Slide 1: Danon Disease Program Update
S E E K I N G G E N E T H E R A P Y C U R E S Rocket Pharmaceuticals Danon Disease Program Update September 11, 2023 1 CONFIDENTIAL AND PROPRIETARY
Slide 2: Disclaimer
Disclaimer 1 CONFIDENTIAL AND PROPRIETARY Various statements in this presentation 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 Danon Di
Slide 3: Danon Disease: Aggressive genetic hypertrophic cardiomyopathy
Danon Disease Aggressive genetic hypertrophic cardiomyopathy with very high early mortality Danon Disease is the most aggressive and lethal hypertrophic cardiomyopathy Monogenic, X-linked disease progresses to severe cardiomyopathy at early ages; characterized by massive LV hypertrophy and end-stage
Slide 4: Natural History: Progression of Danon Disease in Male Patients
Natural History: Progression of Danon Disease in Male Patients Birth to 7 yrs NYHA Class I Muscle pain, lack of energy Learning difficulties HF symptoms (rare) Identification by incidental genetic testing or family history Death avg age: 19 years 8-14 yrs NYHA Class I-II HCM & genetic diagnosis Wors
Slide 5: Phase 1 Data: Benefit Observed Across All Key Clinical Parameters
Phase 1 Data: Benefit Observed Across All Key Clinical Parameters Early LAMP2, BNP, TnI changes associated with sustained clinical improvement and guided Phase 2 endpoint selection Does not include pt 1007 in Ph1 trial who had advanced HF with EF<40% at enrollment and received HTx 5M following tx du
Slide 6: Latest Pediatric Data Shows Sustained Improvements
Latest Pediatric Data Shows Sustained Improvements in Biomarkers, Symptoms, and Function (Updated Data) Variable Baseline2 Most Recent Follow-up LAMP2 protein3 0 1 (M6) Troponin-I (ng/mL) 0.67 0.08 (-88%) BNP (pg/mL) 297 163 (-45%) NYHA Class II I LV Mass Index 83 60 (-28%)4 12 months AGE AT INFUSIO
Slide 7: FDA Engagement and Alignment on Danon Program
Pivotal, single-arm study Peds safety run-in Dosage (6.7x1013 GC/kg) Safety protocol & management plan CMC (product comparability and potency assay) NHS to serve as external comparator RMAT designation granted F2F meeting with review team and senior FDA leadership Co-primary endpoint t
Slide 8: Phase 2 Trial Design
Phase 2 Trial Design – 12 Patients with 12-month Primary Endpoint Duration Dose: 6.7 x 1013 GC/kg of commercially representative RP-A501 material Initial n=2 peds followed for 90 days for key AAV-associated toxicities prior to subsequent ped pt enrollment Key eligibility criteria: male age ≥8y, LAMP
Slide 9: Prospective, Retrospective Natural History Study as External Comparator
9 HTx, heart transplant; LVEF, LVEF, left ventricle ejection fraction. US Retrospective Natural History 9 Males 1 Female 51 Males 21 Males 38 Females Initiated in 2019, study complete Initiated in 2006 Enrollment complete; analysis in Q4 2023 67 Females Prospective Natural History Study EU Retrospec
Slide 10: Totality of Evidence to Demonstrate Treatment Effect
10 Transplant-free survival Totality of Evidence to Demonstrate Treatment Effect Baseline 12 Months 18 Months 24 Months Beyond 24-36 Months HF Hospitalizations Heart Transplant Death Phase 2 RP-A501 Treated Patients External Comparator Natural History (Untreated Patients) Each patient’s baseline AND
Slide 11: Co-Primary Endpoints for Accelerated Approval
Co-Primary Endpoints for Accelerated Approval 11 CONFIDENTIAL AND PROPRIETARY CONFIDENTIAL AND PROPRIETARY
Slide 12: Primary Endpoint Is Reasonably Likely to Predict Clinical Benefit
12 Primary Endpoint Is Reasonably Likely to Predict Clinical Benefit Justification for use of LAMP2 protein expression and LV Mass Mutation of LAMP2 is root cause of Danon disease Epidemiologic support: even modest levels of LAMP2 confer a 2-decade survival advantage in female patients RP-A501 deliv
Slide 13: Mechanistic Pathway: Protein Expression to Cardiac Structure to Clinical Outcomes
Mechanistic Pathway: Protein Expression to Cardiac Structure to Clinical Outcomes Improvements Across Cellular, Cardiac Imaging and Functional Measures in Phase 1 Study Molecular Expression Cellular Structure Cardiac Structure and Function Clinical Status Endomyocardial Bx: LAMP2 protein expression
Slide 14: LAMP2 mutation is the root cause of Danon disease pathology
LAMP2 mutation and associated protein deficit is the root cause of Danon disease pathology Grade ≥1 LAMP2 correlates with evidence of efficacy in Ph1 Absent expression at baseline (Grade 0) in all male patients Improved cardiac biomarkers & hypertrophy, PRO/QOL and NYHA Class – sustained to 3+ years
Slide 15: RP-A501 Increases LAMP2 Protein and Decreases Vacuolization
Rocket AHA 2022 Poster Presentation reflects September 27, 2022 data cutoff. LAMP2, lysosome associated membrane protein 2; M, month. IHC = immunohistochemistry RP-A501 Increases LAMP2 Protein and Decreases Vacuolization Enhanced autophagy leads to improved myocardial ultrastructure and clinical phe
Slide 16: Left Ventricle Mass as Co-Primary Endpoint
Left Ventricle Mass as Co-Primary Endpoint Danon Disease is fundamentally a disease of enlarged hearts; the largest known hearts have been from Danon patients Left ventricular hypertrophy is the most consistent phenotypic feature of disease progression Left ventricular wall thickness has been shown
Slide 17: LVH Predicts Clinical Outcomes in HF and Cardiomyopathies
LVH Predicts Clinical Outcomes in HF and Cardiomyopathies 17 CONFIDENTIAL AND PROPRIETARY Shah A, JACC 2019; de Simone G. Eur Heart J. 2008; Liu, Q, Scientific Reports, 2016; Orsborne C, JACC, 2022; Hanneman K. Radiology. 2020 Cardiomyopathy or CVD Measure of LVH Event HR; CI; p value HFpEF (Shah 20
Slide 18: LV Mass Index in RP-A501 Phase 1 Study
LV Mass Index in RP-A501 Phase 1 Study RP-A501 Phase 1 Low-Dose Cohort: LV Mass Index % Change from Baseline1 Baseline 6M 9M 12M 18M 24M 30M -55% -50% -45% -40% -35% -30% -25% -20% -15% -10% -5% 0% 36M 1002 1005 1008 1009 1 Does not include patient 1001 (unmonitored immunomodulation). 212M visit dat
Slide 19: LV Mass / LV Mass Index Improves in DD with RP-A501
Fabry Disease (Agalsidase alfa) LV Mass @6M 8.8% -4.1% Clinical Correlation: Improvements in LVM out to 36M correlated with HF symptoms (NYHA, CCS); drug approved in EU Amyloid Cardiomyopathy (Patirisan) LV Mass @18M <1% -5.6% Clinical Correlation: Drug approved based on improved CV outcomes @30M Si
Slide 20: LV Mass in RP-A501 Low-Dose Cohort Versus Recently Approved CV Therapies
LV Mass in RP-A501 Low-Dose Cohort Versus Recently Approved CV Therapies -30% -20% -10% 0% 10% Baseline ≤18M DD RP-A501 Tx1 (9-18M); -22% DD RP-A501 Tx1 (30-36M); -36% 30-36M Fabry – Agalsidase Alfa Untreated (6M); +9% DD UnTx @12M (Estimated based on Retro NxHx2); +8% Amyloidosis – Tafamidis Treate
Slide 21: Cardiac Imaging Captures the Progression of Danon Disease
* Unpublished data from International Danon Disease Registry 21 Cardiac Imaging Captures the Progression of Danon Disease Significant Increases in LV Mass and LV Wall Thickness Correlate with Age Trends in LV Mass LV Mass increased by 39.86 ± 4.01 g per year Left ventricular mass [g] r2= 0.846 Age (
Slide 22: Significant and Sustained Reduction in Troponin
Note: Upper limit of normal 0.04 ng/mL, BL = baseline 22 Significant and Sustained Reduction in Troponin (Key Secondary Endpoint) Observed Across Patients in Phase 1 Study Phase 1 Trial: RP-A501 Treatment Conferred Improvement in Troponin-I Levels (ng/mL) 2.00 1.80 1.60 1.40 1.20 1.00 0.80 0.60 0.40
Slide 23: Current Status and Next Steps
Current Status and Next Steps 22 CONFIDENTIAL AND PROPRIETARY CONFIDENTIAL AND PROPRIETARY
Slide 24: Ongoing Danon Global Phase 2 Study Activities
Ongoing Danon Global Phase 2 Study Activities RMAT, Fast Track, Orphan Drug Designations IRB approval at UCSD, CHOP; sites activated Multiple GMP lots manufactured in-house; sufficient drug product produced for full pivotal trial Global natural history study underway FDA alignment on design Initiate
Slide 25: Rocket Pipeline: Disclosed Programs Across Two Platforms
Rocket Pipeline: 6 Disclosed Programs Across Two Platforms with Compelling Clinical and/or Pre-clinical Proof of Concept On-target MOA; clear endpoints Sizeable market to maximize patient impact First-, best- and/or only-in- class Criteria used to 6+ programs with 2 programs fast approaching commerc