Idiopathic cardiomyopathy

The Duchenne Video Assessment (DVA) evaluates the ease of movement in patients by identifying these compensatory patterns. To conduct the assessment, caregivers are instructed to record videos of patients performing designated movement tasks at home using a secure mobile application. Certified physical therapists (PTs) trained in DVA evaluation then analyze these videos using scorecards containing predefined compensatory movement criteria. This study aimed to create and enhance the DVA scorecards. OSP spoke to Mindy Leffler, managing director of Qualitative Research and Psychometrics from Emmes, a full-service CRO to find out more. OSP: Can you explain how the Duchenne Video Assessment (DVA) differs from traditional clinical trial assessments for Duchenne muscular dystrophy (DMD)? ​ ML: ​ The DVA tool differs significantly from traditional clinical trial assessments in that it brings the assessment directly into the home environment of patients. This approach captures the daily function and experiences of patients in their real-world settings, providing a more authentic representation of their abilities. Unlike clinic-based assessments, which may not fully reflect the challenges and nuances of daily life with DMD, the DVA offers a more holistic view. Additionally, the DVA utilizes video recordings to objectively measure functional abilities, enabling a more consistent and reliable assessment process. OSP: How does the DVA incorporate patient and caregiver feedback into its assessment process? ​ googletag.cmd.push(function () { googletag.display('text-ad1'); }); ML: ​ Patient and caregiver feedback are integral to the development and refinement of the DVA tool. The team behind the DVA has personal experiences and involvement with DMD trials, which has led to a deep understanding of the challenges faced by patients and families. This firsthand knowledge, combined with ongoing communication with patients, caregivers, and clinicians, ensures that the DVA addresses the most relevant and meaningful aspects of daily function for individuals with DMD. The input from these stakeholders helps shape the tool's design, functionality, and relevance to the DMD community. What potential benefits do you foresee in using the DVA as a primary endpoint in clinical trials for DMD? ​ ML: ​ Using the DVA as a primary endpoint in DMD clinical trials offers several significant benefits. Firstly, it provides a more sensitive and meaningful measure of patients' functional abilities, capturing subtle changes that may not be detected by traditional assessments. This enhanced sensitivity allows for a more accurate evaluation of the effectiveness of potential treatments, leading to more informed clinical decisions. Additionally, the DVA's home-based approach reduces the burden on patients and families, making participation in trials more accessible and feasible. By incorporating real-world experiences into the assessment process, the DVA offers a comprehensive view of patients' daily lives, guiding the development of therapies that improve quality of life. OSP: How do you anticipate the DVA's qualification by the FDA could impact the broader landscape of rare disease research and clinical trials? ​ ML: The qualification of the DVA by the FDA represents a significant milestone in the field of rare disease research and clinical trials. It sets a precedent for the use of video-based assessments as primary or secondary endpoints, paving the way for more innovative and patient-centric approaches to trial design. By acknowledging the unique challenges faced by rare disease populations and offering a solution that addresses these challenges, the FDA's qualification of the DVA opens doors for similar tools in other disease areas. This shift towards more meaningful and patient-relevant endpoints has the potential to revolutionize how rare diseases are studied and treated, leading to improved outcomes for patients worldwide. OSP: Could you elaborate on the challenges faced in measuring treatment effects in rare disease populations and how the DVA aims to address them? ​ ML: ​ Measuring treatment effects in rare disease populations presents several challenges, including the limited availability of validated outcome measures and the heterogeneity of patient experiences. Traditionally the endpoints were measured in a clinical setting where a patient is expected to perform a certain task to show treatment effect. These tasks are often standardized across disabilities and are not specific to neuromuscular disorders. Traditional endpoints may also not capture the full range of functional abilities and disease progression seen in rare diseases like DMD. The DVA addresses these challenges by providing a standardized, objective, and home-based assessment tool that quantifies daily function. It measures tasks which are more meaningful to the patient for example wearing their own T shirt or eating with a spoon. Through the utilization of video recordings, the DVA provides a more comprehensive perspective on patients' abilities over time. This allows clinicians and researchers to accurately track disease progression and treatment effects. Importantly, it all occurs in a familiar setting for the patient, where they feel most comfortable, without the added stress of travel and clinic visits. OSP: How has the reception been from patients, caregivers, and clinicians regarding the implementation of the DVA in clinical trials? ​ ML: ​ The reception to the DVA from patients, caregivers, and clinicians has been overwhelmingly positive. Patients and families appreciate the tool's ability to capture their daily experiences and functional abilities in a more meaningful way. For caregivers, the DVA offers a less burdensome and more accessible option for participating in clinical trials. Clinicians recognize the value of the DVA in providing objective and reliable data on patients' progress, enabling more informed treatment decisions. Overall, the implementation of the DVA has been met with enthusiasm and support from all stakeholders involved in DMD research and care. OSP: Are there any plans to expand the use of the DVA beyond DMD trials to other rare diseases or conditions? ​ ML: ​ If we take a step back here, the significance for the industry could be enormous, what we are doing will effectively create a precedent and roadmap for other ‘in home’ video assessment endpoints. So we are already looking at modeling a similar system in other trial and therapeutic areas – for example, Angelman Syndrome, Primary Myocardial Myopathies, and Limb Girdle Muscular Dystrophies. It’s difficult to put an exact number of trials but with the rise of remote studies this really could be a big number in the future that have small or larger parts of the patient experience monitored at home. For example, in areas like neuromuscular, and neurodevelopmental disorders, and even trials exploring areas like ALS, it’s easier to see how positive an impact it could have. OSP: Can you provide insights into the timeline for the FDA's review process of the DVA qualification plan and any subsequent steps expected? ​ ML: ​ This a great question, but not one we can answer on behalf of the FDA. However, we do expect feedback by July on the data submitted and, of course, the process from here is that we are collecting and analyzing further data over the next two years. The biggest significance of this is that our submission opens a discourse with the regulators about the potential for video-based outcomes to serve as a primary or secondary outcome in clinical trials. This is completely different from how video in trials is currently used, where until now it’s been used as just an anecdotal tool for applying pressure to regulators. The discourse will enable us to fully differentiate the robustness of what we’ve developed from these anecdotal methods. So it’s very much the first step, and a big one, toward the validation of video endpoints. We are building a tool with an end-to-end audit trail, video quality control, ‘rater’ training, and certification program, it’s a quantifiable methodology. OSP: What measures are in place to ensure the reliability and consistency of the DVA assessments conducted remotely? ​ ML: ​ The DVA incorporates several measures to ensure the reliability and consistency of assessments conducted remotely. These include rigorous training programs for raters who evaluate the video recordings, standardized protocols for conducting assessments, and quality control measures to monitor video recording and data collection. Additionally, the DVA's quantification methodology has been validated to ensure accurate and consistent results across different raters and settings. By adhering to strict guidelines and protocols, the DVA maintains the integrity of its assessments and provides reliable data for clinical trials. OSP: In your opinion, how might the incorporation of home-based assessments like the DVA influence the future design and conduct of clinical trials? ​ ML: ​ The incorporation of home-based assessments like the DVA has the potential to revolutionize the design and conduct of clinical trials, particularly in rare diseases. By bringing assessments directly into patients' everyday environments, these tools offer a more authentic and comprehensive view of their daily functions and experiences. This shift towards patient-centricity not only reduces the burden on patients and families but also improves the accuracy and relevance of trial outcomes. Additionally, home-based assessments enable more diverse and inclusive trial participation, as patients from different geographic locations can participate without the need for frequent travel. Overall, the use of home-based assessments like the DVA enhances the patient experience, increases the efficiency of trials, and leads to more meaningful and impactful results.

Typical symptoms include difficulty in running, jumping, and climbing stairs, with most patients requiring a wheelchair in their teenage years. However, the majority of clinical trials for the treatment of DMD rely on timed testing in the clinic, which doesn't necessarily reflect improvement in daily life function, and as such, could result in a lack of robust and sensitive data. Outsourcing Pharma ​ sat down with Christine McSherry, CEO Casimir, a part of Emmes, to understand how a new approach to designing clinical trial outcome measures. The focus is now on quantifying ease of movement rather than speed of movement and is probably more meaningful to patients and less subject to motivational factors, resulting in a truer picture of the trial efficacy. She notes that the cost of Duchenne clinical trial failure is significant, but says that what truly matters is the loss of valuable time experienced by thousands of families. She added tWith previous trial designs that didn’t fully consider the impact of disease heterogeneity – i.e. that a singular and often ‘pre-packed’ trial approach does not fit all patients – clinical outcomes often failed to capture nuanced and significant compensations in movement. McSherry, in addition to co-founding Casimir, is also a carer for a DMD patient, and therefore has first-hand experience of incorporating the patient's viewpoint into clinical research. In fact, she has been supporting families affected by DMD through programming, educational opportunities and ongoing support since 2002. Her experiences are littered with the frustrations of current DMD clinical trial designs, and it ultimately led her to co-found Casimir with another DMD advocate Mindy Leffler. googletag.cmd.push(function () { googletag.display('text-ad1'); }); The thesis of their partnership, they said, was that, with a little flexibility in approach, they could design less intrusive options that would not only improve the patient experience but also produce more reliable outcomes and in turn better treatments. They wanted to prove that virtual trials and home-based assessments did have the potential to breakdown the centralized site-driven organization of clinical trials and shift assessments to the home environment. They believe this then raises the possibility for more meaningful and less burdensome assessments of function, eliminating the need for patients and their families to travel to trial sites, as frequently, and minimizing disruption to their regular routines. OSP: Can you explain what the Duchenne video assessment (DVA) is? ​ McSherry: ​ Put simply DVA is a method of evaluating changes in motor function in patients using videos of patients performing specific tasks at their homes, and the DVA tasks are assigned per functional cohort (severity of the disease). The idea is that the caregiver can record and upload video recordings with the help of an app in natural (real world) settings. The videos are quality-controlled by data monitors and given centralized scoring by certified ‘raters’ – for example, physical therapists familiar with Duchene patients mobility challenges. To give a few examples, the list of specified real-world tasks can range from the ability put on or take off a T-shirt, to raising hands above head, jumping forward, eating 10 bites of food or rolling over in bed. These criteria therefore assess a patient's habitual way of performing meaningful tasks and in turn remove confounds related to travel fatigue, vacation mode, unfamiliar assessors/environment. OSP: How does a real-world assessment help deliver usable trial data? ​ McSherry: ​ DVA trials offer several advantages over traditional clinical outcome assessments, such as physical exams conducted at the clinic, which include timed function testing. The gold standard, North Star Ambulatory Assessment, involves activities like timed running and standing on heels as outcome measures. However, we have learned that performing activities quickly may not necessarily reflect real-world meaningfulness. Instead, we should consider activities such as feeding oneself, repositioning in bed, and moving arms on and off armrests, which can enable individuals to live independently at home.” OSP: What are the advantages in trial design and do they lead to increased specificity of parameters. ​ McSherry: ​ In short yes – absolutely. The reason it is so applicable is that it enables a more objective and standardized assessment of motor function, allowing for the detection of even subtle changes that may not be apparent during a physical exam when evaluating primary or secondary desired endpoints or outcome measures. This means vital improvements in the patient’s condition that were being missed or would go unrecorded in terms of their relevance to a prospective therapy’s approval are also registered. Our hope is that sponsors will also recognise this and be encouraged to use it – it’s really a win-win scenario. We have focussed largely – and rightly – on the patients, but DVA approach also brings tremendous efficiencies as well and reduces the clinical resource need to conduct the trials– put in simple terms it means we can monitor more frequently if the sponsor desires, but also we can capture patients in their own environment, where they feel, function and survive. OSP: Can you give any details of DVA being used in active trials? ​ McSherry: ​ It’s currently being used in nine of Casimir’s clinical trials to assess the efficacy of potential treatments for DMD and for determining any benefit, stabilization and possible progession in the disorder. Additionally, there are development programs underway for other neurodevelopmental indications, including Limb Girdle Muscular Dystrophies, Primary Myocardial Myopathies, and Angelman Syndrome, among others. The potential new disease targets for DVA include Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, Myotonic Dystrophy, and GM1 Gangliosidosis. In fact, DVA has now also been accepted into the FDA’s Initiative with Critical Pathway Institute to be qualifited as an outcome measure for Duchenne. But perhaps, the most significant breakthrough for DVA to date was when Capricor Therapeutics announced it would be using one of the tasks, eat 10 bites, as a secondary outcome measure in the HOPE 3 clinical trial ​. HOPE-3 is a cell-based therapy for DMD, and the study is expected to recruit up to 68 patients. Earlier this year, qualitative interviews with physical therapists to select movement tasks for DVA were published in Physiotherapy Research International ​, marking an important milestone in DVA development. This publication provided peer-reviewed scrutiny of the selection of the movement tasks that comprise the DVA. It, along with other upcoming publications, will be a key component of the information needed for the FDA qualification package to apply for approval and adaptation of the tool in practice for all DMD trials in the future. OSP: Do you have a closing message to other sponsors involved in similar trials? ​ McSherry: ​ It’s become an industry cliché, but to involve the patient and take the feedback from those in the field – in the case of conditions like this, that often means the family and carers. We have all the technology now to do this, we just need a wider acceptance and familiarity for digital video assessments to become the de facto ​ approach in neuromuscular diseases. The most important perspective is that it allows for the integration of the patient experience into the trials and turns this into a positive clinical data point. Unlike other digital measures, the DVA captures meaningful functional data that can be quantified for regulatory review. The most important aspect of any outcome measure should reflect what is most important to patients and their families. We have found that rare disease patients, specifically those with neuromuscular disorders, really want to be like everyone else and not different. Therefore, the two most impactful concepts of interest are independence and socialization. Patients and their families are most affected by the disease and have first-hand experience of the challenges and limitations that the disease imposes on their daily lives. Incorporating this vital viewpoint or data into the trial design allows for more meaningful assessments of function and better treatments. What is most exciting to me is that while we started with DMD the possibilities now are incredibly diverse and obviously other rare neuromuscular diseases will be ‘low hanging fruit’.

Robust and sustained efficacy in both adult PKD patients up to 30 months post-RP-L301; first pediatric patient results suggest efficacy similar to adult cohort with initial greater than five-point increase in hemoglobin Sustained genetic correction observed in eight of 12 evaluable Fanconi Anemia patients, and phenotypic correction and concomitant hematologic stabilization observed in seven of 12 patients 12-42 months after RP-L102 in Phase 2 pivotal trial 100% overall survival at 12 months post-RP-L201 and favorable safety pro all LAD-I patients with 12-24 months of follow-up Robust preclinical proof of concept studies showed RP-A601 for PKP2-ACM decreased arrhythmias and increased survival CRANBURY, N.J.--(BUSINESS WIRE)-- Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT), a leading late-stage biotechnology company advancing an integrated and sustainable pipeline of genetic therapies for rare disorders with high unmet need, today announced positive data from the Pyruvate Kinase Deficiency (PKD), Fanconi Anemia, Severe Leukocyte Adhesion Deficiency-I (LAD-I) and Danon Disease clinical programs and PKP2-arrhythmogenic cardiomyopathy (PKP2-ACM) preclinical program presented at the 26th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Los Angeles, California. “I am pleased that we continue to deliver outstanding clinical results that highlight the momentum across both our LV hematology and AAV cardiovascular platforms,” said Jonathan Schwartz, M.D., Chief Gene Therapy Officer, Rocket Pharma. “The first pediatric PKD patient in our Phase 1 trial demonstrated initial hemoglobin increase of more than five points, and additional patients in our pivotal Fanconi Anemia trial have demonstrated robust engraftment and hematologic stabilization. All patients in the LAD-I pivotal trial continue to demonstrate improvements in clinical parameters. Regarding RP-A501, as of May 2023, all six patients with ongoing follow-up in the Danon Phase 1 trial continue to demonstrate improvements or stabilization at a time when these patients would most likely experience progressive disease or death.” Dr. Schwartz continued, “In addition, after recently receiving IND clearance from the FDA, we are excited to present robust preclinical proof of concept data from our PKP2-ACM program for the first time at a scientific meeting. PKP2-ACM is a devastating disease that is a frequent cause of sudden cardiac death and represents a significant unmet need given the limited and non-curative treatment options available to patients. Our data demonstrate decreased arrhythmias, improved cardiac structure and function, and increased survival; these results, and our rapid advancement to the first clinical gene therapy trial for PKP2-ACM, showcase our proven and consistent ability to elevate gene therapy research and our dedication to bringing these therapies to patients who need them most.” Global Phase 1 Study Results of Lentiviral Mediated Gene Therapy for Severe Pyruvate Kinase Deficiency (PKD) The oral presentation includes positive updated data (cut-off May 3, 2023) from two adult patients followed up to 30 months and encouraging early data from the first pediatric patient treated with RP-L301, Rocket’s ex vivo lentiviral gene therapy candidate for Pyruvate Kinase Deficiency (PKD). Robust and sustained efficacy in both adult patients up to 30 months post-infusion demonstrated by normalized hemoglobin (from baseline levels in the 7.0-7.5 g/dL range), improved hemolysis parameters, and red blood cell transfusion independence. Both adult patients reported improved quality of life with documented improvements via formal quality of life assessments. The safety pro highly favorable, with no RP-L301-related serious adverse events in either of the adult patients. Previously reported transient transaminase elevation seen in both adult subjects post conditioning and infusion with no clinical stigmata of liver injury have fully resolved. Insertion site analyses in peripheral blood and bone marrow in both adult patients through 24 months post-RP-L301 demonstrated highly polyclonal patterns and there has been no evidence of insertional mutagenesis. First pediatric results suggest similar efficacy as observed in long-term efficacy data in the adult cohort. The first pediatric patient infusion of RP-L301 was well tolerated, with engraftment achieved at day +15, hospital discharge less than one month following infusion, and no RP-L301-related serious adverse events. Hemoglobin normalized six weeks post-infusion and measured 13.4 g/dL at eight weeks (from median baseline of 7.9 g/dL). There were no red blood cell transfusion requirements following engraftment. Adult and pediatric enrollment is completed in the Phase 1 study. Phase 2 pivotal trial initiation is anticipated in the fourth quarter of 2023. Lentiviral-Mediated Gene Therapy for Fanconi Anemia [Group A]: Results from Global RP-L102 Clinical Trials The oral presentation includes positive, updated data (cut-off April 17, 2023) from the ongoing Phase 2 pivotal trial of RP-L102, Rocket’s ex vivo lentiviral gene therapy candidate for Fanconi Anemia (FA). RP-L102 conferred sustained genetic correction in eight of 12 evaluable patients and comprehensive phenotypic correction in seven of 12 evaluable patients with ≥12 months of follow up as demonstrated by increased resistance to mitomycin-C (MMC) in bone marrow (BM)-derived colony forming cells and hematologic stabilization. The safety pro RP-L102 remains highly favorable with no significant safety signals, and the treatment, administered without any cytotoxic conditioning, continues to be well tolerated. No signs of bone marrow dysplasia, clonal dominance or insertional mutagenesis related to RP-L102 have been observed. Polyclonal integration patterns have been observed in each of the seven patients with phenotypic, genetic, and hematologic evidence of engraftment. Pivotal trial enrollment and treatment have been completed, and the final two patients have been treated with commercial drug product in preparation for launch. Based on the positive efficacy and safety data from the Phase 2 pivotal FA trial, Rocket anticipates filing the Biologics License Application (BLA) with the FDA in the fourth quarter of 2023. Autologous Ex Vivo Lentiviral Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I): Interim Results from an Ongoing Phase 1/2 Study The poster presentation includes positive, updated top-line data (cut-off November 2, 2022) at 12 to 24 months of follow-up after RP-L201 infusion for all nine patients. RP-L201 is Rocket’s ex vivo lentiviral gene therapy candidate for severe Leukocyte Adhesion Deficiency-I (LAD-I). Observed 100% overall survival at 12 months post-infusion via Kaplan Meier estimate for all nine LAD-I patients with 12 to 24 months of available follow-up. Data also showed evidence of resolution of LAD-I-related skin rash and restoration of wound repair capabilities. The safety pro RP-L201 was highly favorable in all patients with no RP-L201-related serious adverse events to date. Adverse events related to other study procedures, including busulfan conditioning, have been previously disclosed and are consistent with the safety profiles of those agents and procedures. Based on the positive efficacy and safety data from the Phase 2 pivotal LAD-I trial, Rocket anticipates filing the Biologics License Application (BLA) with the FDA during this second quarter of 2023. Danon Disease Phase 1 RP-A501 Results: The First Single-Dose Intravenous (IV) Gene Therapy with Recombinant Adeno-Associated Virus (AAV9:LAMP2B) for a Monogenic Cardiomyopathy The spotlight oral presentation includes positive, previously disclosed data (cut-off July 11, 2022) in patients followed for up to 36 months in the ongoing Phase 1 clinical trial of RP-A501, Rocket’s investigational AAV gene therapy for Danon Disease. The presentation includes data from patients treated with the low dose (6.7 x 1013 GC/kg) in the pediatric (n=2) and adolescent/young adult (n=3) cohorts, and the high-dose (1.1 x 1014 GC/kg) adolescent/young adult cohort (n=2). As previously disclosed, RP-A501 was associated with favorable safety at the low dose with an appropriate immunomodulatory regimen. There have been no RP-A501-related or steroid-related serious adverse events reported to date in the pediatric cohort. Efficacy results continue to demonstrate sustained improvement or stabilization in all patients with preserved left ventricular systolic function at time of treatment (n=6, across all cohorts) across key clinical, biomarker, echocardiographic, and quality of life parameters. Improvement or stabilization of disease progression in these patients treated with RP-A501, as measured by natriuretic peptides, is in direct contrast to progressive worsening observed over three to 30 months in patients in the prospective natural history study. As of the presentation, all six patients that remain in follow-up continue to show signs of improvement or stabilization; additional follow-up data to be provided at a future date. The Phase 2 pivotal trial of RP-A501 for Danon Disease remains on track for initiation during this second quarter of 2023. Preclinical Efficacy of AAVrh.74-PKP2a (RP-A601): Gene Therapy for PKP2-associated Arrhythmogenic Cardiomyopathy The late-breaking abstract presentation includes robust preclinical proof of concept for RP-A601, Rocket’s investigational AAV gene therapy for the treatment of arrhythmogenic cardiomyopathy due to plakophilin 2 pathogenic variants (PKP2-ACM), a devastating inherited heart disease that can lead to life-threatening arrhythmias, cardiac structural abnormalities, and sudden cardiac death. PKP2-ACM affects approximately 50,000 people in the U.S. and Europe. The current standard of care for patients with PKP2-ACM consists of medical therapy, implantable cardioverter defibrillators (ICDs), and ablations, which are not curative. Even with treatment, life-threatening arrhythmias and progression of disease still occur. Preclinical proof of concept from a translationally relevant animal model has been demonstrated following Rocket-sponsored studies with academic partners. The preclinical studies with a cardiomyocyte-specific PKP2 knockout mouse model of ACM evaluated initial proof of concept and dose-related effects of AAV vectors (RP-A601), including survival, functional and anatomic benefits. Notably, the studies evaluated the delivery of RP-A601 at seven- and 14-days following induction of PKP2 knockout and subsequent disease onset. Results demonstrated increased survival and preserved cardiac function in the PKP2 knockout mouse model following administration of RP-A601. 100% of adult PKP2 knockout mice receiving RP-A601 seven days after knockout induction demonstrated survival to the five-month duration of evaluation, compared to 100% mortality by approximately day 50 in PKP2 knockout mice receiving formulation control. PKP2 knockout mice receiving RP-A601 displayed preserved ejection fraction and right ventricular area at 28 days, sustained to five months. Fourteen days following RP-A601 administration, PKP2 knockout mice demonstrated robust survival with a similar degree of cardiac benefit through five months. RP-A601 was also associated with mitigation of isoproterenol-induced premature ventricular contractions (PVCs) and arrhythmias, which are major morbidity components of ACM. Based on robust preclinical proof of concept that has demonstrated decreased arrhythmias and increased survival and the completion of extensive IND-enabling toxicology studies, Rocket has received IND clearance from the FDA for a Phase 1 study of RP-A601 that will assess the impact of RP-A601 on PKP2 myocardial protein expression, cardiac biomarkers, and clinical predictors of life-threatening ventricular arrhythmias and sudden cardiac death. Rocket is initiating Phase 1 study start-up activities and rapidly advancing the first investigational gene therapy for PKP2-ACM into the clinic. About Pyruvate Kinase Deficiency Pyruvate Kinase Deficiency (PKD) is a rare, monogenic red blood cell disorder resulting from a mutation in the PKLR gene encoding for the pyruvate kinase enzyme, a key component of the red blood cell glycolytic pathway. Mutations in the PKLR gene result in increased red blood cell destruction and the disorder ranges from mild to life-threatening anemia. PKD has an estimated prevalence of 4,000 to 8,000 patients in the U.S. and Europe. Children are the most commonly and severely affected subgroup of patients. Patients with PKD have a high unmet medical need, as currently available treatments include splenectomy and red blood cell transfusions, which are associated with immune defects and chronic iron overload. Recently, mitapivat, an oral enzyme activator, was approved for use in adult patients, however its efficacy is limited in more severely-afflicted patients, most notably in those who are splenectomized, transfusion-dependent, or whose disease results from deleterious mutations. RP-L301 was in-licensed from the Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD). About Fanconi Anemia Fanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations, and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a Fanconi Anemia complementation group A (FANCA) gene mutation, which encodes for a protein essential for DNA repair. Mutations in the FANCA gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Increased sensitivity to DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is a ‘gold standard’ test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patient’s blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as ‘natural gene therapy’ provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells. There is a high unmet medical need for patients with FA. About Leukocyte Adhesion Deficiency-I Severe Leukocyte Adhesion Deficiency-I (LAD-I) is a rare, autosomal recessive pediatric disease caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18. CD18 is a key protein that facilitates leukocyte adhesion and extravasation from blood vessels to combat infections. As a result, children with severe LAD-I are often affected immediately after birth. During infancy, they suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon. There is a high unmet medical need for patients with severe LAD-I. Rocket’s LAD-I research is made possible by a grant from the California Institute for Regenerative Medicine (Grant Number CLIN2-11480). The contents of this press release are solely the responsibility of Rocket and do not necessarily represent the official views of CIRM or any other agency of the State of California. About Danon Disease Danon Disease is a rare X-linked inherited disorder caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2), an important mediator of autophagy. This results in accumulation of autophagosomes and glycogen, particularly in cardiac muscle and other tissues, which ultimately leads to heart failure, and for male patients, frequent death during adolescence or early adulthood. It is estimated to have a prevalence of 15,000 to 30,000 patients in the U.S. and Europe. The only available treatment option for Danon Disease is cardiac transplantation, which is associated with substantial complications and is not considered curative. There are no specific therapies available for the treatment of Danon Disease. There is a high unmet medical need for patients with Danon Disease. About PKP2-Arrhythmogenic Cardiomyopathy (PKP2-ACM) PKP2-ACM is an inherited heart disease caused by mutations in the PKP2 gene and characterized by life-threatening ventricular arrhythmias, cardiac structural abnormalities, and sudden cardiac death. PKP2-ACM affects approximately 50,000 adults and children in the U.S. and Europe. Patients living with PKP2-ACM have an urgent unmet medical need, as current medical, implantable cardioverter defibrillator (ICD), and ablation therapies do not consistently prevent disease progression or arrhythmia recurrence, are associated with significant morbidity including inappropriate shocks and device and procedure-related complications, and do not address the underlying pathophysiology or genetic mutation. RP-A601 is being investigated as a one-time, potentially curative gene therapy treatment that may improve survival and quality of life for patients affected by this devastating disease. About Rocket Pharmaceuticals, Inc. Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) is advancing an integrated and sustainable pipeline of investigational genetic therapies designed to correct the root cause of complex and rare disorders. The Company’s platform-agnostic approach enables it to design the best therapy for each indication, creating potentially transformative options for patients afflicted with rare genetic diseases. Rocket's clinical programs using lentiviral vector (LV) based gene therapy are for the treatment of Fanconi Anemia (FA), a difficult to treat genetic disease that leads to bone marrow failure and potentially cancer, Leukocyte Adhesion Deficiency-I (LAD-I), a severe pediatric genetic disorder that causes recurrent and life-threatening infections which are frequently fatal, and Pyruvate Kinase Deficiency (PKD), a rare, monogenic red blood cell disorder resulting in increased red cell destruction and mild to life-threatening anemia. Rocket’s first clinical program using adeno-associated virus (AAV)-based gene therapy is for Danon Disease, a devastating, pediatric heart failure condition. Rocket also has preclinical AAV-based gene therapy programs in PKP2-arrhythmogenic cardiomyopathy (ACM) and BAG3-associated dilated cardiomyopathy (DCM). For more information about Rocket, please visit . Rocket Cautionary Statement Regarding Forward-Looking Statements Various statements in this release concerning Rocket’s future expectations, plans and prospects, including without limitation, Rocket’s expectations regarding the safety and effectiveness of product candidates that Rocket is developing to treat Fanconi Anemia (FA), Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), Danon Disease (DD) and other diseases, the expected timing and data readouts of Rocket’s ongoing and planned clinical trials, the expected timing and outcome of Rocket’s regulatory interactions and planned submissions, Rocket’s plans for the advancement of its Danon Disease program, including its planned pivotal trial, and the safety, effectiveness and timing of related pre-clinical studies and clinical trials, may constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 and other federal securities laws and are subject to substantial risks, uncertainties and assumptions. You should not place reliance on these forward-looking statements, which often include words such as “aim,” “anticipate,” "believe," “can,” “continue,” “design,” “estimate,” "expect," "intend," “may,” "plan," “potential,” "will give," "seek," "will," "may," "suggest" or similar terms, variations of such terms or the negative of those terms. Although Rocket believes that the expectations reflected in the forward-looking statements are reasonable, Rocket cannot guarantee such outcomes. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Rocket’s ability to monitor the impact of COVID-19 on its business operations and take steps to ensure the safety of patients, families and employees, the interest from patients and families for participation in each of Rocket’s ongoing trials, patient enrollment, trial timelines and data readouts, our expectations regarding our drug supply for our ongoing and anticipated trials, actions of regulatory agencies, which may affect the initiation, timing and progress of pre-clinical studies and clinical trials of its product candidates, our ability to submit regulatory filings with the U.S. Food and Drug Administration (FDA) and to obtain and maintain FDA or other regulatory authority approval of our product candidates, Rocket’s dependence on third parties for development, manufacture, marketing, sales and distribution of product candidates, the outcome of litigation, our competitors’ activities, including decisions as to the timing of competing product launches, pricing and discounting, our integration of an acquired business, which involves a number of risks, including the possibility that the integration process could result in the loss of key employees, the disruption of our ongoing business, or inconsistencies in standards, controls, procedures, or policies, our ability to successfully develop and commercialize any technology that we may in-license or products we may acquire and any unexpected expenditures, as well as those risks more fully discussed in the section entitled "Risk Factors" in Rocket’s Annual Report on Form 10-K for the year ended December 31, 2022, filed February 28, 2023 with the SEC and subsequent filings with the SEC including our Quarterly Reports on Form 10-Q. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and Rocket undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise. View source version on businesswire.com: Contacts Media Kevin Giordano kgiordano@rocketpharma.com Investors Brooks Rahmer investors@rocketpharma.com Source: Rocket Pharmaceuticals, Inc. View this news release online at: