding it hard to find patients.

Secondly, each patient who's in the natural history or on the trial, the index case, we look at the rest of the family. And surprisingly or not surprisingly, there's always 2 or 3 or 4 other family members we find have Danon who didn't know they had Danon or someone died at an earlier age of a particular reason, which is obviously Danon.

So patients are there. They're just not being identified as Danon, largely because even in the U.S. today, only 10% to 20% of centers actually do genetic testing. Even now. Europe, it's a lot more frequent. In the U.S., it's still very low, but that's the mindset and practice that we aim to change. And yes, Rocket is going to be relentless.

Okay. It feels like at least for the time being, we've put aside the female Danon population. I'm guessing they come back into play as you've established the safety profile because they may have a less severe phenotype. And so a more robust safety data package would be warranted. How do we think about time lines and potential to address that part of the market?

So the female program is a very important part of the Danon life cycle. There's a lot of inbound interest from the Danon female community. There are certain Danon females who have devastating severe disease, not unlike the male population. Those are probably the patients that we'll look at first. The FDA has themselves volunteered or asked us to start developing a female trial. So the only thing stopping us is just getting the male trial up and running and far enough to get some traction before we shift focus.

So as we think about kind of the Danon population you've estimated 15,000-plus U.S. and Europe, how should we be slicing and dicing to those who would be suitable candidates for therapy?

So for males, almost all males invariably progress to heart failure on average by the age of 20 or pass away. So there's really a homogeneous population within the male subgroup. There's going to be obviously several who already got transplanted, so they can't get gene therapy. There are some who are going to have antibodies. I think the rest of them who are currently 8 years or older, but in the future, maybe even less than 8 years old are all going to be eligible.

We will address the addressable population as part of this program update, but that gives you a rough ballpark. As we know -- yes. On the female side, it is more heterogeneous, but females also progress invariably and almost always die of heart failure. So it might not be the same penetrants as males, but it's not going to be trivial.

In our checks, I routinely come across docs who at least claim to have adult male Danon patients, maybe a female as well as that. Are those anomalies? Or is there something there that you may be able to pursue?

They're not -- I don't think I've run across more than a couple of male patients who are older than 40 or 50. They are out there. I do know they're out there, but they're not a lot. There are 85 to 90 types of mutations that could constitute Danon disease. If you include some variants of unknown significance, it could be over 100.

And they're not all made the same. There's splice variants, there's truncations. And it could be that some of the splice variants are a little bit less aggressive and those patients live longer. But regardless, they are going to have symptoms of LAMP2 or the lack of LAMP2 over time. So even those milder phenotypes are going to be eligible for the gene therapy.

If we can turn to PKP2, which is kind of 2 problems in one. There's the arrhythmia, then there's the cardiomyopathy component. As you kind of think about advancing this program, recognizing that some patients may have more of an arrhythmia, some may have more of a cardiomyopathy and there are kind of 2 endpoints to consider. How do you advance this towards a pivotal?

Yes. I think arrhythmogenic used to be called ARVC, is now ACM arrhythmogenic cardiomyopathy. The key problem is in the name, arrhythmia. One of our advisers and someone I really respect and trust is Barry Greenberg, who's working with us on some of these trials. It makes sense that if you can shift the profile of arrhythmias, then you can shift the nature of the disease over long term. So arrhythmias have to be part of whatever trial we design, including potentially primary and secondary endpoints.

The RV dysfunction tends to come a little bit later in life. In our trial, we've actually seen someone with RV dysfunction convert from abnormal to normal, which was very reassuring. I think we're going to target sort of the moderate-to-severe population, but not so severe that they can't benefit from gene therapy. So I think that's the Goldilocks for PKP2. The trial design discussions are ongoing with FDA, and we hope to have something as soon as possible.

Got it. And then for BAG3 as a dilated cardiomyopathy, especially maybe in light of some of the FDA questions around Capricor's own program and echo measures and the reliability in dilated cardiomyopathy setting, what do you think are approvable endpoints that you can explore and characterize early on?

Ways to look at LV function, whether it's EF or strain or a clinical exercise output are all valid. I think there are learnings from the Capricor review, including ensuring that we don't have a lot of missing data points, ensuring 100% agreement on the SAP before we embark on the trial. But I think the Capricor experience does not negate LV outcomes as viable outcomes with FDA. It's just how we get there that we need to be careful and thoughtful about, and we are.

I guess, the potential to show a benefit in a single-arm trial may depend on your ability to actually reverse the dilated cardiomyopathy. Is that feasible? I actually don't have a good sense as to the ability to kind of remodel a dilated cardiomyopathy to improve ejection.

Yes. I mean mice and humans are not the same, but we've seen complete reversals in the mouse for sure. We don't know if we're going to see it in humans. My sense is that gene therapy is the most profound type of therapy out there. So if anything is going to reverse it, it's going to be gene therapy, replacing DNA at the core.

All right. Eager to see more updates from Rocket across these programs. Gaurav, Meg, thank you so much for joining.

Thanks for having us.

Thank you.

All right. Good morning. Let's kick off our next session. It is my pleasure to introduce Gaurav Shah, CEO; and Meg Dodge, Head of IR from Rocket Pharmaceuticals. Welcome. Very exciting to be hosting you again this year. Before I have a lot of questions prepared, but before we get to that, I want to kick it off to Gaurav for opening remarks.

Rich, thanks for having us. It's great to be back. This is a very exciting year for Rocket Pharma. We are a gene therapy company. We are focused, laser-focused on cardiovascular genetic medicines, especially rare diseases where there's a high unmet need and where there are no alternative treatments other than heart transplant, which can be devastating in most cases.

So our focus has shifted over the years. We started off as an ex vivo lentiviral-based company with three programs in the clinic, one of which got approved. We're very proud of the first CBER approval this year with KRESLADI for severe LAD-I, but we have since then shifted our resources, finances and focus to be a cardiac gene therapy company. This is an exciting year because while we're laying low and executing, there's a lot of things going on behind the scenes for all three clinical trials that are ongoing right now, one for Danon disease, which is primarily hypertrophic cardiomyopathy; second for PKP2 with -- sorry, which is an arrhythmogenic cardiomyopathy and third for BAG3, which is dilated cardiomyopathy.

These three buckets represent three of the biggest buckets of genetic cardiomyopathies: hypertrophic, arrhythmogenic and dilated, and we're taking a big bite out of the apple in terms of finding potential cures to cardiac genetic diseases.

I see fantastic. So we hosted you guys last year at this conference. It was under a very different circumstance. You guys -- it was right after the clinical hold on Danon's, the pivotal study. And then you fast forward to today, a lot changed, right? You guys have the first FDA approval. The CRL was cleared, and you guys are up and running again with that -- with the pivotal study for Danon. And I believe the company is in a much better place given what happened and -- but the stock is still down 10% year-after-year. What is the market missing?

I think this is a show-me story. I think once we -- so we've got the CRL lifted, first of all, we had the clinical hold lifted last year. We got the KRESLADI approval. We got the Danon trial back up and running. We've started treating patients. And I think as we demonstrate more momentum and achievement of milestones, the cardiac gene therapy that Rocket is will come more and more into focus. I'm very confident about that.

Several catalysts potentially coming up, including treating these patients with Danon disease safely with the revised regimen, number one. Number two, followed by a regulatory and a market update on Danon, I think the market is looking for those answers actively as we speak. Getting some clarity on the PKP2 pivotal trial design is an important part of expanding beyond Danon. And I think treating some BAG3 patients safely as well will put us back on the map in a very real way.

I see. Okay. That makes sense. I think there's a lot of derisking ahead for the company.

We're in the midst of that. So in addition to everything that Gaurav just mentioned, Rich, I'd also say that beginning in 2025, we made the announcement when we came out with earnings from the prior year. So when we announced our 10-K last year, we said that we're leaning into the cardiovascular genetic medicines company.

However, Rocket's origin is -- has a legacy, and that just takes time. So I think that we're in the midst of demonstrating that. And so I wouldn't necessarily say that we are waiting to derisk other things. I think the stock price is -- showed that we're undervalued presently, but we're in the midst of reprioritizing everything that we've already stated that we would.

Yes. And each of these cardiomyopathies represents a potential $1 billion-plus revenue opportunity. So it's there to be unlocked over time.

Got it. Maybe step back a little bit. And how do you find like sort of the investor sentiment towards gene therapy as a class? I'm sure you guys talk to a lot of investors. And then what do you think are the views of just, not just Rocket but gene therapy? And what does it take for this class to, kind of, draw back interest?

Gene therapy is finding its place. It started as a very optimistic space, sort of a blue sky honeymoon period in the -- I would say, in the 2010s for the most part. We had a couple of pretty successful launches and revenue generation opportunities with AveXis and ELEVIDYS. So I think we've demonstrated that gene therapy has a market, it can work. It can be safe in patients with high unmet need and devastating diseases. Gene therapy is not for all diseases. And I think some of the pitfalls on efficacy and not demonstrating efficacy are seen where there's not a clear benefit of something like gene therapy. That's number one.

Number two is we've had to overcome a lot of safety hurdles in the last few years. But I think the page is turning. And I think in this new era, developers are finding a safe path forward as I think we are for Danon. And secondly, they're applying gene therapy to diseases where it will actually work and people will take it and there is a market for it. So I think it's going to come back. It's not for everyone. It's not for all diseases. And I think the market is going to reward real drugs with real markets over time.

That makes sense. So there's a lot going on at Rocket at this point. I think you mentioned a couple of these assets. So what's the status for Danon, PKP2, the BAG3? What are some of the key readouts and milestones for the next 12 months?

Sure. So as Gaurav was mentioning, we've got a bunch of key activities for the remainder of 2026, including some type of update from the pivotal study, which we're in the midst of. We announced that in our May earnings. So with this Danon recalibration, we are also going to be giving a more broad program update later in 2026.

So that's talking about a few things: one, the regulatory path forward for the Danon registrational study. Two is talking about what the statistical analysis plan is with the agency so that we can better spell out to the street, what to expect in terms of the BLA path forward, folding in an epidemiology update. So a refined way of how we at Rocket are thinking about the top-down, bottoms-up approach to the disease as well as the identified patient population. And for this study, it's focusing on males.

We also will be giving an update on PKP2 in terms of announcing where we land with the agency with respect to what a pivotal study looks like for that program. In parallel, we've already announced that we're dosing a few additional patients in the Phase I because we've already disclosed that we found -- we believe that we found the efficacious dose. So that's the dose that we'll be moving forward with in the pivotal Phase II study. But announcing what it is that we've aligned on with the agency is another path forward, and that will really be a differentiator for that indication.

And then thirdly is getting the BAG3 study up and going in the clinic and dosing patients there. So those are three catalytic things that we're looking forward to announcing to show our progress this year.

Got it. And then -- so in March, you guys received the first FDA approval for the company, KRESLADI. And that came along with the PRV and so forth. But since then, right, I think we're all waiting to hear about what's the commercial plan. I think you guys mentioned that potentially later this year, you would disclose what that looks like. What's taking so long?

So what's taking so long? We're in line with other ex vivo lenti launches in terms of when the drug was infused into patients. Usually, it takes 6 to 12 months in general. So we're in that range. Setting up the qualified treatment centers, setting up the payer discussions and reimbursement discussions. And really, the supply chain is very complicated here. It's much more complicated than AAV. So making sure that's pristine. We want to make sure that the patient experience is pure, clear and sort of easy to navigate for patients and families.

So we're doing it the right way and trying not to rush it and especially because it's not a big market, we haven't put any much -- really any marketing dollars behind it. So we're doing it patiently, the right way, but it's in line with other launches as well.

I see. Okay. And then what's the status for the RP-L102 for Fanconi and then the 301 for PKD. I know back then, you guys put that you guys deprioritized or do a strategic review. What's the -- and I think you mentioned that you guys are exploring other options for how do you develop this potentially out-licensing it. What's the status for these programs?

So we're still in those discussions. And both -- especially Fanconi Anemia. Fanconi Anemia is a program that is near the end goal of being ready for BLA submission. The data have only matured and improved over time on the clinical side. So in the right hands, I think that this can get to patients soon. So we're exploring that.

PKD is an earlier-stage program. When gene therapy works, it works. We demonstrated that early on, and hopefully, that sees the light of day for patients as well.

I see. Okay. Why not take Fanconi to the finish line, too, right? I mean there's -- I think there's a PRV that's also that we qualify for. Why not also take that one like you did for [indiscernible]?

You can only do so much. And so when we made the strategic corporate decision last year to reprioritize the pipeline to really demonstrate near- and medium-term value for patients and shareholders alike, you can only do so much and trying to progress six clinical programs at the same pace at the same degree of just perseverance, it can't really be done.

And so we decided that the cardiovascular programs is what we were really going to pour all of our effort into. I like to use the analogy that our LV assets are, kind of, like building a custom house where we need to find the right buyer. So we can be patient with that. But as Gaurav said, the data for FA is only matured. And so in the right hands, there's true potential for that program.

Yes. And the cardiac programs are the highest value by far, by perhaps a log or so. And they're also easier to develop in terms of being in vivo. There's no ex vivo cell therapy component. It's just gene therapy. So therefore, the long-term cost of goods are lower, and we can control it in-house. So that's the story that we're building moving forward.

Right. Does it also make sense to license KRESLADI as well so you guys can focus on that cardiovascular?

Potentially, yes. Some of the -- some of my own mentors in the space in biopharma have said even in larger companies, companies need to focus on a few things and do them very, very well, and we're taking that seriously.

I see. Okay. Can you remind us of the cash position now and then after the PRV sale, what's that runway look like? And what does it include and not include?

Sure. So what we announced when we had the KRESLADI approval and then with recent earnings is that our cash runway has been extended with the monetization of that PRV, which we disclosed that we sold it for $180 million, means that our cash runway is into the second quarter of 2028. So what we're really doing is trying to demonstrate the derisking with each one of our programs and unlocking additional capital to apply to each one of those programs as we achieve different milestones with those programs.

So as we keep moving forward with each of the programs, we'll unlock more capital and resources to invest in those programs.

I see. So in terms of that runway and that 2028 guidance, what does it include in terms of all these different -- we know that Danon still have that pivotal program ongoing. Does that like cover sort of up to potential BLA filing?

A good way to think about it is we'll need to think about additional resources to really commercialize what will be needed for Danon.

I see. Okay. Got it. Let's dive into Danon. So the FDA lifted the clinical hold and then they allow -- I think, August last year, and then they allow sort of the reinitiation of that pivotal study with a recalibrated dose for three patients. So where are you now with these three patients? Are you on track to align with the FDA on the next step in the second half of the year? And when should we expect to see data?

We have initiated dosing of those -- that cohort, that three patient cohort, and we'll provide further updates on those patients as well as a regulatory path forward and also an overall commercial market opportunity update in the second half as -- and we'll announce that ahead of time.

I see. Okay. So now let's forward to second half of the year when you have these three patients dosed and go back to the FDA. What is that process? What is your base case? What is the best case? What's your worst-case scenario, just looking at what the FDA could request?

There are several processes by which one can go back to the FDA. In this case, they've asked us to come back after that safety cohort has been dosed. So it's expected. It's not something that we're going to sort of chase them down for. I think it will be a pretty straightforward discussion and meeting.

I expect that we will treat whatever number of patients that we need to treat at this dose, at the revised recalibrated dose and the revised immunomodulatory regimen. Maybe that's 12 patients. It could be more. I don't know. There's no indication from them that there's any change though to study design or patient numbers. There's -- that wasn't part of any discussion. So I think if things go well, then we anticipate a similar trial as the original one will move forward to as a pivotal trial, but we just don't know yet.

I see. Okay. And I believe you guys now under this new regimen, you guys allow the use of eculizumab, which is a C5 inhibitor in the trial with a lower threshold for intervention instead of the C3 that you guys used before that caused a capillary leak syndrome. Any reason that adding a C5 will not lead to the adverse effect compared to a C3? And then also, I mean, since they both -- they complement system with C3 higher in more upstream and then the C5 in more downstream. How confident are you that the C5 will not lead to the same sort of adverse effect?

Yes. So we've always had the C5. We've always had eculizumab as a rescue dose. If we see signs of complement activation. That's actually not a new thing. That's been there throughout Phase I. We have used it in a couple of patients where we had TMA. We did use eculizumab. It did mitigate the TMA somewhat. And we didn't see the paradoxical reaction that we saw with C3.

So therefore, we decided to keep that on as needed. It's not upfront. It's not something that we're going to pretreat patients with like we did the C3 inhibitor. But we've dosed some patients with this because of the TMA. We did not see a paradoxical capillary leak or anything else untoward from the C5. And therefore, we're continuing it, into this trial as well.

I see. Okay. So the...

C3 was -- and I will just point out that the C3 inhibitor, it's not the C3 inhibitor alone, but the combination with this torrential rain of AAV, it mitigates TMA for sure, but it produces this paradoxical late onset capillary leak that none of us and not the FDA either anticipated.

Right, right. Because I think the reason why you selected that particular C3 was that you guys thought it was safe to begin with, right -- it's a combination of it. But then for C5, you guys are comfortable because you have seen the use of combination and hasn't led to any adverse effects. Okay.

So the dose that you will use in this sort of recalibrated dose for these three patients is half of what it used to be. And I think this dose was kind of similar to what the lower dose for some pediatric patients that you use, but not in the adults. So is there any concern that this dose may not be sufficient for adults?

So what I would say is that -- so it's not half. It's close to -- I would say it's about 60% or so of the original dose. The potency is meant to be matched. So we have good reason to believe that the higher full empties in a disease like Danon, where autophagy is impaired, leads to a more potent product, even if you have the same transgene dose. And there's various reasons for that, that Jonathan Schwartz and others have presented publicly.

But what I can say is that we saw in the Phase I, there were two patients on the pediatric side who were dosed lower. And they were actually dosed at the Phase I around 4E13 dose because their body mass index was too high and they were children. But if you compare that product with the new product, the Phase I to Phase II, the equivalent current Phase II dosing for those pediatric kids would have been around 2.5 to 3E13, right? So it was actually a pretty low dose, even lower than what we're doing now, potency to potency. And those patients 3 years out, still have very robust protein expression, and they had pretty profound improvements in LV mass index and other markers in the first year as well. So we did see all of that.

I see. Okay. And then...

Sorry, I think there's a range of dosing here, and it's better to err on the lower side for the benefit of safety. Or the mid side, right?

Okay. And then of the patients who were previously dosed from that first batch before the CRL, how are those patients doing? I mean, obviously, they were treated and you're still monitoring them. How have they been performing so far? I mean the ones without the...

Capillary leak, yes.

Right, exactly.

Yes. So we treated six patients, two had the capillary leak. The other four, we don't have an official follow-up but they're alive, they're not transplanted. Anecdotally, they're doing well. And those who had TMA, the TMA has resolved completely.

Right. Okay. Got it. And how is the FDA going to look at those patients, right? Those patients probably have to benefit from the treatment. So when you go back to the FDA, are they also part of that package when you go back and present the data?

They will be part of the package. I think it will help with the supportive data package, both for this discussion and for the BLA. I don't know if they'll count for efficacy just given the recalibrated dose, but I think that's an unknown right now.

I see. Okay. And what about outside the U.S., have you -- what's the development status there?

Yes. So we have three centers up and running in Europe and U.K. So we anticipate -- and we've had discussions with EMA along the way, and we anticipate that we'll do the BLA in the U.S. first. The U.S. is the first and most important market here just because it establishes the commercial footprint for us. But Europe is a very big part of it to follow soon after.

I see. Okay. So given what happened, let's say, you go back to the FDA, they request that you do more patients. What's the feedback from the Danon disease community so far? Because there's obviously could be some concern given what happened. How supportive do you think that community still is for this treatment?

Very supportive. I mean we've hosted a number of events with the Danon community through the Danon Foundation and otherwise. And the support is overwhelming to please don't stop this study, please continue to bring this therapy to market because we as Danon patients want to see something. We want to have options. So there's overwhelming support by the Danon community to continue to pursue the program.

I see. Okay. Let's shift gears to the PKP2. I think that's also another very exciting program. Can you give us a quick reminder of the data so far? What let you guys move straight into a pivotal before completing the rest of the Phase I dose escalation study?

Yes. So for that program, we started at a dose, PKP2, that we thought would potentially be the effective dose. So we had a dose escalation, but the intent was like for all our programs that we want to hit it right the first time. It's a traditional design, three patients treated. We treat additional patients if there are DLTs experienced, which we did not have any disease, dose-limiting toxicities. So we just enrolled three.

We saw directionally a trend in the right direction for all three. And therefore, we approached the FDA who agreed that this could be the dose for a pivotal trial. We have let the natural history work that we're doing play out a bit this year so that we can approach them with a robust proposal for what a pivotal trial design would look like at this dose. So that's the history of why we're moving quickly with a low number of patients.

Having said that, there are patients who are interested in the therapy, and we've kept the Phase I open to treat more patients, both to give them the benefit of treatment while setting up the Phase II, which won't be starting until next year, but also because it gives us some more data long term as a supportive data set for the BLA.

I see. And what's the status for that alignment of the pivotal program with the FDA? And when should we see that design? And then is there any risk that the FDA would want you to collect more and maybe longer patient data before you can proceed with that pivotal study?

Yes. We expect to give an update in terms of what the pivotal study design looks like later this year. So we look forward to being able to disclose that once we complete conversations with the agency. So that's well underway. We may additionally choose to put out additional long-term follow-up data from the Phase I cohort. So that's something else that we're trying to explore and find a way to get that out into the community as well.

Yes. And I don't anticipate an ask for a much longer data set. I only say that because we've already started these discussions, and we would have known that by now.

I see. No, the reason why I asked is that I think your competitor obviously has longer data and they're starting those type of conversations after these data.

Yes. I mean, well, I believe we probably dosed first. So we haven't necessarily put the data out there, but we have pretty long-term data for the three patients at this point that continues to show directionally that there's potential benefit here.

Okay. Great. And can you walk us through the patient prevalence? I know we -- obviously, a lot of people have done work on this, I believe it's fairly large. But in addition to that, but how many of them are actually suitable for treatment and for gene therapy? Maybe help us think through all the different qualifying or just qualifying cuts that based on the overall prevalence down to who are suitable for gene therapy?

So a robust comprehensive analysis of this is something that we will provide as the program moves forward. Right now, we're in discussions regarding what the most eligible population should be, right? Because patient selection is very important for the pivotal trial. And the pivotal trial will determine the answer to your question, right? So my sense is that unlike Danon males, in which gene therapy should be for every Danon male out there, whether they have manifestation of disease or not. I think for PKP2, it's going to be a subset of patients.

We do know that 80% of these patients have ICDs. So obviously, a lot of them or most of them are experiencing problematic arrhythmias, which can be fatal. There's a lot of sudden cardiac death or shocks that these patients have. So there is a lot of arrhythmia burden. There's also a lot of right ventricular dysfunction in these patients, especially as they grow older. So I think we need to target a population or a segment of these patients who are moderately progressed, but not so severely progressed that there's too much fibrosis and the gene therapy can't enter the heart.

So there's, again, that middle zone. It's not going to be like Danon where it's really for all and we'll define that moderate population over time.

I see. So you're going to, I guess, give the market more guidance in terms of who are going to be eligible and how many patients with that.

Yes. I think getting clarity on the Phase II will help us answer that in a more concrete way.

I see. Okay. And what are some of the endpoints that you guys have been thinking about? I know it was very -- this is very novel in some way. And how long does it take to, kind of, reach those endpoints do you think?

It's an arrhythmogenic cardiomyopathy. So obviously, the name arrhythmia is a logical endpoint. There are several types of arrhythmias in these patients, of course, PBCs and SVTs, but also T-wave inversions which are arrhythmias, but they're EKG findings. We can also look long term at ICD shocks.

So there are a variety of arrhythmias, which are predictors of fatal outcomes or progressive disease. We'll also look at heart function, especially the right ventricle. We'll look at protein. And I think we will also look at clinical endpoints, how patients function and feel. This is a disease that causes a lot of anxiety because of the shocks and people just feeling better, being able to exercise with some confidence and reducing the number of shocks are all something that this community values quite a bit.

I'll just point out on protein expression, we showed not just protein expression improvements either by western blot or immunofluorescence, which we saw in all patients. We also showed trafficking of PKP2 to the cardiac junction. And I think that combination of events is important for robust protein expression. So that will be part of the story as well.

I see. And usually, like how long do you think for these benefits to manifest?

I think in the cardiac world, I mean, look, in traditional adult cardiomyopathy, it sometimes takes years to see benefit of beta blockers, et cetera. In this setting, because these are especially like for Danon, but also

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starts manifesting, there's pretty rapid symptoms and signs. So we think in 1 to 2 years for these conditions, we can see a change from either natural history or if there's a randomized arm, a randomized arm. I don't think it's longer than that, but I also don't think it's less than 1 year.

I see. Okay.

So it just takes time to remodel a little bit.

Right. So potentially, when you think about a pivotal program, you have to build the sort of time line into like the endpoint observation and on that. I see. Okay. Got it.

So your competitor presented interim data for, I think, 10 patients with different doses. It looks pretty encouraging. And I think there's some liver tox increase and some other safety effects that we saw there. How does your data compare to what you saw from your competitor? And what's giving you confidence to go straight into a pivotal program?

So it's not our place necessarily to comment on other data sets. I will say that the rh74 capsid, we have a lot of experience in the clinic with it. And the doses that we're dosing these patients in the mid to upper E13 range, especially with the higher full empties that we're able to generate now are way lower than the total capsid exposure that the Duchenne World has seen with Sarepta and others.

So I think we feel pretty good about the experience with rh74 with this type of cardiac disease. There's just a lot of patient experience and regulatory precedent for it. So I think that's a key advantage. But look, it's a big market and there's potential room for more than one, and there's people who have antibodies to different capsids, and let's see how it plays out.

Right. Because they use a different capsid. You use the one that's similar to what's been used in DMD, which has some safety on its own.

At higher doses that are about 2 or 3x the capsid exposure that we have here.

I see...

It's not at these doses, far lower.

I see. Okay. Got it. And how do you think about in terms of the time line for -- into the pivotal? Are you able to leapfrog over Lexeo? Because I think first to market is important because this is a disease that you want to be there first to, kind of, be the one who educate people, be the face of the treatment for these patients.

Yes. I think leapfrog is an interesting term. I think we need to do this the right way. Yes, it is important to be first, but it's also -- it's actually more important to win. So if we have a drug that works, we need to design a trial that shows that it works reliably, consistently, reproducibly. And I think having a very collaborative dialogue with the FDA, which we have been having is important because in our interactions with them, we get a sense that they want this trial to succeed.

And with that end in mind, it is important to be first, but it's also important to have a trial that actually works, right? So that's what we're going for.

I'll jump in here for just a second. So there are a couple of other players in the PKP2 space, and it's great for the patient community to have these options out there. But as Gaurav said and what he mentioned earlier is we're most interested in being thoughtful, slowing down and patiently designing our study so that in the long run, it's a safe, efficacious study that will really benefit the PKP2 community, and we're taking our time to do that. So this collaborative engagement to properly design what we feel is going to be a great pivotal study is something that's of the utmost importance to us.

Right. Okay. Makes sense. You guys are also enrolling additional patients besides the three that you guys showed earlier. And -- but also at the same time, you announced that you're -- the intention to go into a pivotal study. So are these patients that you're enrolling from the same dose cohort that you presented earlier? And also based on these patients, are you going to present a longer follow-up on the three patients that you showed before? And also these additional patients that you're dosing now?

We will. We will. We tend to empower our partners in the academic and clinical world to define when they think it's ready to be presented. So I think that will be up and coming at some point.

How many patients should we expect when you finally show that data? I mean the three and then how many additional patients do you expect to do?

I would say we're treating up to three more. So that's -- but again, that's not in the pivotal trial. The pivotal trial, obviously, will have a lot more. So yes, I would say 3 plus 3.

Right. And on those additional data that you're -- additional patients enrolling, is it to more or less help inform the pivotal design? Or is it more just to kind of better understand the treatment than that?

Yes, it's not to inform the design. We're ready to discuss the design already, and we're in that process. There's only so much that you can learn from additional patients. And we've seen, fortunately, the same directional improvements in 3 out of 3 patients consistently long term.

So I don't think adding more patients would help that. And I know that just from discussions. It is, however, again, for the patients who want to be treated, provide them the benefit of not having to wait for the Phase II. And also, it provides a longer-term data set when we do file a BLA because you want to have some patients who are out a few years when you file the BLA.

Right. I see. Got it. So we're out of time. I do want to ask you about BAG3. So I'm going to turn it back to you for closing remarks. And if you don't mind, please include something about BAG3 about the status, the plan there, and I'll let you close the meeting.

BAG3 is a very exciting opportunity. I would say prevalence-wise, it's somewhere between Danon and PKP2. We have a Phase I trial that is starting and we'll be treating patients soon. And I think, again, that potentially opens up the third door of access to dilated cardiomyopathies, which is the biggest bucket of cardiomyopathy out there. So I think BAG3 is a big opening for the future of cardiac gene therapies. And we're excited to start soon.

Fantastic. Gaurav, Meg...

Thanks for having us.

Glad to host you guys, and thanks everyone.

Thank you.

Appreciate it.

Wonderful.

We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for listening in. And it's my pleasure to have the Rocket team with me. To my direct left is Gaurav Shah, CEO; and to his left, Meg Dodge, SVP of External Affairs. Welcome, both of you.

Andrew, thanks for having us.

As always. Yes. So there may be some people in the audience who are less familiar with the Rocket story. So can you help us level set where you are, what programs you're working on, your strategy and then catalyst milestones over the next 6 to 12 months would be very helpful.

Great. We are Rocket Pharma. We are a cardiac-focused genetic medicines company, primarily focused on genetic cardiomyopathies that while each one is a rare disease together, they're not rare. Each disease is rare, but rare disease is not rare. It ends up becoming very common when you add them all together.

So our focus is on 3 genetic cardiomyopathies. One is a hypertrophic one called Danon disease, a disease of autophagy that primarily affects both boys and girls, but boys in their early years and females later in life. We are in a pivotal trial aimed at an accelerated approval path in agreement with FDA for that program and are actively enrolling patients right now for the safety run-in portion of that.

The next program is an arrhythmogenic cardiomyopathy called PKP2, which is the most common type of ACM, which is the second big bucket for cardiomyopathies. In that program, we've -- we're in the Phase I trial. We've found the pivotal dose, and we're in discussions with FDA regarding the next steps for an accelerated or full approval pathway. The third cardiac program is BAG3 dilated cardiomyopathy. A devastating disorder, multifactorial in nature with regard to the protein.

And in that program, we are entering Phase I, we're about to start treating patients. So 3 big programs in cardio genetic medicines. Historically, Rocket has been a 2-platform company, cardiac being one with an in vivo AAV approach. The original programs in the company were bone marrow programs where we use an ex vivo lenti technology, LAD-1, Fanconi anemia and pyruvate kinase deficiency.

We're very happy to get the first FDA approval from CBER this year for LAD-1 with a product called KRESLADI, which we're -- we got done through the accelerated approval pathway, and we're in the process of getting that out to patients as soon as possible. That also came with a large PRV sale, which allows us to have cash runway for another 2 years into second quarter of 2028.

So we are a genetic medicines company, focused on cardio, but also have a legacy programs in ex vivo lengthy bone marrow-derived disorders. And moving forward, we're going to continue to focus on cardiac, build that out.

We have other programs that are behind the scenes and are also rare, but you add them all together, and we're talking about hundreds of thousands of patients and really opening the door to cardiovascular genetic medicines here.

Right. Hundreds of thousand patients on a gene therapy price. It's a big huge opportunity. Okay. And so starting with some bigger picture questions. When -- when we think about gene therapy, it's gone through like this important maturation period over the past few years, safety, manufacturing, clinical execution. So how are you guys thinking about these aspects? And what differentiates you from other gene therapy players out there?

I would say, primarily, we are very proud of the fact that we invested early on in an in-house AAV manufacturing facility. And what this allows us to do in addition to having a long-term path to reduce cost of goods and good margins is that it allows us to develop the process and the release criteria and potency assays and all those aspects of things in our hands.

And control is the most important thing with regard to CMC discussions with FDA because often there's back and forth with FDA. It's iterative dialogue, and having it in-house really accelerates those pathways, and also ensures that we control the product and not somebody else. So we're very proud that the Danon program is being produced in-house and the other programs will be as well.

I would say that's one big differentiating factor. The other is just that we have the experience and we've gone through these programs with multiple patients. We've developed a muscle memory for how to treat these patients, how to read labs, how to pivot around safety issues, how to maximize efficacy and for example, how to read protein expression. So I think out of the companies in this field, we have the most in-depth experience with regard to those key aspects of drug development.

Very good. Makes sense. And then...

I can add a few words, Andrew. So I think the sector as a whole for gene therapy is also in a period of execution. I mean we got earlier guidance this week from FDA. And so if you compound what it's going to take with respect to execution, that means that we, as an industry, have developed our science tremendously, but it's going to be a matter of manufacturing, as Gaurav said, clinical engagement and also regulatory engagement.

And FDA has really tried to step up. And so I think we're in the next -- in a period here next of working with the agency to really bring genetic medicines to the forefront on both the development side, the manufacturing side, as well as the regulatory front.

Right. You guys are very thoughtful and careful about all these thinking things through. And then to your point, like the FDA, I think they released a new guidance document or something early this week.

On Tuesday, yes.

Okay. So FDA really wants to collaborate with you guys.

Yes. I would also say that guidance documents are important, and they're a good template for us for the whole field. At the end of the day, with the FDA, it's about individual dialogues and collaboration with the review team. We've had a track record of being engaged respectfully both ways and getting to a good landing spot for all of our programs, and I anticipate that will continue.

Great. And so maybe before we touch on the Danon program, which to me is the core thesis of your story. But congratulations on KRESLADI's approval, though, where you earned a PRV voucher. So how are you thinking about the sequencing treatment center onboarding and the overall TAM of this product? When can we learn about when you might launch the pricing strategy, the reimbursement strategy and so forth?

I can take this one. So what we tried to do and what we aimed to disclose to the Street and to the community in 2025 was a reprioritization of the pipeline. And that's when we define ourselves as being a cardiovascular-focused company. And so with that, we had KRESLADI at the finish line with a potential FDA approval kind of on the cusp.

And so what we really wanted to do was get that on the -- across the finish line and then be able to talk to partners about getting those lentiviral programs into the hands of someone that's better able to commercialize them. So we've gone through the steps to prepare to make KRESLADI available to patients. We're talking to potential partners about assuming that program.

However, in the event that you can't find the right buyer for what I call a custom-built house, we're prepared and able to make KRESLADI available to patients. And so if you're asking about our preparation to be able to make KRESLADI available to patients, that will be later in 2026, towards the tail end of the year.

Got it. Got it. And so when I think about how this reads across to your other programs, should you launch, gain payer access, reimbursement, gain experience launching feels like there could be potential scale as your other follow-on programs become approved. Is that kind of fair? And anything else you'd add?

Yes, consider it muscle memory. Once you go through the process of developing your in-house commercialization team and going through the steps to have a company be able to provide access for a therapy, you can apply that to other programs. So yes, it's building the infrastructure, but it's also developing the team, the know-how and the skill set to be able to do that directly, so you can apply it to other programs.

Okay. Very good. And so shifting gears to your Danon program. It's great to see that it's been resumed, but bigger picture, help us frame the U.S. market opportunity of Danon, how many U.S. patients you think there are, how many diagnosed identified, for instance? Any -- just so we can have a sense of the peak sales opportunity here.

So I would say that we will be able to answer that question in much more depth during a full program update that we anticipate second half of this year. We will have a top-down breakdown of the Danon opportunity that's based on epidemiology as well as genotyping. And we'll also have a bottom-up approach going out there and seeing where these patients are and who they are.

So we'll have that update. I would say that historically, we've stuck by the number of at least 15,000 patients in the U.S. and Europe. It's -- Danon is a frequency of hypertrophic cardiomyopathy and you can extrapolate from the HCM population to figure out how much is true Danon disease out there. There's a big gap between true prevalence of Danon and actually diagnosed Danon because Danon disease was identified as a genetic cardiomyopathy as recently as the early 2000s.

So there just hasn't been that much time for people to understand what Danon is, how it manifests. And also even doing genetic testing for cardiomyopathies is a relatively novel thing. So there's going to be a gap between true prevalence and diagnosed. So even beyond this update, our next step ahead of the commercial launch is to find these patients through genetic testing and other means. So we'll answer the question, but that's sort of the big-picture answer.

Okay. Very good. And so can you remind us in the Phase I program, which led you to have this accelerated approval pathway within this Phase II pivotal that you're doing? What did you see in Phase I for these Danon patients? How many patients on efficacy on the Phase II kind of co-primary endpoints, what did you see in Phase I that gives you the confidence you'll make it through the goal line in Phase II?

In Phase I, we treated 6 patients who were followed for more than 1 year. And out of those 6 patients, we had results that were published in New England Journal of Medicine about 1.5 years ago. And those results showed that all 6 patients had florid protein expression. In fact, the -- a couple of them out to 5 years or more. We showed that -- all of them had a reduction in left ventricular mass index, LVMI, which is now agreed upon as one of our co-primary pivotal endpoints.

In fact, protein and LVMI are the co-primary endpoints for the ongoing pivotal trial. In Phase I, we showed that all 6 patients would have met that endpoint at the 1-year point if this were a Phase II trial. So that gave us a lot of confidence to move forward into Phase II. Also, those patients showed a massive reductions in troponin and BNP for as long as we follow them until the NEJM paper.

Great. So 100% success rate basically in Phase I. And so then you started the Phase II, although you faced a little slight hiccup last year with the clinical -- partial clinical hold, but then you got it resolved very quickly within 3 months. And then now you're resuming it with the safety initial safety cohort now. And so can you kind of describe what happened? What learnings have you had with that experience?

So early in the Phase II trial, we saw a higher incidence of thrombotic microangiopathy TMA than we would have anticipated or that we saw in Phase I. And in an effort to further mitigate the risk of TMA. And by the way, the patients who had TMA early in the Phase II trial, they've resolved the TMA and those patients are fully resolved with regard to the safety issues and hopefully moving on to look at efficacy.

But to address the TMA, what we did is we added a C3 inhibitor. And the issue that we faced as soon as we treated patients with the C3 inhibitor is that there was a paradoxical unlocking of direct endothelial damage with the combination of a torrential rain of AAV9 plus a C3 inhibitor. It's not what we expected, but there's no good preclinical models for cardiomyopathies and some of these things play out in the real world and the clinic.

So we had an unfortunate case of a patient death due to the combination of C3 plus AAV9. So in the resumed trial, which we negotiated with the FDA very rapidly, lifted the hold in about 3 months. We agreed to remove the C3 inhibitor.

That addresses the capillary leak syndrome, the endothelial damage risk that we saw with the C3 -- it keeps the TMA risk on. In order to mitigate the TMA risk further, we did an analysis of the patients and the product, and we determined together with FDA that the Phase II product that we were using was likely higher in potency than the Phase I product because it was an enriched product with higher full empty ratios.

And because of the higher full empty ratios, the potency applied to both efficacy and safety. So we recalibrated the dose to a lower dose to match the Phase I potency. So while the new dose is -- appears lower in number, it's around 4e13, it is intended to match the dose of the Phase I product, which is closer to 6.77e13.

So we're moving forward with a recalibrated dose, absence of C3 and a couple of other tweaks in patient selection as well as drawing out the doses of rituximab over time to further eradicate B cells ahead of treatment, and that trial has resumed.

Okay. It makes a lot of sense. So we should not expect capillary leak syndrome because there's no C3 and then TMA risk is heavily reduced because now we are back to the Phase I equivalent dose kind of thing.

Correct.

Okay. Great. And so now you're trying that out in the initial batch of 3 safety patients. Have you dosed the first patient by chance? And when does the third patient get dosed exactly?

Yes. We have initiated dosing. We haven't guided on exactly when we'll finish, but we'll have an update -- a comprehensive update, as mentioned in the second half.

Second half. Okay. And is it fair to say that TMA generally pops up pretty immediately after dosing. So if you see something -- I don't know how to ask it, but is it true? And so is no news good news kind of thing?

I would say no news is good news. TMA usually manifests in our experience in the first 2 weeks or so. So yes, -- we'll have a comprehensive update as soon as we can.

And it makes sense why you'll share a comprehensive update in the second half. My understanding is the initial 3-patient cohort or staggered dosing a month apart. Then this is the strategy to talk to the FDA, then you come back to the Street in that update.

That's correct...

Those FDA discussions kind of thing.

That's correct. And to be clear, the FDA has asked us for a 3-patient safety run-in, and they have not commented on what the rest of the trial would look like or that it should change. So we don't anticipate it would change, but we do want the optionality of discussing with, again, what the best trial -- trial design is moving forward.

The original agreement was a 12-patient single-arm trial with a co-primary of protein plus LV mass index. We have no indication that that's going to change, but we were asked to go back after the safety dialogue. So we want to make sure that we do our due diligence there.

Right, right. Understood. And so as you dose -- establish what's needed, and then you dose more patients, which I understand it can be done not sequentially, but just all at once. Then as I think about the likelihood of success, sure, optically, the Phase II dose now seems like a lower dose, but at the same time, it is the Phase I equivalent dose where you saw 100% success rate. So confidence should remain unchanged. Is that the line of thinking from you guys?

We are hopeful both on safety and efficacy, just seeing what we've seen through our experience that this Phase II is intended to match the Phase I. And if all goes well, I think the safety overhang is the main thing to get through in the near term.

Right. And -- so once you talk to the FDA, can you just remind us then the original plan for an accelerated approval, how many patients out to 1 year was the original agreement? And so best case in your minds, how many patients left after the 3 patients are dosed would you need to fill that original agreement?

I would anticipate that they probably want to see all the patients in the trial treated with the same product in the same way. So while we have started treating patients at a different dose and slightly different immunomodulation profile, I would anticipate that we might have to treat 12 additional -- a total of 12, 3 plus 9, but we'll see what happens. It's a discussion.

Okay. But then there could be an upside surprise given your base case. Okay. And so second half 2026, you'll come back with a seemingly major update because it's not only next steps, but also top-down or epidemiology. And then I'd assume you'll share the bar for success, too, from the FDA meeting to be clear.

Yes, absolutely. This is an update that's been long in the making. And because of the event last year, it got delayed. But the update would include certainly status of the trial, next steps for -- to finish the pivotal trial and epidemiology bottom up, top down and also an understanding of what it's going to look like to have a win on the trial. All of that, we will have a comprehensive update.

Okay. And so then shifting gears to then PKP2, we'll just wait for Danon and fingers crossed, everything turns out right. And so PKP2, maybe talk to us about the disease indication. How big is this indication relative to Danon and we can go from there.

PKP2 now borders on what is in the common knowledge base or common sort of spirit of how we understand cardiomyopathies. These are patients who often have sudden cardiac death or palpitations at a young age, especially when exercising. So this becomes a cardiomyopathy that we are familiar with in day-to-day life, right, athletes and runners and others.

So this PKP2 is a disease of the junction between cardiomyocytes, which are not in ideal condition because of the lack of PKP2 protein. And because of this, these patients have recurrent arrhythmias manifesting as PVCs, NSVTs, T-wave inversions and often fatal arrhythmias for which they need ICDs placed. 80% of these patients do have ICDs placed.

So the population here is at least 50,000 in the U.S. and Europe. So it's, again, rare but not so rare. It's one of the more common types of cardiomyopathies out there. And the program is now -- the Phase I is ongoing, but we've treated all the patients we need in order to go to the FDA with the Phase II trial design and approach.

All 3 of our Phase I patients had manifestations of protein expression, improvements in arrhythmias and general improvements in clinical status out to at least a year. So with that information, we've gone to the FDA. We're in discussions with them as to what a pivotal trial would look like and more on that in the second half as well.

Second half. Okay. And with the Phase I data set, how would you say you compare to your competitors, actually, on those efficacy measures?

I've seen the data from others in the field. I should, first of all, say that because it's a more common rare disease, there is room for more than one treatment. There's a lot of patients out there with a high unmet need. Having said that, we're very -- I guess, we're reassured by the fact that all of our patients that we treat, although they were only 3 patients, they saw the improvements that I described pretty uniformly.

There was no patient who got worse suddenly or certainly. So I think we're positioned well to be in the lead for this program. And it's not always about the number of patients treated, but having the right types of patients and the right endpoints to lead to a win in the trial if the drug works, right? And I think we're in pole position for that.

I'd also add that in the Phase I, we align with what we feel is the proper dose to proceed with respect to the pivotal Phase II study. So we feel that we're moving forward with the Phase II with the dosage that we used that was efficacious in the Phase I.

Got you. So the Phase I cohort was 3 patients. Are you dosing more in the meantime as you talk to the FDA to be clear in Phase I?

Yes. We will dose more patients, not because we need to do that for the Phase II discussion, but because it just gives us more information. There are patients who are waiting for the treatment. So we're opening the trial up again, but it's not necessary for the FDA dialogues themselves.

Right. And I guess for the initial batch of 3 patients, would you consider sharing data is my question, the additional Phase I data, not only on new patients, but also longer follow-up? Is that a second half event?

Potentially. Yes. We would like to show the long-term follow-up results from those 3 initial patients. And then as Gaurav was alluding to, having additional patients enrolled and treated in the Phase I at the same dose that we plan to proceed with will be further supportive of BLA submission later on down the road.

Right. And with your KRESLADI experience, your Danon experience so far, just with your FDA, it seems like you have a know-how or advantage or a good relationship with the FDA on study design, big picture. So PKP2, is that kind of the strategy? I think Danon, the original agreement was 12 patients, and that's it. And is that kind of the strategy here for PKP2 for you?

I would say Danon is a one-off, very aggressive cardiomyopathy with an easy-to-understand pathology. This is a disease of big hearts. So it makes sense that the endpoint here should be shrinking of the heart. That made a lot of sense. It's also a disease that rapidly progresses in natural history unequivocally.

So that leads to an easier dialogue when it comes to justifying a single-arm small trial. I don't think that's going to apply to any of the rest of the genetic cardiomyopathies, including PKP2 or BAG3 others. So it's a different dialogue from Danon, and I would not expect the same outcome.

I see. And any color how FDA discussions are going by chance?

I would just use the word collaborative -- and I think in all of our programs with the review team that we've been assigned, especially for these programs, it's always been sitting at the table figuring out how to design a trial where we can win if the drug works, not designing the smallest trial or trying to have the biggest short-term win.

It's about getting the drug approved in a way that the FDA agrees with and it's also -- we try to go for written communications there as well. So while it takes time, I believe that we're going to get to a good outcome here.

Great. And then lastly, the BAG3 program. It sounds like you're starting Phase I backtrack one more time. BAG3, how many patients do you think there are? And in this Phase I, what is a good no-go/no-go scenario for you?

So BAG3 as a patient population is probably somewhere between Danon and PKP2 in terms of the prevalence in the U.S. and Europe. Our Phase I program, the IND is cleared. We're going to start treating patients soon. And the cohorts are designed as 3 plus 3. So 3 patients unless there's a DLT, we may elect to treat more than 3 patients if the first dose looks like it's working so that we can expand the trial and get more information in anticipation of a pivotal Phase II discussion like for PKP2.

I see. And what would be a reasonable efficacy endpoint?

So dilated cardiomyopathies are part of a better-trodden path with drug development because the left ventricle is dysfunctional, it's easier to come up with endpoints where the left ventricle improves such as EF, peak VO2 and even exercise testing.

So there are ways to measure the left ventricular function in a predictable way where there's drug development expertise and regulatory precedent already in place, whereas for Danon, we have to have these discussions from scratch with the FDA and come up with a new endpoint. So we feel good about once we get to that point to have an easier dialogue with the agency.

I see. Okay. And then with the PRV sale of KRESLADI, the big picture, you have cash, I think you said until second quarter of 2028.

Correct.

So you can execute on a lot of these milestones starting in second half of 2026, it sounds like across these programs.

Yes, lay low and get things done. That's the motto this year.

Okay. Was there anything else you wanted to add, but otherwise?

I don't think so. I think we're at the beginning of a journey for cardiac genetic medicines, and we're very, very excited about the future.

Yes. Much respect to you for pioneering these spaces and best of luck into second half.

Thank you.

Thank you, Andrew.

Thank you, everyone.

Good day, and welcome to the Rocket Pharmaceuticals Investor Conference Call to discuss the FDA approval of KRESLADI RP-L201, a lentiviral vector-based gene therapy for patients with severe leukocyte adhesion deficiency type 1 or LAD-I. As a reminder, today's call is being recorded.

I'd now like to turn the call over to Meg Dodge, Senior Vice President of External Affairs. Meg, please begin.

Thank you, operator, and hello to everyone who joined today's call. Earlier, Rocket Pharmaceuticals announced that the U.S. Food and Drug Administration has granted accelerated approval to KRESLADI, a gene therapy for the treatment of pediatric patients with severe leukocyte adhesion deficiency type 1. KRESLADI represents the first and only gene therapy approved for severe LAD-I, and this milestone marks the first commercial product approval in Rocket's history. On today's call, you will hear from Dr. Gaurav Shah, Chief Executive Officer; Dr. Jonathan Schwartz, Chief Science and Gene Therapy Officer; and Sarbani Chaudhuri, Chief Commercial Officer. Following prepared remarks, we will open the call for questions, and joining the Q&A will be Martin Wilson, Chief Corporate Officer and Principal Financial Officer.

Before we begin, I would like to remind listeners that today's call will be making forward-looking statements and within the meaning of the Private Securities Litigation Reform Act of 1995. These statements are based on our current expectations and assumptions and are subject to risks and uncertainties that could cause actual results to differ materially from those described in such forward-looking statements. Forward-looking statements on this call may include, among other things, statements regarding the timing and execution of commercialization activities for KRESLADI, expected patient identification and treatment time lines, anticipated launch readiness, manufacturing and treatment center preparedness, projected financial runway, potential monetization of a rare pediatric disease priority review voucher and the continued development of our pipeline programs.

Important factors that may affect future results are described in Rocket's filings with the U.S. Securities and Exchange Commission, including our most recent annual report on Form 10-K. These forward-looking statements speak only as of today's date, and Rocket undertakes no obligation to update them, except as required by law.

With that, I'll turn the call over to Gaurav.

Thank you, Meg. Today marks an important milestone for Rocket Pharmaceuticals and most importantly, for patients and families affected by severe leukocyte adhesion deficiency 1. I'm excited to share that the FDA has granted accelerated approval to KRESLADI, the first gene therapy approved for this devastating pediatric disease. This milestone is meaningful for 3 reasons. First, it addresses a devastating ultra-rare pediatric disease characterized by recurrent life-threatening infections and high early childhood mortality without definitive treatment. Second, it demonstrates Rocket's ability to execute across the full continuum of gene therapy development from clinical research and complex manufacturing to regulatory approval. And third, the approval makes Rocket eligible for a rare pediatric disease priority review voucher, which represents a potential source of meaningful non-dilutive capital to support advancement of our broader pipeline.

Importantly, this approval also positions Rocket to leverage our gene therapy expertise across additional rare disease programs. Severe LAD-I is an ultra-rare inborn error of immunity, formerly known as primary immunodeficiency caused by mutations in the ITGB2 gene that impair normal immune function. The disease is characterized by an inability of white blood cells to effectively migrate from the bloodstream into tissues to fight infection and support wound healing. As a result, affected children experience recurrent severe bacterial and fungal infections beginning early in life, often requiring frequent and prolonged hospitalization. Despite supportive care, these infections and related complications can become life-threatening. In the absence of definitive corrective therapy, severe LAD-I is associated with a very high risk of mortality in early childhood.

Historically, the standard definitive treatment option for severe LAD-I has been allogeneic hematopoietic stem cell transplantation, a complex endeavor associated with frequent and clinically meaningful risks, including graft failure and graft-versus-host disease, which are documented even in the most recent medical literature. Allogeneic transplant is further limited by donor availability. Today's approval reflects the dedication of patients and families, our clinical investigators, advocacy partners, regulatory reviewers and the Rocket team. It also represents an important step in Rocket's evolution into a commercial stage gene therapy company.

With that, I will now turn the call over to Jonathan to review the clinical data supporting the approval.

Thank you, Gaurav. KRESLADI is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of pediatric patients with severe LAD-I due to biallelic variants in the ITGB2 gene, who do not have an available human leukocyte antigen-matched sibling donor for allogeneic hematopoietic stem cell transplant. In LAD-I, ITGB2 mutations lead to deficient or absent expression of the CD18 protein on white blood cells. As a result, children with severe LAD-I experience recurrent and often life-threatening infections beginning early in life and historically face a high risk of mortality in early childhood in the absence of definitive corrective therapy.

Following treatment with KRESLADI, which is administered as a onetime intravenous infusion following myeloablative conditioning, functional copies of the ITGB2 gene are introduced into autologous hematopoietic stem cells, leading to expression of functional CD18 that forms CD18/CD11 heterodimers, enabling leukocyte adhesion to endothelial surfaces and extravasation into tissues. This indication was approved under the FDA's accelerated approval pathway based on increases in neutrophil CD18 and CD11a surface expression, biomarkers indicating restored beta-2 integrin activity and leukocyte function. The approval is supported by data from an open-label single-arm international clinical study evaluating a onetime infusion of gene-modified autologous hematopoietic stem cells in pediatric patients with severe LAD-I.

The clinical study evaluated survival without allogeneic transplant and biomarker restoration of neutrophil CD18 and CD11a expression, which served as the basis for accelerated approval. Following infusion, neutrophil CD11a expression increased in all treated patients as did CD18 expression in all patients in whom it was severely reduced, each exceeding prespecified response criteria and sustained over extended follow-up. All patients are alive and none have required an allogeneic transplant with follow-up of 3.6 to 5.7 years after treatment. Measures of gene marking, including vector copy number in peripheral blood cells have remained stable over time, supporting durable engraftment of gene-corrected hematopoietic stem cells.

Supportive clinical observations during follow-up include substantial reductions in infection-related complications and hospitalizations relative to the pretreatment period. Integration site analysis to date demonstrate highly polyclonal gene marking without evidence of clonal dominance, consistent with the expected safety profile of lentiviral gene therapy. As described in the prescribing information, key risks include serious infections, veno-occlusive disease, delayed or failed engraftment, hypersensitivity reactions and the potential for lentiviral insertional oncogenesis requiring long-term monitoring. Consistent with the accelerated approval framework, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory clinical trials. Rocket will continue long-term follow-up of treated patients and additional post-marketing data collection to further characterize long-term outcomes.

With that, I will now turn the call over to Sarbani to discuss our commercialization approach.

Thank you, Jonathan. The approval of KRESLADI represents an important milestone both for patients and for Rocket's evolution into a commercial stage organization. Our commercialization approach begins with the patient. Severe LAD-I is a devastating pediatric disease associated with high early childhood mortality and a substantial burden on families and health care systems. Severe LAD-I is an ultra-rare condition. Approximately 25 children are estimated to be born with LAD-I each year in the U.S. with roughly 2/3 having the severe form of the disease. In practice, treatment volumes are influenced by factors such as diagnosis timing, referral pathway, transplant status and the complexity of delivering an individualized ex-vivo gene therapy.

As a result, we expect the number of patients treated annually to remain in the single-digit range, including in the years following launch. Accordingly, our approach emphasizes disciplined and dependable delivery, comprehensive patient support and step by scaling as we bring this therapy to market. The sequencing of our launch is deliberate and focused on execution excellence, consistent with the specialized requirements of ex-vivo gene therapy administration. We anticipate commercial availability and initiation of patient enrollment beginning in the fourth quarter of 2026. This time line reflects the operational requirements associated with delivering an ex-vivo gene therapy. Key launch readiness activities include ensuring product supply readiness with external manufacturing partners, establishing coordinated vein-to-vein treatment processes and onboarding a limited number of highly experienced qualified treatment centers.

Given the complexity of treatment and the vulnerability of this pediatric patient population, KRESLADI will initially be available at a limited number of specialized centers to support operational excellence and patient safety during early commercialization. We are working closely with leading immunologists, transplant physicians, patient advocacy organizations and payer stakeholders to support early diagnosis referral pathways and access planning. We intend to provide guidance on pricing and access considerations as we approach commercial launch, consistent with the timing typically observed for therapies addressing ultra-rare diseases. From stem cell collection to infusion, the treatment journey spans approximately 4 to 5 months. As a result, we expect first patient infusions and therefore, initial product revenue to occur in 2027.

Our focus is to ensure that once the patient enters the treatment pathway, the entire vein-to-vein process is coordinated, predictable and optimized for successful outcomes.

With that, I will now turn the call back to Gaurav.

As Sarbani outlined, our launch approach is deliberately phased to ensure operational excellence and patient safety. Our approach to launching KRESLADI is intentionally disciplined. Ex-vivo gene therapy requires a coordinated ecosystem involving manufacturing partners, specialized treatment centers and payer processes. We made a deliberate decision to sequence certain commercialization investments following regulatory clarity and alignment on final commercial specifications. This approach ensures that when patients begin treatment, the full treatment pathway is operational, coordinated and reliable. Our focus is on building a highly reliable treatment ecosystem from the outset, which we believe is critical to long-term commercial success.

Given the ultra-rare nature of severe LAD-I, KRESLADI is not expected to be a significant near-term revenue driver. However, the importance of this approval extends well beyond near-term revenue. We believe KRESLADI creates value for Rocket on several levels. First, it delivers the first approved gene therapy for children with severe LAD-I. Second, it demonstrates Rocket's ability to successfully execute complex gene therapy development across clinical, manufacturing, regulatory and commercial functions. And third, the approval makes Rocket eligible for a rare pediatric disease priority review voucher at PRV, representing a potential source of meaningful non-dilutive capital to support advancement of our broader pipeline.

As of December 31, 2025, Rocket reported cash, cash equivalents and investments of approximately $188.9 million. Based on our current plans, we expect this capital to fund operations into the second quarter of 2027 and potentially into 2028 with monetization of the PRV or other non-dilutive sources of capital. And as stated in our earlier press release announcing this approval, we intend to evaluate strategic options for monetization of the voucher with the objective of enhancing financial flexibility and supporting advancement of our pipeline.

As we move forward, key value drivers for Rocket will include commercial launch execution, continued clinical progress across our AAV programs and strategic capital management. We will provide further updates on commercialization progress and platform milestones in the quarters ahead.

Before moving to questions, I want to again thank the patients and families who participated in the clinical trial, our investigators and advocacy partners, our regulatory and agency colleagues and the entire Rocket team. Their dedication made this milestone possible. Together, we are working toward delivering new treatment options for patients with serious and life-threatening rare diseases.

Operator, please open the line for questions.

[Operator Instructions]

And the first question this morning is coming from Andrew Tsai from Jefferies.

Big congratulations on the execution and approval. It's exciting times. So you're planning to launch in Q4. Maybe describe the gating steps you need to accomplish or address before you're ready to launch? And secondly, as we await your pricing disclosure, are there any kind of drug precedents or comps you'd mentioned to the extent you're willing to share any bookends could be interesting to hear.

Andrew, thanks for the question. The critical requirements prior to patient enrollment to make sure that we deliver seamless treatment with something as complicated as ex-vivo gene therapy requires a few steps, as you mentioned. First, product supply and readiness with external manufacturing partners; second, vein-to-vein operational infrastructure; and third, the onboarding of select few qualified treatment centers. We've also been engaging with payers to ensure reimbursement. So those are the steps that are in between now and access for patients. In terms of other analogs, as you mentioned, we're not providing pricing guidance just yet, but the other analogs with ex-vivo monogenic diseases that are in the market are reasonable analogs and precedents.

And bigger picture, how does this approval maybe embolden you to pursue other rare diseases in a similar manner, single-arm pivotal Phase II type studies and similar in size. You're kind of doing this for Danon. And can we expect this to be the case for PKP2, BAG3 and maybe your other future programs?

Yes. Thanks. So we are going to shift our focus in development. We have shifted our focus to monogenic cardiovascular conditions, many of which are rare. like Danon and like PKP2, there will be more. This PRV certainly helps us invest in those programs with a bold mindset, as you mentioned. Also, Danon in itself comes with the PRV. So some of these diseases may also have their own PRVs. PRVs have been a great program to help companies like Rocket advance the broader pipeline.

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

Passing on my congratulations as well. So just on the point of the PRV received today, could you provide a little more implications -- a little more context for the implications to cash runway there? Is there sort of a certain go or no-go amount that you're looking for? And I guess the second question is, how might the cash burn be impacted by commercialization activities related to KRESLADI?

Great. So thanks, Patrick. So the PRV sale, with regard to PRV sale, we are in active discussions and engaging with external parties as we speak. So more on that as soon as we have more information. In terms of the cash runway, without speculating on what the price will be, we anticipate the cash runway to be extended into early 2028. And in terms of KRESLADI commercial efforts, we are going to execute what we would call a minimal viable launch, meaning we will make the product available to patients and physicians who deem it something that a good option for those patients. And we are not actively otherwise marketing or putting a lot of money into the commercial efforts for KRESLADI. We are instead going to focus those commercial efforts into expanding the Danon commercial setup and the other cardiovascular programs.

Your next question is coming from Josh Schimmer from Cantor.

Congrats on the approval. Three quick ones. First, maybe semantics, but Gaurav, at the outset indicated KRESLADI is eligible for a PRV. When do you actually get the PRV? What actually has to happen to go from actual eligibility to enhance? That's number one. Number two, do you still plan on exploring perhaps less severe patients? I think you had indicated that at one point that might have been a consideration for KRESLADI. And then number three, for the side effects listed on the package insert, just confirming that you did not see any of those in the clinical trial. Those are only theoretical based on the mechanism of intervention.

Thanks, Josh. So I should clarify that with the approval, we have the PRV in hand. So that's an important clarification. Thanks for raising it. In terms of the moderate patient population, this may be part of our life cycle management. But right now, we are focused on severe LAD-I patients. And for the third question, I'll pass it to Jonathan.

Thanks for the question, Josh. Most of the serious adverse events that were identified in the pivotal study were infections, which occurred during the post-conditioning neutropenia period, and these are fully resolved. One patient did experience a veno-occlusive disease and then the full set of side effects are available in the prescribing information as well as in the New England Journal publication from 2025. I would emphasize that we did not identify any instances of engraftment failure nor did we identify any instances of delayed neutrophil or platelet engraftment. We did not observe any hypersensitivity reactions. And very importantly, there were no evidence for insertional oncogenesis. The integration site analysis at all time points for all patients indicated a very highly polyclonal integration site patterns.

Your next question is coming from Mani Foroohar from Leerink.

This is Lili Nsongo on for Mani. Can you remind us the estimate size of the addressable market given the approval in patients with no HLA-matched donor sibling? And additionally, you mentioned a patient journey of 4 to 5 months. What are the rate-limiting steps to that? And how should we -- what should we expect this to look like at a steady state?

I will answer the addressable market question, and I'll pass the second part of your question to Sarbani. On the addressable market, so there are -- we estimate about 25 patients born with LAD type 1 in the U.S. every year. 2/3 of them are severe. Half of them will get a transplant and about 1/4 would have an HLA matched sibling donor transplant. So you can see just from this math that we anticipate single-digit numbers even long term in terms of treatments, but we'll be able to provide more guidance as we get closer to the actual launch. In terms of the vein-to-vein time and aspects of that, I will ask Sarbani to address that.

Thank you, Gaurav. So to clarify, we had mentioned that our vein-to-vein time is around 4 to 5 months. It is in the range of what we would expect with an ex-vivo gene therapy and it's primarily driven by the individualized patient collection, manufacturing to infusion and the time it takes for our manufacturing to happen as well as the release of the final drug product. Of course, in the beginning, it is a little bit more unpredictable because we have to see about the time it takes for payer access. But over time, we expect this to be in the 4 to 5 months range from the time a patient is enrolled to the time they actually get infused by drug.

Your next question is coming from Jason Zemansky from Bank of America.

Congrats on the milestone. I appreciate that most of the treatment will happen in the United States. So curious about the pathway for non-U.S. patients simply because if we're talking about single-digit number of patients treated, what does the inflow from Europe or other markets look like?

Thanks, Jason. Our focus right now is the U.S. market, and we have not made specific plans beyond that at the moment. And if we do, we'll update everybody.

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

So I'm curious, based on the FDA communications that you've had and received, what's your level of confidence that the long-term follow-up from this trial would suffice for this post-marketing requirement that's labeled by the language in the label? Or do you think there will be another confirmatory trial that would have to start? And if so, what would that look like and a potential time line?

Thanks, Tara. So the FDA guidance on the path to full approval is very clear with regard to the clinical program. It is further follow-up of the current ongoing clinical study as well as evaluation of a subset of patients in the post-marketing registry. In other words, patients who are actually treated in the real world, a subset of those. There is no new clinical trial required at all, and that's very clear in the post-marketing requirements.

Your next question is coming from Yun Zhong from Wedbush Securities.

Congratulations on the approval. I understand that you're not going to actively market this product, but anything that you think that you could potentially learn from bluebird's experience given that the lentiviral gene therapy launch and commercialization was maybe a little disappointing as compared to your expectation?

I'll ask Sarbani to address that.

Thank you, Gaurav. So as we stated, we are operating already under the assumption that this is an ultra-rare patient population at both and our go-to-market model is optimized for that. We are both being efficient in our commercialization approach as well as in our manufacturing approach. So we're starting with realistic expectations and having realistic expectations on how we get this to market in the most efficient way.

Your next question is coming from Tessa Romero from JPMorgan.

This is [indiscernible] on for Tess. Congrats on the news. So just one question from us. What is the right way to think about the amount of data the FDA would want to see from treated patients in the ongoing clinical study and post-marketing registry to adjust accelerated approval to a traditional approval?

Jonathan?

Thanks for the question. The level of data that the FDA will require from post-marketing patients is really data that's going to be available through what would be considered routine clinical management from our treating physicians and the primary immunodeficiency experts that would be referring patients into the study. And largely, this would include things like survival, transplant status and the flow cytometry results on the white blood cells indicating CD11 and CD18 levels, which is something that would be conducted in patients with severe LAD-I. So it's not some extraordinary requirement. It's very consistent with the way the expert immunodeficiency clinicians will manage the patients.

Okay. That's helpful. And if I may ask additional one. How is resumption of patient dosing in Danon tracking timing-wise? Any updates on that?

Yes. Thanks for the question. I think you asked about Danon. I couldn't hear it quite clearly, but Danon patient tracking is on course to begin first half of '26.

Your next question is from Michael from Morgan Stanley.

Congratulations on the approval as well. Maybe just a quick one on the launch plans. Can you maybe give a little more color on the number of specialty centers you plan to target to have online maybe by the end of this year? And then how that could evolve as the launch progresses in the outer years?

Sarbani?

Thank you. As we mentioned earlier, we plan to activate a very small number of highly specialized treatment centers. And given that it's an ultra-rare disease. So at this point, we cannot give specific numbers, but our hope is we have a handful of them activated by the time we're ready for launch, which is in Q4. And then over time, we will evaluate if we need more centers. And then in terms of the question of where these patients are, the good part and why we feel we don't -- we can have a very efficient commercialization approach is these patients are primarily in about the 40-plus PIDTC specialist centers across the country. And large -- I would say, all the patients that will come to any qualified treatment center will be coming from these specialty centers, and they have very good peer-to-peer networks.

[Operator Instructions] There are no further questions in queue. Ladies and gentlemen, this concludes today's conference call. Thank you all for participating. You may now disconnect, and have a great day.

Welcome back to the next morning session of our second day of the 2026 Leerink Partners Global Healthcare Conference. I am Mani Foroohar, Senior Analyst Genetic Medicines. And for this session, I'll be hosting Gaurav Shah, CEO of Rocket Pharmaceuticals. Welcome to Miami.

Starting to like Miami. Good to see you, Mani.

It's not bad. All are welcome, [ bienvenidos ]. So before we dive into the details, I'm sure we'll talk data positioning. Let's talk about where your interactions are with the FDA, just to level set where in discussions you are on Danon and where in discussions you are on PKP2 because you're engaged across a couple of different -- and then we'll talk across all day. You're engaged across a few different assets simultaneously with them.

Yes. Great question. So good to be here. Thank you to Leerink for having us back year after year. Before I answer, we are a gene therapy company focused mostly on rare cardiac assets. We also have a historical portfolio of lentiviral assets that are more ex vivo oriented and headed toward hematologic conditions such as Fanconi Anemia, LAD-I and PKD. We'll come back to that in a second.

Getting straight to the answers on Danon and PKP2. So for Danon disease, we have not interacted on the clinical side since the clinical hold was lifted, at which time we agreed that we would treat 3 patients in a staggered fashion. We're going to do that -- we're going to start that the first half of this year. And at the end of that period, we would go back to the FDA to seek guidance on what the rest of the trial looks like. There's no indication that it would be any different from previously, but we -- that is a discussion that is pending once those 3 patients are treated.

For PKP2, we've started a dialogue last year with the FDA at the end of our Phase I. And we got agreement that we have reached the right dose, the correct dose. We are in the process of putting together a study design and discussing it with them. We hope to have some clarity on that this year. So yes, both are in progress. And as far as we know, they're progressing pretty well.

Okay. And with that table setting, let's see. We'll start with the -- let's start with Danon. How should we think about the tempo of communications in terms of dosing 3 patients? When you -- we should expect you guys to be back in touch with the FDA and CIRCA and giving us disclosure around the path forward once you have that data in hand and what that means on the path to pivotal and approval?

So we plan to do a program update for Danon disease that hopefully includes a safety information. Hopefully, there's clearance there. Along with that, we've been talking for a while about an overall epidemiology update that's both top-down and bottom-up. Top-down, we've made a lot of progress in thinking about the cardiomyopathy genetic frequency models and applying them to Danon. We'll be able to talk about that. We've also been out there not in a big commercial setting way yet, but finding patients one by one and we'll be able to marry those 2 streams together along with the safety update and hopefully some FDA guidance in the path forward second half of this year.

That's helpful. While we're doing our sort of around the horn, let's hop over to PKP2 before we dive into individual programs. You guys are engaging with the FDA on potential regulatory path to approval. You're definitely carving a path through the jungle for a number of other companies. You're going to be first to go to the FDA. Talk to us about how you think about what are endpoints that really matter, both from a clinical outcome perspective for patients, but also on something that has a little bit of statistical meat that you can have a regulatory review and discussion. And those 2 things I know are not always the same thing.

It's a great question, and it's a question that many of us are trying to answer. Danon disease, by the way, was a one-off. It was one of the most aggressive cardiomyopathies out there in boys, especially these boys progress rapidly in the course of 1 or 2 years, you can see differences that are clearly well differentiated from a natural history of what happens to patients if they are not treated. Therefore, we were able to design a single-arm trial that was pretty small in size with a potential large benefit, magnitude of benefit, right?

I think all the other cardiomyopathies are not going to be like this. They're going to be a little more complicated. There will be potentially more than one endpoint. In Danon, we had LV mass index. I anticipate in PKP2, we would have some combination of arrhythmias, right ventricular function and size and potentially clinical outcomes. I think also, I can't guarantee that we will have a single-arm trial in PKP2 because the natural history of PKP2 is more heterogeneous than what we've seen in Danon disease, for example.

Therefore, the jury is out. There are many possibilities here, including a single-arm trial, including an observational crossover and other designs as well. As far as endpoints, people have talked a lot about PVCs, NSVTs and other arrhythmias. I think that cannot be the only endpoint here. I think it will be a combination of one of those types of endpoints, potentially protein expression and potentially even a third composite that might include something around right ventricular function because that's the ultimate marker of progression of disease in PKP2. So I'm laying out the buckets of endpoints without committing to anyone only because we haven't had that dialogue yet.

And remind me, what's the time horizon in which we should expect to hear back?

For PKP2 regulatory clarity, I would say we anticipate an update this year, 2026.

Great. I want to stay here before we hop over to legacy lenti programs. I think one of the conversations we've had, we've had a couple of your -- a couple of other companies looking at these patients. Obviously, PKP2 is a hot target. There's the question of where along the funnel you're supposed to be studying and then treating patients between people who have a genotype and then those who have a phenotype given variable preference was further down the funnel and then further down the funnel, those with meaningful symptoms, those an ICD, those with frequent shocks, you can cut the pie pretty thinly in terms of once you get to very severe patients. At what point where in that funnel should we be dosing patients in a pivotal trial? And what does that mean for who gets gene therapy out in the real physical world of commercial therapies?

Yes. This is always the conundrum in drug development. The highest magnitude of benefit is going to come in patients who are moderately progressed. Now how you define that could -- so that the other side of that conundrum is that how you define that moderately progressed patient could be wide, could be narrow, could narrow your label, could narrow your addressable market, right? So that is the question that we seek to address this year.

I would say that without committing to a specific population, PKP2, like Danon, like BAG3, like Fanconi Anemia, you have to find that Goldilocks zone where patients are progressed enough to show real benefit and have a positive trial, but also not so far progressed that they have too much fibrosis or there's a point of no return, right? So that is a zone. It's a great question, Mani. That's what we're figuring out. But it's probably a combination of arrhythmias as well as right for function. There's a moderate zone there that we're going to be targeting.

That makes sense to me. So let's talk about -- I'm going to hop over to the lenti side of the house, if that's okay. So one way or another, we have some clarity on Priority Review Vouchers for approval for pediatric diseases, which give some more clarity and an alternative source of financing for companies that's not dilutive to ownership.

That increases the financial benefit of unwinding from your current CRL on the lenti side. Let's talk about the path to getting out from underneath CRL and the path to commercialization, what that means in terms of for you guys financially, balance sheet-wise, but also just in terms of becoming commercial on the lenti side.

So we're -- our PDUFA date for KRESLADI LAD-I is March '28. So we're in a quiet period, I would say. It's tough to talk too much on the actual interactions there. We do think that LAD-I in our trial, we've demonstrated pretty robust -- as robust as possible clinical benefit with 100% survival in the Kaplan-Meier curve and all patients is doing well at an age that they probably would not be doing well.

So we feel good about the file, but I can't discuss more at the moment. We will plan to put KRESLADI up for commercial readiness and have accessibility for patients as soon as possible. I think that, that is, first of all, part of the agreement for PRVs that you have to have products be commercially ready. We also believe that the infrastructure and muscle memory that we will develop in the KRESLADI commercial readiness efforts, payer discussions, reimbursement discussions, qualified treatment center discussions, getting a team that's up and ready, thinking about branding for these gene therapies, all of that muscle memory will read forward positively when we launch Danon and other programs.

We are not putting a lot of commercial efforts into the lenti pipeline at the moment. We're funneling our resources fully to AAV once KRESLADI is launched. So that's the plan. That was a pivot point last year to reprioritize and focus the company. And I think now we've emerged in 2026 as a rare cardiac genetic enterprise that we're very proud of.

Perfect. Let's talk about as that transition is happening, let's talk a little bit about the state of the company as you sort of rightsize the headcount. Are there any further operational nuances that need to get worked out? Obviously, you have a new manufacturing facility in New Jersey, et cetera. Is there any additional restructuring or operational changes that need to happen? Or do we -- are we in a position to manufacture commercial scale AAV in New Jersey?

Yes. So we -- at this point, we have the right lean team of leadership team as well as leaders of functions and associates around the company. We have around 200 colleagues, we call themselves Rocketeers at Rocket. And we believe at this point, we have the infrastructure operationally to execute on both AAV manufacturing internally. We're also building a commercial force to be able to scale up to Dan and launch and other launches as well. So I would say we're in pretty good shape operationally at this point...

Perfect. As we think about the path forward commercially, I think there's been a lot of discussion independent of regulatory debates back and forth. I think an ocean of ink has been spilled, let's say, the FDA. I'm going to look past that for the moment. For Danon in particular, where are we in terms of quantifying the number of Danon patients that are diagnosed, those who are misdiagnosed given the complexity of the patient journey and scope the population, which I know has been a topic of a lot of debate because this is not a disease that's been historically -- it's not historically well understood like something agent like sickle cell. It's a relatively novel discovery in the modern era.

Yes. So to expand on your point, the Danon gene and clinical syndrome connection was made in 2001, right? So it's a newly understood disease. Awareness is relatively recent. The LAMP2 gene was not even on the cardiomyopathy panel until the mid-2010s. So there are a lot more cases of Danon out there than we know or that we've diagnosed. The ICD-10 code, for example, is something we just put together a couple of years ago.

So over time, we're going to see the true frequency of Danon manifest in the real world, and we're just not going to see that until then. Now in terms of how we find those patients, I think that we have to look at both -- you mentioned earlier, a genotypic approach as well as a phenotypic approach. I think you applied it to PKP2. But for Danon, for male Danon, the genotype is mostly the phenotype. So that simplifies things because if you go out and look for LAMP2 and cardiomyopathy panels and their males, they're going to get Danon disease. The penetrance is almost 100%.

In females, it's also almost 100%, but the manifestations might be softer or delayed. So the genotype and phenotype match in Danon disease, that's a very unique position of strength that we have as we unleash our medical affairs and genetic diagnostic efforts.

When we think about the opportunity in Danon, we talked about discovering new patients, getting LAMP2 into routine testing. How is that playing out OUS versus U.S.? The evolution and build of novel indications and novel markets can be pretty choppy globally. Talk about where we are in Europe, Japan and elsewhere.

Believe it or not, genetic testing, especially for cardiomyopathies is more widespread in Europe and especially Japan, actually. So in some ways, the physicians there have seen more Danon are more aware of Danon. We are opening up 3 European countries into our pivotal trial. And I think there are lessons to be learned from the European experience of diagnosing genetic cardiomyopathies to apply to the U.S.

I think in the U.S. the last time that we've done a survey, only 10% to 20% of patients with cardiomyopathy ever get a genetic test for their cardiomyopathy. That needs to increase. And I think as that does increase, especially earlier in life, we'll be able to diagnose more Danon patients over time.

So I'm going to hop over and keep moving down the cardiac pipeline. Obviously, when you think about PKP2, if we can go back to the clinical data there, what's the right steroid prophylaxis for each of these indications. We'll start with PKP2, but you can run through the whole pipeline. And how do you determine what is the right prophylactic regimen, steroid complement inhibition, et cetera? Is it determined by dose? Is it determined by construct/vector? Sort of what have we learned because now that we've had experience across a few different indications, both at Rocket, a couple of other companies, like as a sector, what have we learned?

First of all, I would say that we have to remain humble. We thought we had cracked the code and we hadn't. So curiosity, humility are paramount as we move all these trials forward. There are lessons to apply across the cardiac indications, whether you're using AAV9 or Rh74 or another capsid. Our approach has to be -- has been to be moderately aggressive in prophylaxis, including pretreatment Rituxan, sirolimus and steroids with hopefully a rapid taper, that combination and eculizumab on a PRN on TAP ready if and when needed for complement activation.

We've now canceled the C3 inhibitor approach for reasons that that you know, but primarily because it exacerbated endothelial damage and caused capillary leak syndrome in 2 patients. So we've removed the C3 inhibitor. We remain with rituximab, sirolimus and steroids for all of our indications, whether it's Danon, PKP2, BAG3, et cetera. That's been our approach. It's moderately aggressive. And I think the lessons on dose have more to do with making sure that the total viral capsid dose is capped at a certain point and you're not overdosing these patients with too much viral vector, which can overwhelm the complement system and liver system and others.

Those 2 lessons were we had to learn in the clinic. Unfortunately, in the AAV world, there are not strong preclinical predictors or models of safety signals. There are good predictors of efficacy, but not safety. You just don't see complement activation or liver elevations in the same way that you do in the real world in real patients. So we have to learn in the clinic. I think we've learned a lot of lessons. There may be some more to learn. But I think that between the dose between the capsid and this moderately aggressive regimen, we feel pretty good about safety.

I think one of the conversations that I've had is around the importance of dose because we've seen a lot of safety issues across AAV driven by dose. And I found that there's a little bit of misunderstanding around dose versus how much empty capsid you have in terms of what you're actually putting into people. Can you talk to us a little bit about the state of your manufacturing process and where we are in terms of empty capsid rates across the portfolio, what that means in terms of potency and efficacy at any particular headline dose?

This is a hot topic. It has been for years. I think that the industry has applied learnings from the cell therapy world into gene therapy. And I'm not sure it was always well thought through. I'm not sure that a super high full empty ratio is necessarily better than a moderately high full empty ratio. I think we're learning that there might be some advantage to not having a perfect full empty ratio.

The higher fulls, at least in Danon disease affect potency in a very big way and can affect safety when you have an enriched product. Now we've improved our full empty from Phase I to Phase II. In the Phase I, it was, I would say, moderately on the lower side, and now we're moderately on the higher side. I don't want to give exact numbers here. But I believe that we are in a pretty good place now that's acceptable to the FDA that allows for appropriate efficacy, better safety and long-term reduced cost of goods and more patients treated per batch as well. So I think we're in that balanced zone with the current full empty ratio.

So let's talk about that. I think there is -- the received wisdom and consensus right now is you should go for as much -- as high a full empty ratio as possible to drive your dose down as low as possible while delivering a defined number of viral genomes per target cell that's not deliver, assuming it's not the indication. That is sort of the state of consensus currently. Talk about specific data points that suggest that's not true and nuances that investors should keep in mind. I think that's about your programs, but also across the space.

So I think you have to look at each program disease by disease. It might be that in a certain indication with a certain capsid with a certain super high full empty ratio, you get that Goldilocks zone of efficacy safety combination. That could be. In our experience, I can tell you about Danon disease when we enriched the product from Phase I to Phase II with a much higher full empty ratio, we ended up with a more potent product. I would say that is specific to Danon because Danon disease is a disease of autophagy.

Once you get certain complement factors and interleukins build up in the cell, it's hard to extrude them. So you create this positive cycle of feedback and you can exacerbate the complement activation just by having an enriched product, potentially also subject these patients endothelial damage. We saw that in Danon and what we did in the Phase II -- from the Phase I is we then corrected the total dose for the enriched higher full empty ratio by about 40%. So that's why the new dose is lower than the old dose. It's recalibrated. It's actually the same drug potency, but it looks like a lower calibrated dose, right, [ 3.8.0E13 ]. So that's the application to Danon.

I suspect there are other diseases like that, where just blindly improving the full empty may backfire. I don't know what those diseases are, but one has to be careful. I think the current state of consensus is probably appropriate for some diseases and some vectors, but not others. You just can't compare apples to oranges. I would also caution since you asked about the general field and not just Rocket, I would caution against comparing dose for dose from company to company because the way that we measure doses, whether you use area under the curve or ELISA may differ.

The FDA tries to standardize the guidance, but it might be different for different companies. So one company's 7E13 is not the same as another company 7E13. It's just not right to compare those. Capsids are different. The way we measure the vector is different, the full-empties are different. The regulatory elements in the vector are different. There's CPG islands might differ. There's a lot of differences. So you just can't compare across. And you have to interpret each program for what it is in the clinic. That would be my consensus statement.

That's helpful. And I think a great summary of a lot of the things that we've learned in the last few years. Let's talk about BAG3, which we always talk about a lot because it's earlier stage, an asset that you guys brought in as part of a small transaction a couple of years ago. All the focus on the late-stage pipeline tends to forget that. Talk to us about where we are in terms of data we have in hand and path to patients and sort of what the future is for that program and how it fits into your broader strategy?

So our preclinical models from BAG3, which we first looked at through the Renovacor acquisition, but we've done our own work in the last couple of years. This is a dilated cardiomyopathy, I come back to that in a second. In dilated cardiomyopathies, there's a more standard trodden path in terms of endpoint selection. You can look at ejection fraction. You can look at cardiac output, you can look at LV strain. There are other ways -- there are ways that are established and sort of paved before we came into this dilated cardiomyopathy space.

So we feel that there could be a clinical path here that's more straightforward than something like PKP2. We're going to enter the clinic. The IND is cleared in mid-2026, a small 3 to 6-patient Phase I trial, standard dose escalation. The dose is based on the preclinical models as well as your experience in the other programs. We hope that even the first dose we start with like we did for Danon and PKP2 could be the final dose. That's the intent of the dosing strategy here. Now as far as endpoints, obviously, it's too early to talk about this. We're developing natural history.

We're developing a deep understanding. I think one other advantage for BAG3 and why we're super excited about it as a potential hidden gem is that there's much less competition here. We do things the right way. We have a very strong ownership of IP in the U.S. for BAG3. And I would say that the -- this particular acquisition from Renovacor, we're especially proud of. We'll have more to talk about in the months and years to come.

Great. We're winding down to the end of time here. This was tremendously useful and looking forward to seeing more data throughout the year.

Thank you, Mani. Thank you.

Pleasure to have you.

Thanks, everyone, for being here for TD Cowen's 46th Annual Healthcare Conference. Our next session we have here is with Rocket Pharma. And from Rocket, we have Gaurav Shah, the CEO. Thanks so much for being here. It's really a privilege to have you. I guess let's go ahead and get started on your overview, the history of some highlights before we get into Q&A. So go ahead.

Great. Thanks. [indiscernible] Cowen as well. [indiscernible] always back here in Boston. Rocket Pharma, we are a late gene therapy company. We are linearly integrated everything from discovery to development, internal [indiscernible] AAV commercialization. Our focus is rare cardiac diseases using the AAV platform. We also have a hematology and immunology platform using LV ex vivo, more on that in a bit. At the end of last year, we had $189 million, and that will be sufficient to cover cash into Q2 '27.

And I thought I'd use this time to go through what I think are the most important milestones for the year, and that will be a way to talk about each program one by one. First and foremost, we're very excited that we have a potential approval with the PDUFA date of March 28, 2026, for KRESLADI, which is our LAD-1 ex vivo lenti program, something that we've been working on. You asked about history since near day one of Rocket more than 9 years ago.

LAD-1 is a primary immunodeficiency affects children whose neutrophils cannot extravasate to fight sites of infection and most boys and girls pass away in their single-digit years. And we are excited to be partnering closely with the FDA to try to get this over the finish line this month. That is, of course, an opportunity to get an infrastructure built around commercialization, but it's also an opportunity for non-dilutive financing through PRV. The recent numbers have been trending up. So we're very excited about the potential of non-dilutive capital that could then potentially push us past Q2 of 2027. So that's KRESLADI. That's milestone #1 this month.

Number two, Danon disease is our signature lead program in the AAV rare cardiac space. It's a disorder of autophagy. Patients in their heart cells cannot extract debris that builds up because their system of autophagy, the garbage recycling center is disrupted because these patients lack LAMP2, which is a gene and protein required for autophagy. Without autophagy, this debris builds up and the heart muscles cannot contract in sync, leading to heart failure. It's X-linked, so it affects boys more than girls and before girls. Most boys only make it to 19 or 20 years of age without a transplant and even transplant is hard to come across and is associated with more than a 50% 10-year failure rate and/or the need for a second transplant. So really a fatal, rare, devastating disease in boys, but also in girls and women.

So Danon disease, we've had a program for a while. We published our Phase I data in the New England Journal of Medicine and which showed that in 6 of 6 patients, we have prolonged protein expression, improvement in labs like troponin and BNP and improvement in heart function 3 to 5 years after treatment. In fact, 2 of the first patients who were treated are past 5 years continue to have those results as well as protein expression.

Danon entered a Phase II pivotal trial. And last year, in attempts to improve the immunomodulation regimen to reduce the risk of TMA, we introduced a C3 complement inhibitor, the combination with AAV9 of which we believe led to massive capillary leak syndrome in 2 patients, one of whom passed away last May. We were put on hold. We were able to negotiate and lift of the hold in less than 3 months with the FDA through collaboration and transparency. And the trial is now up and running.

We have agreed with the FDA that we would enroll 3 more patients without the C3 inhibitor and with some other tweaks to the regimen one month apart -- at least one month apart and come back to them to finish discussions about the final trial design. The current trial design that we've agreed upon is a 12-patient single-arm trial of treated patients versus their pretreatment baseline with primary endpoint of LV mass index plus protein expression. Once we treat these 3 patients safely in the near term, we hope to go back to the FDA and get clarity or ratification of a similar design as we've already discussed.

Danon program is the pivotal program. It is something we're very excited about here at Rocket, but also with the patients and the patient community and the physicians who are dealing with these very sick boys and girls. That's the second milestone, second half of this year. So one is KRESLADI, Danon program update, which will include discussions about safety on this trial, but also an overall program update, including where patients are, both top-down and bottom efforts to find these patients.

Number three is PKP2. Now PKP2 is an arrhythmogenic cardiomyopathy. I should take a step back and say that in our cardiac portfolio, we've now addressed a large component of HCM, hypertrophic cardiomyopathy, which is Danon, ACM, which is arrhythmogenic cardiomyopathy, which is PKP2 and GCM dilated cardiomyopathy in DAC3. So we've now addressed 3 of the biggest buckets of genetic cardiomyopathies that are out there. So it's a real entry into the rare cardiac space for Rocket.

So coming back to the third milestone, PKP2, we treated 3 patients in the Phase I at the right dose, meaning the final dose without any dose escalation of 8.0E13 vector genomes per kilogram. And we saw in all 3 patients moderate improvements in arrhythmias, right ventricular function, protein expression and trafficking to the intercalated disc as well as improvements in how patients function and feel. So we saw consistent improvements across 3 of 3 patients, went to the FDA, agreed that we can start talking about a pivotal Phase II design. So the big milestone this year could be a discussion and finalization of that trial design with the agency. Again, this is something that's not going to happen in the first half, but potentially in the second half. That's PKP2.

Number three is BAG -- sorry, number four, the fourth catalyst is BAG3, the dilated cardiomyopathy. We have an IND that's open. We anticipate starting the Phase I trial this year. That's on track, and that's the fourth major catalyst, I would say.

So each of these diseases is relatively rare. If you add them all together, though, the Danon, PKP2 and BAG3 patient populations, we're looking at more than 100,000 patients prevalence between the U.S. and Europe. So while each rare disease is rare, rare disease is not rare. So those are the 4 currently existing pipeline catalysts.

The fifth catalyst I would say is we are very proud that we started the company with an LV ex vivo portfolio, including LAD-1, which has the PDUFA date coming up, Fanconi Anemia and PKD, we are looking to potentially externalize or partner these assets as yet a fifth catalyst at some point. So KRESLADI, Danon, PKP2, BAG3 and the [indiscernible] portfolio, all could be potential milestones and catalysts by which we can continue to build Rocket.

And thank you for your attention.

All right. We can move to Q&A. So maybe I'm going to invite you to sit next to me so we can be closer. All right. As you're resetting up your microphone, I'll get started. So I like the way you outlined that by milestones in order of programs. And so I feel like we can go through the questions in a similar manner. And so starting with KRESLADI with the PDUFA date that you have coming up. You mentioned at the end that you'd be interested in potentially partnering that. And so I'm curious what's the rationale for partnering a program like that? And what would an attractive partnership look like to you?

Well, I think we've gone through a journey at Rocket with many years of clinical successes, a couple of setbacks with the LAD-1 CRL and the patient safety issues on Danon. And we've had to learn to really, really learn how to focus and prioritize. We would love to do everything. We just can't. If we try to do everything, we'll do nothing, right? So we've taken a deliberate approach to focus on rare cardiac starting this year, actually starting in the middle of last year, which required us to size down our LV capabilities, both in-house and just general capabilities and to refocus our resources and money on AAV.

So therefore, given that these programs do work, obviously, KRESLADI, the Kaplan-Meier curve on there is something that is one can only dream of with 100% survival over 5-plus years in some cases. The Fanconi program works. There's minimal safety issues on it. PKD in our Phase I is also a very exciting program where the hemoglobin is normalized or near normalized in all patients treated. So these are gene therapies. When gene therapy works, it works.

So I think that there is an opportunity to partner with a group who can take these to the finish line and maximize access for patients and physicians and families. So that's the approach. Which program gets partnered or not, it's too early to tell. But the whole LV portfolio is something that we want to partner in order to maximize both patient access and shareholder value for ourselves.

And if a partnership takes more time than the next few weeks for LAD-1, you would begin launching that on your own regardless?

Correct.

Okay. All right. Now I think we should move on to Danon. I will say when I was a brand-new associate and writing my very first initiation, it was on Rocket, my first week as an associate. And I just remember sitting and writing for hours and hours on end about Danon and thinking like, man, I can't imagine a better indication for gene therapy than something like this. And so now here we are today, we're in the pivotal trial, and you have some ongoing FDA discussions and a lot going on this year for that.

So I'm curious, during this interruption period, what are the major learnings from that, that you're really taking forward? And especially as you begin to redose patients, how are you looking at -- what success looks like for each of those dosed patients?

I think that the biggest learning in gene therapy, I believe, is to go fast, you have to go slow. You cannot rush things. You have to take time to do the proper analysis, work with the agency and other experts around the world to really figure out how to optimize safety. Gene therapy works, but it's hard. And to think otherwise is foolish. So for these patients coming up, we've optimized the program as best we can. We have recalibrated the dose to account for a higher full empty ratio, which in Danon and with AAV9 might portend more potency. So the same dose with more full empties might be a more potent product, likely is a more potent product. And therefore, we have to adjust down the actual dose delivered to match the Phase II with the Phase I product, right? So that's a big change.

We've removed the C3 inhibitor, which we have very good reason to believe was responsible for the capillary leak syndrome in combination with the AAV9 with a high massive dose of AAV9. We have tweaked the criteria by which we administer the C5 inhibitor eculizumab. We would administer earlier than usual just with these changes. And we've changed some things about how long and frequently we administer rituximab in order to abrogate B cells ahead of treatment.

So those are the 4 big changes. This is the best foot forward. We feel good about it. I feel good about it. There's no way to know, of course, until we see the results. The unfortunate thing with AAV on safety is that there are no preclinical models that predict what happens in the clinic. We didn't see TMA in preclinical models. Certainly, there's no [indiscernible] leak issues in preclinical models. So we have to learn these safety improvements real time with people. And I must say that the Danon community, because of the devastating fatal nature of the disease and their openness, they've been very supportive in figuring this out together for the long-term health of Danon.

Yes. That's great to hear. And I'm not surprised to hear that either. So how about then with the FDA? So with those interactions that you have with the redose patients, and you expect to give us a regulatory update later in the year. And so what could that potentially look like besides a protocol modification? Is there any chance that they may ask to change the pivotal trial design, more patients than this? What are the potential scenarios that could come out of this?

We've heard no indication from them that there's an intent to change the design itself. Of course, we don't know. We have to be humble and take our time to do this the right way, right? I think the FDA's philosophy, I think, is very pro rare disease. It's very pro-gene therapy, but we don't know what's going to happen until it's done, just to put that caveat out there. But we've got no indication that the FDA intends to change the actual trial design. What I don't know is how many patients we will need to continue to treat at this recalibrated dose. Is it enough to finish a total of 12? Is it a new 12? Is it something else? That I don't know. And I think that's the discussion. And some of it's going to depend on what the safety looks like and other factors. But I will say that our experience with the Danon reviewers at the FDA so far has been pretty consistent, rapid and collaborative.

Okay. And with that review group and all of the recent changes in the FDA, can you maybe take a few minutes to discuss at a high level what your thoughts are for FDA receptiveness to biomarkers previous alignment that you have on endpoints and how confident you are that the previous interactions with the review group and anyone at the FDA should remain predictable and in line with your expectations?

I think that where we've been deliberately thoughtful since the beginning of Rocket since day one, nothing has changed here, is that the diseases that we pick are either fatal or highly devastating and most of them manifest at an early age. And I think all of those factors are part of this focus from the current agency on rare pediatric focused disorders using bespoke gene therapy. I think all of those factors fit.

On top of that, in Danon, we've been able to demonstrate, if you look at the green slide and from the NEJM presentation or on the website, 100% consistent improvement across every parameter we looked at, whether it's troponin or BNP, protein expression, reduction in vacuoles that you see on TEM, NYHA class improvements, KCCQ improvements, LV mass index, which is the most important one. Every single cell there is green.

So compared with patients who are not treated, whose LV mass, we've demonstrated increases by about 8% a year, the troponin increase. They're moving toward heart failure. So they're not going from NYHA class 2 to 1, they're going from 2 to 4, right? So in contrast with what's obvious in a rapidly progressive disease in the mid-teens, I think the results here are exactly what I think what the agency is talking about when we're talking about demonstrating results in a small trial. That's my view. I don't think that's true of all programs out there.

So we feel good. That's not to say that the dialogue is done. But I think we're standing on strong ground with Danon. The same is true for LAD-1 with the potential upcoming approval, and we hope the same is true across the portfolio.

Yes, definitely. Okay. So then you also said later in the year that you'll be updating a little bit on epidemiology. And without front-running that, maybe a little sneak peek. Maybe just tell us how has your market research changed and evolved over the years? Is the market opportunity larger than you originally anticipated, smaller, maybe similar, but shifted male and female. I'm just curious how that's evolved over time.

So it's still a work in progress. I think as rare disease epidemiology research develops, numbers change over time. Right now, we're still thinking around the same ballpark in general. Certainly, the addressable market and the market opportunity and revenue opportunity is similar as it's always been. I think that we will be able to do 2 downloads second half of this year. One is exactly what you asked, a top-down analysis of the true patients out there using both phenotypic and genotypic methodologies and then patients that we've actually found in the real world. And I think at some point, those 2 will match.

Remember one thing in Danon that unlike Duchenne, unlike cystic fibrosis, even unlike Fanconi Anemia, this is not a disease that's been well characterized because it masks as other things. It masks as Fabry or Pompe or learning disabilities, in many cases or muscle pain. So the link between Danon as a clinical disease and the gene was only made in the 2000s. So there just hasn't been that much time for awareness. And over time, I think the true epi will come out, but we are part of creating that awareness.

Okay. Great. All right. Down the line, the next one you mentioned, PKP2. So can you start by comparing and contrasting the data that you have so far versus at least the other 2 that we know of that have clinical data?

Yes. I mean, having looked at these data sets myself, they are complicated, little things go a long way, right? Do you use a 2-day holter versus a 7-day holter to monitor rhythms? How much are we interrogating devices versus looking at holters? How much are we thinking about PVCs versus T-wave inversions versus NSVTs? How closely are we looking at heart structure and size and function? And how well are we capturing how patients are functioning and feeling? I think those nuances are not comparable across programs.

So in some ways, I'll plead the fifth in commenting on the other data. What I can say is that for -- even though we've only treated 3 patients, all of them have demonstrated improvements and no worsening and improvement certainly in the arrhythmias we've measured in the right ventricle size, where we've been able to measure it and all 3 have demonstrated improvement in how they function and feel. So I think that's differentiating without necessarily commenting on the other data.

Okay. Fair enough. All right. So for the next trial, I know you're working on a potential design and endpoints. So maybe you could update us on your current thoughts there of what you would most like to assess and how you would like to assess it?

Yes. So Danon, I will say we got -- we found probably the most aggressive cardiomyopathy -- genetic cardiomyopathy that's out there, where patients get worse in a couple of years and move to transplant within 3 or 4 years. That's not going to be the case for any of the other genetic cardiomyopathies. And I think we have to be more thoughtful, deliberate and take our time to figure out the right trial design to actually win and have a positive result. So we haven't certainly finalized any sort of trial design, but under consideration, of course, are single-arm trials versus pretreatment, single-arm versus natural history, randomized crossover design, I think, is just as viable, if not more likely to produce a positive result if the drug works.

We will be careful to have 100% agreement with FDA before stating what the actual result is. I would say that -- so those are the trial design options. There may be more. In terms of length, I think this is going to take longer than Danon to demonstrate a difference between treated and untreated. So instead of a year, it could be a little bit longer. I don't want to capture an exact guess there either. But all in all, we still anticipate a gene therapy -- appropriately gene therapy size trial, right, and not something that's going to blow the bank here for PKP2. So we're excited. We're in those dialogues. We have been, and we hope to get some clarity on that later this year.

Okay. Great. And I think among investors, just the Street in general, one of the biggest questions here is the market opportunity of this versus implantable devices. Maybe you could position that for us?

Well, ICDs are the standard of care in PKP2-ACM, and they work. About 20 years ago, there were breakthrough fatal arrhythmias. In some papers, you can say 50%. That doesn't happen as much anymore. There are still fatal breakthrough arrhythmias, but they're more rare. So ICDs are a good treatment. More than 3/4 of patients who have the disease will get an ICD. However, ICDs are associated, number one, with intense anxiety and it's horrific anxiety because when patients get these shocks, it's not a near death experience or a death-like experience, it's a death experience, right? Their heart stops and they're shocked.

And when that happens repeatedly, these patients live with fear, anxiety, social issues and they just can't function normally anymore. That's one thing that we need to correct for by reducing ICDs and getting ahead of the problem even at some point, preventing ICD placements or the need for them.

The long-term issue for these patients, though, is that this is a disease now with the right and left ventricle, but primarily the right ventricle, the right ventricle fails over time and ICDs don't prevent that. They have -- they don't treat that at all. So I think getting a gene therapy approach, both to reduce arrhythmias and long term to improve and stabilize right ventricular function will translate into long-term mortality. So that's the clinical unmet need here.

Yes. I would say that's pretty compelling. Well said. Okay. All right. Then again, down the line, let's do BAG3 next. Maybe you could just tell us what is it that excites you the most about this program?

Yes. So DCMs are more prevalent and diagnosed than HCM. It is one of the most, if not the most diagnosed kind of cardiomyopathy. BAG3 is a large chunk of DCM. What excites me is that figuring out, first of all, safety but efficacy in BAG3 could open the door to many other DCMs that could really capture a big chunk of cardiomyopathy. The other thing is that BAG3, because it's a DCM, DCM patients have reduced ejection fraction. So this is a better trodden path in programs and companies who have looked at cardiomyopathies with DCM, EF has been an endpoint. You can look at LV strain, you can look at peak VO2. There's other ways to capture endpoints that has already been done. So we're not going to be trying to figure this out and create something from scratch. So I think there's already a body of work that can support a variety of endpoints in BAG3. We hope to capture 1 or 2 of those as we have a trial started.

But for now, what I'm excited about is the Phase I, just getting patients treated, getting through safety and then having this dialogue with experts and FDA. I will call BAG3 sort of a hidden gem. We're -- I'm proud of the partnership and the eventual acquisition of Renovacor that led to the BAG3 program a few years ago. It was a bet we made then, but we think that BAG3 will eventually could become maybe the biggest genetic cardiomyopathy program that we have even more than PKP2 and Danon. And so we're investing in that as sort of a hidden gem. But until we see the data, we'll just sort of be quiet about it.

Okay. Well, before we see the data, what would you call success? I know you mentioned safety there that you'll get the safety data from us, take it to the FDA. Is that something that -- I mean, really where our focus should be on in that initial data is just looking at safety? Or are you going to have preliminary efficacy measures as well?

Safety overhang in AAV is major. So even getting through safety in any of these programs, I think, is a big leap forward. We are going to be starting in BAG3 at a dose that could be a functional dose. We are dose escalating, but we're trying to start at a dose that like Danon work the first time around. So if we see safety, then I think we're going to give these patients a real shot at efficacy as well. So yes, safety is a big hurdle. I won't say hurdle, a big river to cross and looking forward to the other side of the river.

Definitely. Okay. Great. So I mean, I guess, in the remaining minute that we have, maybe you could tell us what is the most underappreciated aspect of Rocket right now?

I think we've evolved as a company and as a team and with our advisers and how we think about gene therapy. And I think we've arrived at a place where we can truly be leaders in this field through transparency, deliberate thinking, taking appropriate measured risks and being mindful about resources and resource allocation. I think we're uniquely positioned because we've gone through everything, we've gone through, both clinical successes and challenges, and we've come through all of it feeling confident in our stride.

Great. Okay. Well, with that, we are out of time, but thank you so much, Gaurav, for being here.

Thank you.

And thanks, everyone, for listening.

Thank you.

Welcome, everyone, to the JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Rocket Pharmaceuticals. And presenting on behalf of the company, we have CEO, Gaurav Shah. Gaurav, over to you.

Thank you for having us. Welcome to 2026. Thanks, Tessa, for hosting us and JPMorgan as well. Standard disclaimer, forward-looking statement disclaimer here. So Rocket is a late-stage biotech company. We have a pipeline of gene therapies that are designed to correct the root cause of complex and rare genetic diseases. We have 2 platforms, AAV and lentiviral and we do everything from discovery to manufacturing, including in-house manufacturing for AAV.

And we think that the secret sauce to success in gene therapy is an asset selection. And we're focused on assets that target medical conditions that are not only rare, but are devastating or fatal. Often in childhood and that have a direct mechanism of action that can be targeted and focused on the protein that is responsible for the disease and have a reasonable market size to create a business opportunity that can expand over time.

As of September 30, 2025, Rocket reported $222.8 million in cash, cash equivalents and restricted cash. We expect that these resources, excluding any sale of a PRV that could be granted on the KRESLADI approval that's slated for March 28, 2026, the cash that we have now will be sufficient to fund operations into the second quarter of 2027. And while we don't expect major revenue from KRESLADI given that it's ultra-rare, a BLA approval could yield this PRV, which there are some analogs that are out there currently, but we view that opportunity as strategic non-dilutive capital that could extend our runway much further and support investment in our growing cardiovascular pipeline.

2026 is the year of execution for us. We are going to advance 3 cardiovascular programs where we believe we can generate durable clinical data and therefore, create long-term value for patients and shareholders.

In 2026, Rocket enters a more focused company, focused on cardiovascular, each with a clear biological rationale, a defined regulatory path, meaningful long-term value potential as well as a pipeline of other cardiac programs right behind. We have been, as I said, increasingly focused on putting our resources towards AAV platform, including our lead late-stage program for Danon disease, which is a devastating heart failure syndrome associated with autophagy and leading to heart failure early in life.

Now in the context of Rocket's refocus on programs with the clearest regulatory and commercial paths, we made the extremely difficult decision to deprioritize internal investments in Fanconi Anemia, including withdrawal of both the U.S. BLA and European MAA applications. This prioritization does allow us to concentrate resources in areas where we can have the most immediate and sustainable impact for patients and shareholders.

We are seeking alternative options, potential partner options for both Fanconi and PKD so that they may see the light of day and that patients may benefit from access to these therapies. We have recently shared that we've limited our current LV investments to a KRESLADI approval for the treatment of severe LAD-1, which, like I said, has an upcoming PDUFA on March 28, 2026.

Now in 2025, looking at last year, we fully immersed ourselves in becoming the leader in cardiovascular gene therapies. We now have over 5 years of efficacy and safety data with our cardiac gene therapies, have treated numerous patients across these programs. We support these programs through our proprietary AAV manufacturing that's in-house at our more than 100,000 square foot facility in Cranbury, New Jersey, which is close to Princeton for those who wonder.

Each cardiac program was hand selected to be the first, best and/or only in class, has an on-target mechanism of action with clear endpoints and contains a sizable market to maximize patient impact. Cumulatively, our clinical programs focus on all 3 of the major phenotypes of genetic cardiomyopathies. There's hypertrophic, there's dilated and there's arrhythmogenic, and we're going to talk about each one of these.

Altogether, these programs represent more than 100,000 patients in the U.S. and EU with a multibillion-dollar commercial potential. Looking forward this year, that was 2025. This year, we expect to continue to advance and provide updates in the final clinical stage for our lead program in Danon disease. We also expect to initiate our clinical trial in BAG3, and we will get further clarity from FDA on a trial design for a pivotal Phase II study for PKP2.

We'll talk about each of these shortly. But first, let's talk about Danon, which is sort of the first cardiac gene therapy of its kind to demonstrate benefit through gene therapy. And this is a severe X-linked cardiomyopathy that's caused by deficiency of LAMP2. This leads to progressive cardiomyopathy arrhythmias and early mortality.

The mutation in LAMP2 or the series of mutations result in the accumulation of autophagic vacuoles. They're like these cells do not have a vacuum cleaner or a recycling center anymore, especially in cardiac and skeletal muscles. And with impaired autophagy, male patients often require heart transplantation, in fact, invariably require heart transplantation and typically pass away during adolescents from progressive heart failure.

When transplant works, patients often need a second transplant and mortality at 10 years is less -- is greater than 50%. So that's the male experience. Females with Danon disease can also be affected, but they often have a delayed presentation because they retain some LAMP2 from their other X-chromosome. So back for a second. The prevalence of Danon is estimated to be between 15,000 and 30,000 in the U.S. and Europe. Last fall, we shared a top-down approach and the results of that approach and how we have supported this range in more detail. We'll have further updates toward the second half of this year on both the top-down approach and bottom-up approach, including patients that we've actually found with Danon disease, both male and female.

So in the next few slides, you're going to see slides that have already been presented. We have some verbal updates to share those. So these are data on biopsies and protein expression of LAMP2 that we have already published at AHA at the end of 2024 and also in the New England Journal of Medicine. Nothing is new here. However, I am happy to share verbally that we continue to see strong durability in RP-A501 for Danon disease.

And for the patients in the Phase I trial who were treated, 100% of them continue to express LAMP2, either grade 1 or greater with the shortest follow-up at 36 months and 2 patients who have actually passed the 5-year mark. So this is the first time that we've shown long-term expression that's durable and invariable in cardiac gene therapy, greater than 5 years. This is the green slide, the magic key slide from the NEJM and AHA data from the end of 2024. This is really, really transformative in a way that only gene therapy where you're replacing faulty DNA with correct DNA can be.

We show key efficacy assessments across every parameter, representing change from baseline to most recent follow-up, in this case, out to 54 months in one patient. And we are in the process of processing updates from additional patient visits, and we'll share those at some point. Again, two patients have passed the 60-month mark and continue to show similar benefit.

So all our patients in the Phase I trial, adults as well as pediatrics continue to flourish beyond the age where they would typically demonstrate heart failure, be on a transplant list or unfortunately, even pass away. And we know that these patients are not only alive and surviving, but they're thriving.

LV mass index, which, by the way, is also a component of the co-primary endpoint for the pivotal Phase II trial that's ongoing is a measure of left ventricular mass as measured by echo or MRI. And here, you see an ongoing and durable robust reduction in LV mass index over time out to 4 years with a median reduction of around 24% at the most recent visit.

Now LAMP2 protein expression and LV mass improvements, again, are the co-primary endpoints for this ongoing pivotal trial, which I'll talk about in just a second. And this design itself is one that was set with the FDA before a clinical hold occurred last year. This clinical hold occurred because of an unfortunate safety event due to a patient death associated with capillary leak syndrome. It's the first time we've seen this in the field. It was thought to be through extensive data analysis to be the result of a combination of high dose of AAV therapy with a C3 complement inhibitor.

At that time, Rocket paused dosing. We conducted a comprehensive root cause analysis, and we modified the protocol and resubmitted the FDA. We got the hold removed in under 3 months, which is really record time. We recalibrated the dose to 3.8 E13 vector genomes per kilogram, which is down from 6.7, which was the original dose in the Phase I. We also accounted for this higher full empty ratio, which we haven't disclosed publicly, but it was a substantially higher full empty in the Phase II instead of the -- compared to the Phase I, which supported the reduction or the recalibration in dose to around 4e13.

We will now implement a safety staggered run-in, a staggered safety run-in that will treat 3 patients in the first half of this year. And after that, we will revert with the FDA and establish what the rest of the trial looks like. We don't anticipate there should be much change, but we have no indication that there will be any change, but there may be additional patients that are added.

Now I want to note that this recalibrated dose, which should account for the improved full empty is not new to these studies, to the pivotal Phase II study. Based on weight and age-adjusted dosing in the Phase I, two pediatric patients, the last 2 that were dosed received lower doses around 4e13, which is this recalibrated dose. And those patients had either similar or superior efficacy with actual cleaner safety profiles compared to the initially intended higher dose of 6.7e13. And both of these patients just had their 3-month -- 3-year visit last year and continue to demonstrate robust durability and efficacy.

We will, like I said, mention -- we will resume dosing in the first half of 2026 by treating these 3 next patients 1 month apart each and this, if they pass the safety profile will give us confidence that the program is advancing with the appropriate balance of safety and efficacy.

Now the revised protocol also reflects lessons from others in the field more broadly and is designed to preserve the biological activity we observed in Phase I while reducing risk in subsequent patients. And we will revert in the second year with agreement with FDA on our go-forward path to complete the study.

So our next most advanced AAV cardiac program is the AAV-Rh74 gene therapy for the treatment of PKP2 ACM arrhythmogenic cardiomyopathy. This is an inherited autosomal dominant progressive heart disease caused by mutations in the PKP2 gene and is characterized by life-threatening ventricular arrhythmias, structural abnormalities of the heart and sudden cardiac death. Loss of PKP2 at the cardiomyocyte junctions compromises both structural integrity and electrical signaling, leading to progressive electrical instability, arrhythmias and ultimately heart failure. These days, most patients are managed by ICDs for primary prevention, but there are no disease-modifying therapies available at all.

Gene therapy has the potential to directly address the underlying cause of disease by restoring the PKP2 protein and cardiomyocytes, stabilizing cell junctions, improving electrical conduction and potentially halting or even reversing disease like we saw in Danon rather than just preventing further complications. PKP2-ACM is about twice the size of Danon in terms of prevalence, affects an estimated 50,000 adults and children across the U.S. and Europe, although the true prevalence is likely higher given the challenges of diagnosis.

Many individuals remain undiagnosed or misdiagnosed as in Danon because early symptoms such as palpitations, fainting or arrhythmias that can overlap with other cardiac conditions. As awareness, genetic testing, which is common across all these programs and family screening improve, the number of identified patients is expected to increase. Underscoring the unmet medical need and the opportunity for a targeted gene therapy approach.

With this program, RP-A601 for PKP2-ACM, we are currently in a Phase I study, and we are assessing its safety and preliminary efficacy at 12 months post infusion. A natural history study is also being initiated to provide context for the Phase I trial, along with capturing further retrospective natural history data.

So the preliminary data from this Phase I trial for adult patients with PKP2-ACM was shared midyear last year at ASGCT. And overall, the preliminary safety and efficacy results show that the gene therapy was generally well tolerated and demonstrated initial efficacy. There were no dose-limiting toxicities. In all 3 of the patients who were treated, the gene therapy promoted desmosome localization of PKP2 and also promoted associated transmembrane intercalated disc proteins between 3 and 12 months after treatment.

We saw preliminary indications of improvement or stabilization in arrhythmias, heart functions and quality of life. We've already presented this data previously. PKP2-ACM is an active area of interest in gene therapy, and there are multiple groups exploring this approach. We actually view that as a validation of the biology and the unmet medical need. We believe that there are sufficient numbers of patients to support more than one successful therapy in several types of patients and disease characteristics as well.

What differentiates Rocket's approach is not just choice of vector, which is different across the programs, but it's a combination of evaluation of cardiac tissue targeting, efficient myocardial transduction and the actual effects on efficacy that we're seeing in these patients. We're using the rh74 vector that's selected for cardiac tropism. And again, we've observed clear localization of this protein to the intercalated disc. So it's not that just that we're seeing improvements in Western blot and immunofluorescence, but the proteins are going to the right places.

Now we believe that we have reached the right dose to demonstrate both safety and efficacy for RPA601 and PKP2-ACM. So we're no longer dose escalating. The 8E13 vector genomes per kilogram dose will be the dose to move forward into the next part of development. We're in discussions with FDA, and we're focused on defining the right registrational pathway for PKP2-ACM this year. A number of the common clinical features of this disease are correlated with the risk of ventricular arrhythmias. Therefore, we don't think that a single marker is going to be the marker like we have LV mass index in Danon.

Therefore, we see the importance and the criticality of a comprehensive data set similar to Danon to show the clinical benefit across many factors. We also think that longer follow-up is likely at least 1 year to 18 months needed to further elucidate our endpoint selection for the pivotal study. And we expect FDA alignment on this design and move a path forward for the pivotal Phase II study in the near term.

It's important to emphasize that dose alone is not a proxy for success in gene therapy. We have to look at differences of capsid biology, tissue distribution and intracellular trafficking. They all matter. Our focus has been on achieving meaningful myocardial transduction and protein localization that translates into clinical benefit rather than just optimizing to the lowest dose that's possible.

So based on the totality of data so far with this program, we believe RP-A601 has the potential to be a differentiated disease-modifying therapy for patients with PKP2-ACM.

And the third program, which is what I believe is a hidden gem for near-term growth of the cardiac portfolio is BAG3 dilated cardiomyopathy. We had IND clearance last year, and we are working toward initiation of the Phase I study. DCM is the most common form of cardiomyopathy versus HCM and ACM, which were represented by Danon and PKP2. It's the most common form of heart failure due to genetic cardiomyopathy and is characterized by progressive thinning of the walls of the heart, resulting in enlarged heart chambers that are unable to pump blood.

Mutations in the BAG3 gene are among the most common mutations observed in DCM. The BAG3 protein is an interesting protein. It's expressed primarily in the heart, but also other tissues. In the heart, it plays a role in multiple key cellular functions. Loss of BAG3 leads to accumulation of misfolded and damaged proteins, which can impair the heart's ability to contract, thus leading to impaired cardiac function and premature death.

We view BAG3-DCM as our potential largest market opportunity to date with around 30,000 individuals affected just in the U.S., and this is our next durable value-driving engine that is distinct from both Danon and PKP2. Patients with BAG3-DCM have an urgent medical need and the current medical and interventional therapies, including implantable ICDs, pacemakers and/or heart transplant do not consistently prevent disease progression and are associated with major morbidities and mortalities, including inappropriate ICD shocks and transplant-related complications.

Ultimately, they do not address the underlying pathophysiology or genetic mutations. Because BAG3 plays a role in multiple critical myocardial cell functions, we believe that the AAV-Rh74 gene therapy has the potential to restore or stabilize cardiac function in these patients. We are going to use the same approach of rh74 that we are going to use across cardiovascular programs and have used in PKP2. We believe this vector offers efficient myocardial transfection even much more than for muscle. And also, this approach allows us to apply lessons that we're learning from other indications.

Finally, from a competitive viewpoint, while BAG3 is gaining increased recognition as a genetic driver of dilated cardiomyopathy, we believe it remains less crowded in the landscape overall relative to other cardiomyopathy indications, allowing for thoughtful, data-driven unfettered clinical development. Where are we in BAG3? We are currently in the process of initiating the first-in-human Phase I trial. This study will be a multicenter dose escalation study that's designed to evaluate the safety, biological activity and preliminary efficacy of RP-A701 in adults with BAG3-DCM.

We'll also be looking at BAG3 protein expression and functional cardiac endpoints such as ejection fraction and exercise capacity. So looking forward into March of 2026, we anticipate the potential approval and commercialization of KRESLADI. This is summarizing what we look forward to in 2026 for severe LAD1, which represents Rocket's first opportunity to bring a commercial gene therapy to patients. So we hope to move from a late-stage clinical company, clinical stage company to a commercial stage gene therapy company.

Again, severe LAD-1, which we have not mentioned much here today is an ultra-rare condition affecting a low single-digit number of patients annually, making KRESLADI a highly targeted launch for these patients. And while we do not expect substantial revenue, approval could bring a PRV, there are analogs in the field as to the value of the PRVs as additional nondilutive capital and thus extend further -- further extend our cash runway.

We also see the potential commercial launch of KRESLADI serving as a way to build infrastructure and capabilities for our future larger AAV program launches. So that's the first catalyst. For the AAV programs, there should be 3 potential catalysts. First, the initiation of clinical activities for BAG3 DCM, and these are not in any particular order with the dosing of our first patients in 2026.

Second, we will announce our alignment on the initiation and continuation of the pivotal Phase II study for PKP2 once we get the alignment with FDA. And third, we will resume dosing with Danon and hopefully establish a safety profile and come back with a clear path forward to approval. So it is a year of execution, a year of excitement, and we look forward to sharing more as things evolve. Thank you very, very much.

Okay. Great. Thank you so much for this presentation. So I'd love to start with a little bit of a bigger picture question for you. The presentation really outlined the strategic priorities for the company. How do you think about relative risk across your portfolio? And which of these assets do you think could deliver the highest reward?

Well, you ask different folks in the company. I think everyone is going to have what they think is the highest value driver. I believe Danon is something in the cardiac gene therapy field that is unique because it's possible to demonstrate a clear differentiation between untreated patients and treated patients in a meaningful way that regulators will understand, patients and caregivers will understand and payers will understand. It's also a large enough market to be the single highest near- to medium-term value driver.

So I would say Danon. I think BAG3, like I said, is also a hidden gem with endpoints that are relatively easy to define and there are precedents for those endpoints. So that's how I would sequence them in terms of value driving.

Okay. So let's just jump right into the Danon program. Can you specifically talk to precisely what the gating factors are to resuming patient dosing here?

Mostly logistics at this point. just getting IRB approvals and other technicalities to resume dosing, we do anticipate moving forward in the first half of this year. So we're close. Just one point to note also is that there's a 3-month troponin run-in before patients are treated, and we can't use last year's troponin values. We have to rerun them as well before the treatment. So we're getting through those.

Okay. And something we've been trying to think a little bit about is like -- and would love to get your thoughts and perspectives. Like what is a reasonable rate of complement-mediated thrombotic microangiopathy in the context of this disease state where there's meaningful unmet need?

I would say that -- I'll make a couple of points. I don't think -- it's a great question. I don't think TMA risk is going to be 0 for high-dose AAV therapies. I think there will always be some risk. The overall benefit risk has to work out. The TMA cases that we've seen as far as we know and others have seen in the field have resolved. So those patients long term, we believe, will demonstrate clinical benefit despite having had TMA because they're reversible events.

We're not talking about capillary leak, just TMA, right? And so there is a ratio or there is a percent of TMAs that I think is acceptable for regulators, patients and all stakeholders. I don't know what that percent is, but it's probably not 0. Danon is a disease, just to reemphasize, that leads to mortality around the age of 19 or 20 in boys and in the 30s for females. And once patients know they have Danon, they often go on a transplant list within 2 or 3 years anyway.

So a low modest risk of TMA for this community has been deemed acceptable. They've communicated that with us as well. As long as it's reversible, the benefit of the gene therapy far outweighs that risk.

Okay. And thinking ahead here to your anticipated treatment of 3 more patients at your recalibrated dose level, how do you think about what defines a positive data set?

Our hope is to replicate what we saw in Phase I, the green slide, the transformative slide. That's the hope. There's no reason to think otherwise. And the safety as well was tolerable in that Phase I trial for the patients that were followed for at least a year at the right dose. So that's what we hope to replicate. Obviously, we can't guide to that, but that's the hope.

Okay. And what makes you confident that this dose will drive sufficient efficacy and a safe profile?

So we mentioned briefly earlier that 2 of the patients, the pediatric patients in the Phase I were treated at around the same dose. And actually, they had the earliest and most robust efficacy that's now durable out to 3 years. So it could be that there's a range of dose here between 4 and 6, 7E13 and actually the lower end could be the best dose just based on that pediatric data. So that reassures us quite a bit.

Yes. And I'd also love to talk a little bit about the feedback that you've gotten from the kind of physicians and institutions that you interact with in the community. What is the feedback that you've gotten on the overall emerging profile of the asset so far? And what are they looking to better understand?

I think I can speak to the -- they're all different, right? So Danon, PKP2 and BAG3 patient communities are all very different. I can speak for the -- what I know about the Danon community. These boys and females have one of the most aggressive cardiomyopathies, if not the most aggressive cardiomyopathy known to humans, especially the boys. So they're used to illness. They're used to coming in and out of hospitals. They're used to uncertainty, unfortunately. So array of hope is -- has transformed this community in a very, very big way. Even when we had this very, very unfortunate patient death last year, I will say that after processing it, we were able to get on a call with the Danon Foundation, the Danon community, and there is still very strong interest in the trial even amongst the families whose boys are affected, right?

And I think this is a unique type of situation. PKP2, these patients have ICD firings that are highly anxiety provoking. They live in constant fear. There is the early mortality from the heart failure as well. So it's also a community that's really looking for something different because there's no disease-modifying therapy. So I think that's what we're seeing with these aggressive genetic cardiomyopathies. They're not like the slower-moving cardiovascular ischemic-related cardiomyopathies and others that evolve over time. These are very dedicated, focused and cohesive communities that are really looking for hope.

And how is -- I believe you have a concurrent natural history study. How is that progressing? And what have you learned so far in the study? The natural history study.

For which program?

For sorry, Danon.

For Danon, yes. Yes. So there is a concurrent concomitant natural history study. Just to be clear, it is not the comparator arm. The comparator is the pretreatment, the same patients who were before they were treated as a comparator. But this complementary natural history study to the main trial of 36 patients is both males and females. It is progressing. It's enrolling. It will be enrolled by the time of the BLA. And it is -- we are learning a lot about how these patients would do without treatment.

Right now, it's still validating the same points that we saw in the retrospective data set where LV mass increases year-by-year and that these patients decline, and they declined pretty rapidly. This is not -- doesn't take 5 years. You can see the change year-to-year. And again, this is why we were able to negotiate a small pivotal design with the FDA because of the big differentiation there.

Okay. And sorry, I'm just doing a time check here to keep us on track. So I think you've outlined 12,000 U.S. Danon's disease patients after age adjustment and accounting for non-HCM presentations. Are there any ways we should be further breaking down the population to think about like who would be most likely to come on RP-A501?

Yes. The numbers that we have shared and will share on overall prevalence, of course, include males, females, transplanted patients, pre-transplanted patients. We have not talked about the addressable market in a lot of depth in detail. I will say that just focusing on males for now, males invariably progress to heart failure by the late teens or early 20s. So we anticipate that most males should be eligible for this therapy who are not transplanted. For females, we'll define that further as we go.

Okay. Okay. And just switching gears here and maybe briefly touching on a couple of other topics. So maybe on PKP2-ACM, are you planning to present further follow-up from those 3 patients this year?

We have not decided yet, but I think if there's meaningful change from previous, we may. But for the most part, we've gotten what we want out of these data sets to inform a pivotal trial.

Okay. You beat me to the punch. Do you think you have enough information to know the best -- like the best design and derisk the study to the best of your abilities?

It's a great question. The Phase I does remain open. So it's possible we collect more data. But between protein expression, arrhythmia changes and structure and function and how patients function and feel, we have what we need. What we don't have is the natural history build-out as a comparator. At the end of the day, we'll have to start a pivotal Phase II trial. And for anyone who does that, that's where the risk is going to lie.

Our challenge is to design the trial that captures the highest probability of being positive if the drug actually works, right? So I think in a short time period, we're not going to learn that much more about how these patients fare in the first year to 18 months. So I think we have what we need. However, the Phase I trial does remain open for data collection if patients would like to enroll.

Okay. Okay. Great. And how is the regulatory review proceeding around your BLA for KRESLADI?

We're about mid-cycle. And so far, there don't seem to be any showstoppers. That's what I know right now. But we remain cautiously optimistic given how the landscape is evolving and how others have experienced this. We're cautious, but so far, things are moving forward as expected.

Okay. Okay. Great. And I'd be remiss if I didn't ask about manufacturing. Can you talk a little bit about your capabilities at Rocket? And what are your near- and long-term plans?

So our internal capabilities are all focused on AAV, and we have enough capacity, enough space, first of all, and the infrastructure and capacity overall to support all of these programs that we've disclosed, right? Danon, PKP2 and BAG3 at commercialization. If we grow beyond those programs, we may have to build more. But we believe that having in-house manufacturing controls cost of goods in a very, very meaningful way, thus driving the highest margins. That's number one.

Number two, it also controls time lines and puts the control in our hands. So we're not dependent on outside vendors and CDMOs. And third, it allows us to improve the process as needed over time and just manage the life cycle in a much better way. So this was an investment at a time when biotech was in a much high. XBI was 160 or so when we built out this manufacturing facility, and it was a good investment because it's going to pay for years to come, payback for years to come.

Should we may -- in the last couple of minutes, if you could just remind us of your cash position. What cash gets you through? And yes, any other considerations there?

So not accounting for PRV, which could form additional non-dilutive capital after the PDUFA date if we get the approval. So not counting that, the cash of $222.8 million as of Q3 last year, we'll obviously have an update soon, gets us into quarter 2, 2027. So it's a nice runway even without the PRV, but with the PRV, the potential PRV, I should say, it extends us much further.

Okay. Okay. Great. And are we going to hear about Wave 2 programs at Rocket this year? Or is that further out? For the company?

No. The Wave 2 is still very active. We just slowed things down to focus on the highest value drivers right now on Danon, PKP2 and BAG3, but we have other programs that are right behind ready to apply the learnings and ready to go. And I don't want to commit to one program a year or anything like that, but there's enough to keep the pipeline steady and stable for many, many years to come.

Okay. I think that might be a good place to leave this conversation. Thank you so much.

Thank you, Tessa. Thank you, everyone.

All right. Welcome, everyone. Thanks for joining in. This is Gavin Clark-Gartner from the Evercore ISI Biotech Research Team. Really happy to be here down in sunny Miami for the first day of our healthcare conference. And first up, we have the CEO of Rocket Pharma, Gaurav Shah.

Thanks for joining us, Gaurav. I'm going to turn it over to you just for an overview of the company, where things stand today, then we'll get into it.

Thanks for having us, Gavin. Great to be down here and warmer weather in our midst. And so Rocket Pharma, we're a gene therapy company. We have 2 platforms. One is cardiovascular AAV-based therapies. One is Ex Vivo Lenti-Based therapy for hematology. We have 3 disclosed clinical programs in each with proof of concept in the clinic in most of these programs. The last one, BAG3 is just now entering the clinic now. So the 3 hematology programs that we started with included LAD-I, Fanconi Anemia, and Pyruvate Kinase Deficiency. And the 3 cardiovascular programs include Danon disease, PKP2 and BAG3.

And our focus is increasingly going to be on the AAV portfolio given the high unmet need, the high patient numbers, the greatest opportunity for value creation there. So one thing we did this year was to pivot more and more toward the AAV programs as a way to be good stewards of capital, extend the cash runway and focus the resources in the company on the most high-value programs. We are in the midst of getting the Danon program started back up again after a safety event last year, and we're in the midst of getting PKP2 and BAG3 further in the clinic as well and very excited about the future.

Awesome. All right. So let's dive right into the AAV side. We'll start off on Danon since you just got the hold lifted, as you noted. Maybe just kind of walk through next steps, timing, cadence of dosing, all of that.

Yes. So the lifting of the hold was -- from a timing viewpoint, was really fast. It was really rapid, one of the most rapid that we've seen. Our focus really has been on structured benefit risk as we open the trial back up again. In terms of dosing, so we had dosed in the Phase II 6 total patients. The goal was 12. Two of these patients had a Capillary Leak Syndrome and associated edema that in one case, did lead to a patient death. So we paused the trial. We were on hold for 3 months. In restarting the trial, we removed the complement inhibitor, which, along with AAV9 was jointly responsible in our total analysis for the Capillary Leak Syndrome.

So without the C3 inhibitors, that's 2 patients that we cannot count. So we anticipate likely replacing those 2 patients and still having at least a total of 12 patients treated. We will begin that trial in the first half of 2026, treat 3 patients in a staggered fashion 1 month apart, go to the FDA, get alignment on a full and confirm a path forward. We've heard no indication otherwise that it's anything other than what they've said in the past in terms of a single-arm, 12-patient trial and then move forward pretty rapidly in a non-staggered fashion once we're past the staggered phase. So all of that starts up in first half of '26.

Yes. Like thinking about gene therapies, just given kind of the logistics involved in dosing, I mean, think about the timelines. First half is a fairly broad window to start, and then there's a minimum 1 month, but it's probably hard to sequence exactly for that 1 month given all the start-up activities. So the kind of -- is this going to be rolling through to end of '26 into '27? Or do you think it could be done kind of quicker for the first 3 staggered patients?

Well, our target is first half '26 as fast as possible. We've identified these patients. Patients have not dropped out of the trial. So we have that group of patients that are still eligible. We do have to do a 3-month troponin run-in, which adds some complexity to it. And these patients, some of them also will need vaccines ahead of potential eculizumab. So there is some staggered time period that could extend beyond 1 month, but because the patients are already selected, we know who they are, we're going to try to make it as close to 1 month staggering as possible. Probably won't be perfect, but we'll try to be close.

Looking ahead then, as you're planning to give us the next updates for Danon kind of as you progress, I'm assuming you're not planning to give us updates patient by patient and you kind of look at some of the patients together. Would you plan to give us data at the end or wait for a regulatory meeting also and give that in one update? What are you thinking?

I would say we do the staggered safety run-in, get alignment with FDA. And as folks may recall, last year, when we were going to finish the trial, we were going to do a comprehensive trial and epidemiology and patient finding update as well. So we want to do all of that at once when we have real clarity on both the trial, where the patients are and the full market opportunity to be able to give some wholesome information to the Street at the same time at once.

And do you still have additional claims analyses that you have ongoing in the background or the commercial analysis?

Yes. It's a lot of work ongoing, both from the top-down perspective, really honing in on what the exact epidemiology is based on a variety of different sources and then the bottoms up, which I think is going to be the real setup for the commercial launch.

Great. What -- you mentioned this before. Like what gives you confidence that the FDA is still aligned on the 12-patient, single-arm study, and there's not going to be any changes to that?

So you never know. As we know, the FDA's viewpoints are in flux. And for Rare Pediatric Fatal Diseases, our opinion is that they're moving in a favorable direction in general. All of our interactions with them so far have not been derailing. They haven't questioned things that are in writing already and the agreements that we already have in writing have not been questioned to date. We try to interact frequently and transparently with the FDA. And when we do reference things like pivotal trial and study design, we haven't heard of any specific pushback, right? So every indication right now is that there's general ongoing support.

We did design the Danon trial to be pretty robust in terms of stats and the assumptions because, as you know, patients who are not treated with gene therapy who have Danon disease progress pretty rapidly in 2 or 3 years, they're on a heart transplant list or unfortunately passed away, their heart grows pretty fast. And as the NEJM article showed last year, treated patients have the exact opposite trajectory with shrinking of heart size, they're starting to feel better and not just quality of life, but every single biomarker moves in the opposite direction in a positive way. So there's a wide gap between treated and untreated. So the design from an objective viewpoint makes a lot of sense. It continues to make sense. And that's why I don't think there's been pushback. But obviously, we need to pivot. We need to be agile. We need to be humble and we need to learn and listen from the FDA right now.

Yes. And on that point of kind of trial design statistics, I think you were planning to give an update this year on some of that -- those details. Is that planning to be with the next update on the clinical data, regulatory, commercial, all rolled together?

Yes. So all one big update is the plan after the patients are hopefully treated safely and we have the FDA path forward.

And now that I guess the dust has settled a little bit like after the safety events, what are you hearing from the community in terms of where they stand with adoption and if any of their perceptions have changed?

Yes. First of all, our commitment to the patients, the families, the patient advocacy groups, the Danon Foundation is unparalleled in the sense of how much we lean in and rely on them for -- to help us understand the disease and to help them educate us and us educate them when we need to update on trial issues, right, which we have been doing pretty regularly. And in the couple of weeks after this patient death happened, obviously, community was shocked. We were shocked. We went through a mourning phase there for sure. About 2 weeks later, though, we had a webinar with the full patient advocacy group, which included some of the family of the patients who have been treated.

And there was almost unanimous understanding and ongoing enthusiasm for the trial, just understanding that this is a fatal disease. We are figuring things out. The reality is that there are no preclinical models that predict safety in AAV for Danon, really in almost all AAV. There's no preclinical models that predict safety. So we're going to have to learn from real live human beings with complex biology that just can't be replicated in preclinical models.

And I think these families are brave, courageous, they understand that, and they've stood by our side as we've stood by theirs. So I think there's going to be enthusiasm as the trial opens up again. And if we can replicate some of the data that we saw in the Phase I, I think this community is really going to come behind the gene therapy. And also, there's no alternatives other than transplant. And transplant itself has a 50%, 10-year survival rate with risk of retransplant. And even transplanted patients who "do well" are feeble, frail and have very difficult quality of life. So I think that community is really waiting.

So let's move on from Danon here. Let's go over to PKP2. I guess one place to start, what's the timing of FDA discussions? When do you think you'll have an update on kind of the registrational path to market?

So we started that trial at a dose that we thought would be the final dose, and it is. And we do have FDA agreement that this can be the final dose. So we're in discussions about -- primarily about trial design, and we're open-minded about what that trial design could be. At the end of the day, what you want to do is have a design that wins, right? Not necessarily just the smallest design or the quickest path to market. You want the most robust trial that demonstrates unequivocal benefit risk to regulators and to payers. So that's our focus right now. It's going to take some time just like it did for Danon. PKP2 is a disease that progresses more slowly than Danon. You don't see the rapid changes in months like you do in untreated Danon patients. It takes some time. So we're going to have to be thoughtful and disciplined about how we approach that trial design.

Do you have the preference for what endpoint you would want to pursue? Understanding it's a collaborative discussion. I know you've kind of spoken about composites before because there's heterogeneity and some patients have different manifestations, like some patients have a more acute PBC involvement, there's QT inversions. So like what would you want to do if they were up to you?

I think we have to study and we are studying the natural history data carefully. And it may not end up being a single endpoint like we have in Danon disease, which is LV Mass Index. It may be a totality of evidence that includes a couple of arrhythmias, maybe some right ventricular parameters and some clinical function as well along with protein expression. It could be a composite of things there, which is not unusual in the cardiac fields. So we just don't know yet, and we remain pretty open-minded and ask people to remain pretty open-minded about how this turns out.

How important do you think kind of the symptomatic side, quality of life? I guess KCCQ is one of the measures. How important is that to adoption commercially?

We've seen the 3 patients that have been treated improve pretty substantively in how they feel and function day-to-day. These patients are a year out or more. And at some point, we'll have updated data on that. And so it matters a lot because the right ventricular sometimes improves and you can't always tell because the EF itself isn't necessarily changed. You might see some improvement in function like we did in one patient on echo. But in general, just having trafficking of these intracardiac membrane proteins or the junctional proteins in the right place when they were before maybe intracellular or they were in the wrong places before, seeing them go to the right place, there is a benefit that patients are feeling that isn't always necessarily translated to arrhythmia reductions and/or other clear biomarkers. So I think that needs to be part of the story, whether it's a primary or a key secondary, but I think it's going to be an important part of the story just as it is for Danon.

Let's go over to BAG3 actually. Like there's been less focus there historically just as you're just getting into the clinic there. Maybe you could just kind of walk through not just cadence of site activation dosing, but then all the early measures you're looking at here? Like what's going to move first in this population?

So BAG3 is a DCM. By the way, with BAG3, we now have entry into each of the big buckets of cardiomyopathy, hypertrophic with Danon, arrhythmogenic with PKP2 and dilated now with BAG3, right? So -- and hopefully, that opens the door to many more like that to come at Rocket and beyond Rocket. So the BAG3 program will start in the clinic next year. It's a DCM. Now DCMs are much better characterized. There's more DCM in general. So there's more research on it.

And because it's a dilated cardiomyopathy, more traditional endpoints such as ejection fraction, LV strain, peak VO2, even 6-minute walk test, et cetera, may predict good outcomes in patients, right? So in some ways, it's a more predictable set of monogenic DCM disease states that I think we can go after starting with BAG3. And the BAG3 program is going to start with a Phase I, pretty traditional approach. We're starting again at a dose that I think could be beneficial. We do have a dose escalation built into the trial if we need to, but hopefully, we don't need to.

And do you have any expression targets here? Are you looking at co-expression of other proteins as well? What about that side?

We'll be looking at protein expression just like we do in all the other programs. Unlike PKP2, where there's Desmocollin and other proteins that when they light up, you know that there's sort of joint signaling and joint trafficking to the junction. In BAG3, it's just BAG3 primarily. So there's no downstream proteins necessarily. I mean we're still developing the validated potency assay, which will require some ancillary proteins. So that's still in discussion, but not necessarily as part of the protein expression database.

What about the cadence of dosing? How spread out is it also?

We've spread the Phase I out in a pretty traditional design, several weeks apart between patients, 3 patients, and it's 3 to 6 per cohort. If there's no DLTs, we stick to 3 patients, but we may or may not elect to enroll more depending on how those patients are doing and if they're doing well, we more and more want to leverage the Phase I data given that we're trying to use a commercial-ready product as much of the Phase I data that we can leverage into pivotal trials as possible is good.

And I did want to touch on the lenti side. I haven't actually looked at this in detail. I just saw that the PRV got reauthorized in the House. I know you're going forward with LAD-1. Has that changed anything on the Fanconi side, too?

Well, we've made a very conscious intentional, deliberate effort to make sure that in this landscape, market landscape that we find ourselves in, that we're judicious with cash spend and putting resources, meaning people as well as money in the highest value programs. Now Fanconi is a program that we started with at Rocket. It's dear to me, it's dear to many of us in the patient community. And at this point, we can either focus on building AAV or building everything, and we think it's better internally to focus on AAV and to focus more and more on partnerships for the lenti programs. The KRESLADI PRV is important, getting that done, getting that over the regulatory hurdle, we will commit to as Rocket. I think everything else, including FA and PKD are partnering opportunities. Having a PRV opportunity for those, I think, is a great selling point for partners. and it's high return on little investment. So look forward to those dialogues with potential partners.

Is Fanconi PRV eligible?

Yes.

Okay. Yes.

So Fanconi -- so LAD, Fanconi, PKD and Danon are all PRV eligible. So potentially all non-dilutive cash sources for the future.

Yes. Maybe you could just -- while we're talking about KRESLADI, maybe could just kind of update us on the CMC side. Just kind of remind us what were the CMC discussions previously? What did you change? Why are you really confident in this go around?

There were a host of basically virtually all CMC findings there were a few, a handful, less than 5 that were focused on stability and sterility that were specifically gating for the approval. We have now addressed them, done some experiments mostly externally to validate and do what -- exactly what the FDA asked for. We checked every single box exactly as asked for with no push-back. And we've submitted the response to those gating questions and also a path to addressing the full gamut of PMC and PMRs. So we feel pretty good about the package that was resubmitted. We're in discussions with FDA about questions, IRs, et cetera, and hope to get this approved by the PDUFA date, March 28, and we're very excited about that.

All right. Sounds great. We're just at time here, but with another program going into the clinic, it's going to be an exciting year next year. So thanks for joining us, Gaurav.

Thank you, Gavin.