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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 20549

FORM 8-K

CURRENT REPORT
Pursuant to Section 13 OR 15(d) of The Securities Exchange Act of 1934

Date of Report (Date of earliest event reported):  September 30, 2022

Rocket Pharmaceuticals, Inc.
(Exact name of registrant as specified in its charter)


Delaware
001-36829
04-3475813
(State or other jurisdiction of incorporation)
(Commission File Number)
(IRS Employer Identification No.)


9 Cedarbrook Drive, Cranbury, NJ
 
08512
(Address of principal executive offices)
 
(Zip Code)


Registrant’s telephone number, including area code:  (646) 440-9100


Not applicable
(Former name or former address, if changed since last report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2):

☐
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class
 
Trading
Symbol(s)
 
Name of each exchange on which
registered
Common stock, $0.01 par value
 
RCKT
 
The Nasdaq Global Market

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Item 8.01
Other Events

On September 30, 2022, Rocket Pharmaceuticals, Inc. (the “Company”) announced positive clinical updates from its Phase 1 Danon Disease Trial for RP-A501 through an oral poster session at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2022. This included updated safety and efficacy data from patients in the pediatric and adult cohorts which demonstrate that RP-A501 was generally well tolerated and conferred clinical benefit.

Safety Profile of the First Pediatric Cardiomyopathy Gene Therapy Trial: RP-A501 (AAV9:LAMP2B) for Danon Disease and Extended Results from Phase 1

The data described in this oral poster presentation (data cut-off September 27, 2022 for pediatric patients, and August 19, 2022 for adult patients, with source data verification through July 11, 2022) and in this report are from the ongoing first-in-human Phase 1 clinical trial evaluating a single intravenous infusion of RP-A501, the Company’s investigational gene therapy for the treatment of Danon Disease. The presentation includes early efficacy data with updated safety data from the low-dose (6.7 x 1013GC/kg; n=2) pediatric cohort, as well as updated efficacy and safety data from young adult and adolescent patients in the low-dose (6.7 x 1013 GC/kg; n=3) and high-dose (1.1 x 1014 GC/kg; n=2) cohorts.

•
Early pediatric efficacy data were consistent with initial improvements observed in adult patients at a similar timeframe of up to nine months follow-up and sustained clinical benefit across biomarker, clinical and functional parameters in currently enrolled adult patients at 24 to 30 months of follow-up.
o
Gene expression: In the pediatric cohort, LAMP2B gene expression by immunohistochemistry was 21.1% in patient 1008 at six months and 34.7% in patient 1009 at three months. Evidence of durable and meaningful cardiac LAMP2B protein expression as read at a centralized core lab was achieved in all patients across pediatric and adult cohorts at three months and sustained through six to nine months in the pediatric cohort and 24 months in the adult cohorts in patients with a closely monitored immunomodulatory regimen.
•
The following assays were performed and reported for patients with at least six months of follow-up.
o
Vacuolar area: In the first pediatric patient, vacuolar area as assessed by an automated method in representative biopsy samples was found to have decreased by 77% at six months. Six-month biopsy results were not yet available for the second pediatric patient. All adult patients showed meaningful decreases in vacuolar area ranging from 26% to 74% at most recent available timepoints.
o
Brain natriuretic peptide (BNP): In the pediatric cohort, BNP, a key marker of heart failure, decreased from a pretreatment baseline by 78% in patient 1008 at nine months and by 62% in patient 1009 at six months. The majority of patients in the pediatric and adult cohorts showed stabilization or meaningful decreases in BNP, with the most dramatic decreases observed in patients with higher baseline BNP (90% for patient 1002 in the adult cohort at 30 months and 78% for patient 1008 in the pediatric cohort at nine months). The four currently enrolled adult patients demonstrated reduction in BNP of greater than 75% from mean pretreatment baseline compared to mean values at 18 to 24 month timepoints.
o
Troponin: The pediatric patients, despite a more limited six and nine months of follow-up, were observed to have meaningful decreases in high sensitivity troponin I (hsTnI), a protein in the blood showing signs of cardiac injury, of 90% and 85%, respectively. Patients in the adult cohorts demonstrated significant decreases in hsTnI. Notably, the two adult patients were observed to have a reduction in troponin of greater than 75% from mean pretreatment baseline to mean values at 18 to 24 months that was sustained in the two adult patients who are currently 30 to 36 months post-treatment.
o
New York Heart Association (NYHA) Class: In the pediatric cohort, an improvement (from Class II to I) in NYHA class, a measure of the symptoms and functional limitations resulting from heart failure, was observed in both patients. In the adult cohorts, all three patients treated with a closely monitored immunomodulatory regimen showed improvement in NYHA class. Stabilization of NYHA class was observed in one adult patient treated at the low dose without a closely monitored regimen.
o
Kansas City Cardiomyopathy Questionnaire (KCCQ): Patients in the pediatric cohort showed significant improvement in KCCQ Overall Score, a measure (0-100) of physical and social limitations, symptoms and quality of life in patients with heart failure. Specifically, patient 1008 demonstrated improvement from a pretreatment baseline of 50 to 93 at nine months and patient 1009 demonstrated improvement from a pretreatment baseline of 52 to 81 at three months. All patients treated in pediatric and adult cohorts with a closely monitored immunomodulatory regimen showed improvements ranging between three and 43 points when comparing baseline to the most recent available timepoint.
o
Left ventricular (LV) wall thickness: In the pediatric cohort, patient 1008 demonstrated reduction in maximum LV wall thickness by 3% from treatment baseline after six months of follow-up. In the adult cohort, three patients demonstrated a reduction of greater than 15% and greater than 15% from mean baseline in both LV posterior wall thickness in diastole and maximum LV wall thickness, respectively, compared to mean values at 18 to 24 months, which represents improvement of the ventricular hypertrophy.
•
RP-A501 was observed to be generally well tolerated at the low dose with a manageable tolerability profile across pediatric and adult cohorts.
o
In the pediatric cohort, RP-A501 was well tolerated in both patients with six to eleven months follow-up. The patients were observed to have normal-range platelets, minimal complement activation and no complement-related adverse events. The two patients received a modified immunomodulatory regimen to mitigate adverse events. No significant immediate or delayed toxicities, significant skeletal myopathy, or late transaminase elevations have been observed to date.
•
Taken together, RP-A501 has been generally well tolerated in adult and pediatric cohorts in Danon Disease.
o
Phase 1 enrollment and treatment are complete.
o
RP-A501 together with the enhanced immunomodulatory regimen appears generally well tolerated and has mitigated adverse events in the pediatric cohort.
o
In the adult cohort, RP-A501 stabilizes and potentially improves Danon Disease cardiomyopathy.
o
Early pediatric data are encouraging and consistent with improvements at similar or earlier timepoints compared to the adult cohorts.
o
Findings are supportive of Phase 2 evaluation of RP-A501 in Danon Disease.

Rocket Cautionary Statement Regarding Forward-Looking Statements
Various statements in this report concerning Rocket’s future expectations, plans and prospects, including without limitation, Rocket’s expectations regarding its guidance for 2022, the safety and effectiveness of RP-A501 for the potential treatment of Danon Disease, trends for RP-A501 safety and efficacy based on the adult patients treated to date, the expected timing and outcome of Rocket’s regulatory interactions and planned submissions, including in connection with the potential advancement toward a Phase 2 pivotal study for RP-A501, Rocket’s plans for the advancement of its Danon Disease program 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 “believe,” “expect,” “anticipate,” “intend,” “plan,” “will give,” “estimate,” “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, our expectations regarding the delays and impact of COVID-19 on clinical sites, 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, Rocket’s dependence on third parties for development, manufacture, marketing, sales and distribution of product candidates, the outcome of litigation, and 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, 2021, filed February 28, 2022 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.

In connection with this announcement, the Company utilized a slide presentation which is substantially in the form attached as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
Item 9.01
Financial Statements and Exhibits.

(d)
Exhibits

Exhibit No.
  
Description
 
Presentation of Rocket Pharmaceuticals, Inc.
Exhibit 104
  
Cover Page Interactive Data File (embedded within the Inline XBRL document).

SIGNATURES
 
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

Date: October 3, 2022
Rocket Pharmaceuticals, Inc.
 
 
 
 
By: 
/s/ Gaurav Shah, MD
 
Name: 
Gaurav Shah, MD
 
Title: 
Chief Executive Officer and Director


Exhibit 99.1

 Update from Phase 1 Trial of RP-A501 Gene Therapy Treatment for Danon DiseaseSeptember 30, 2022 
 
 DISCLAIMER  Various statements in this release concerning Rocket’s future expectations, plans and prospects, including without limitation, Rocket’s expectations regarding its guidance for 2022, the safety and effectiveness of RP-A501 for the potential treatment of Danon Disease, trends for RP-A501 safety and efficacy based on the adult patients treated to date, the expected timing and outcome of Rocket’s regulatory interactions and planned submissions, including in connection with the potential advancement toward a Phase 2 pivotal study for RP-A501, Rocket’s plans for the advancement of its Danon Disease program 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 "believe," "expect," "anticipate," "intend," "plan," "will give," "estimate," "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, our expectations regarding the delays and impact of COVID-19 on clinical sites, 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, Rocket’s dependence on third parties for development, manufacture, marketing, sales and distribution of product candidates, the outcome of litigation, and 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, 2021, filed February 28, 2022 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. 
 
 Danon Disease (DD): Serious Condition with Unmet Medical Need   Standard of care:   Heart transplant (HTx)  Limitations:  Considerable morbidity and mortality   Only ~20% of patients receive HTx  Not curative of extracardiac disease  Therapeutic Challenges  X-linked, dominant, monogenic disease   Loss-of-function mutations in LAMP-2B​  Disease Etiology  Impaired autophagy  Prominent ​autophagic vacuoles  Myocardial disarray  Clinical Manifestations  Addressable Market – US and EU  Prevalence of 15,000 to 30,000 individuals  Annual incidence of 800 to 1,200 individuals  Severe cardiomyopathy  Mortality secondary to heart failure or arrhythmia  Males: Aggressive disease course, median overall survival: 19 years  Females: Delayed median presentation (~20 years later) due to additional X chromosome, highly morbid and fatal disorder  Other clinical manifestations  Skeletal myopathy  CNS manifestations  Ophthalmologic manifestations  CNS, central nervous system; LAMP-2B, lysosome-associated membrane protein 2B.  Boucek D et al. Genet Med. 2011;13(6):563-568. Brambatti M et al. Int J Cardiol. 2019;286:92-98.  RP-A501: Danon Disease 
 
 RP-A501: Prospect of Direct Benefit  Age (years)  5  10  15  20  25  30  Cardiac Pathophysiology   Symptom onset  Diagnosis  Progression to end-stagecardiomyopathy (potential for heart transplant)  Death   Gene therapy(hypothesized optimal treatment interval)  Stabilization or improvement  Trajectory of cardiac pathophysiology and heart failure in male Danon disease patients  Figure modified from disease progression by age data from Boucek D et al. Genet Med. 2011;13(6):563-568 and Brambatti M et al. Int J Cardiol. 2019;286:92-98.  RP-A501: Danon Disease 
 
 Pathophysiology and Clinical Manifestations of Danon Disease HCM  DD, Danon disease; LAMP2B, lysosome-associated membrane protein 2B; VT, ventricular tachycardia.  Adapted from Jones & Arnold. 2014. Hypertrophic Cardiomyopathy: Pathogenesis and Clinical Findings  Pathophysiology  Mechanism  Patient impact  Pathogenic LAMP-2B mutation causing DD  Autophagic vacuoles,  myocardial disarray,   myocardial thickening   Impaired ventricular filling during diastole (diastolic dysfunction)  No Cardiac LAMP2B protein expression  Disorganized myocytes disrupt signal conduction  Microvascular ischemia,  apoptosis with fibrous substitution  Ventricular arrhythmias   Decreased cardiac output  ↑ Left-sided pressure   ↓ Coronary artery perfusion, mismatch of myocardial oxygen supply & demand   Tissue hypoxia  Stimulus to breathe  Myocardial injury  Fibrosis  Impaired systolic function   Pulmonary edema and ↑ work of breathing  Sudden cardiac arrest  End-Stage Heart Failure  Tachypnea  Fatigue  Dyspnea on exertion  RP-A501: Danon Disease 
 
 Phase 1 Study: Non-Randomized Open Label   Non-randomized open label study in male DD patients  INCLUSION CRITERIA  Male  Confirmed LAMP-2B mutations  Cardiac involvement confirmed by imaging or ECG  NYHA Class II or III  Able to walk >150 m unassisted during 6-minute walk test (6MWT)  EXCLUSION CRITERIA  Anti-AAV9 neutralizing antibody titer >1:40  Cardiopulmonary instability  Prior organ transplantation  LVEF <40% (​implemented prior to pediatric cohort)  Pediatric 8-14 years  n=2​ at CHOP  Adults (& Adolescents) >15 years  n=5​ at UCSD  Single Intravenous Dose of RP-A501 (AAV9.LAMP2B)  Low Dose:     6.7 x 1013  GC/kg  High Dose*:  1.1 x 1014  GC/kg *No further enrollment at this dose.  Early and long-term safety   Target tissue transduction & LAMP2B protein expression​  Improved myocardial histology  Clinical improvement or stabilization  PRIMARY OUTCOMES  36 months  ***Enrollment Complete***  Data Reporting Details  Pre-dose (baseline) value defined as the mean values from all visits prior to infusion  Core lab data presented for echocardiographic parameters, cardiac serologies, and cardiac histology  Data cut September 27, 2022; source data verification through July 11, 2022.    6MWT, 6-minute walk test; AAV, adeno-associated virus; CHOP, Children’s Hospital of Philadelphia; DD, Danon disease; ECG, electrocardiogram; LAMP-2B, lysosome-associated membrane protein 2B; LVEF, left ventricle ejection fraction; NYHA, New York Heart Association; UCSD, University of California San Diego.  RP-A501: Danon Disease 
 
 RP-A501: Safety Monitoring of Phase 1 Patients  Pt  Age  Wt  1001a  17.5  52.5  1002  20.4  89.1  1005  18.3  91.8  Cohort 1: Low-dose adult  Cohort 2: High-dose adult  Cohort 3: Low-dose pediatric   1.1 x 1014 GC/kg  6.7 x 1013 GC/kg  6.7 x 1013 GC/kg  RP-A501  Steroid (prednisone 1mg/kg)  Tacrolimus  Tacrolimus  Rituximab   (2 doses)  Steroid (prednisone 0.5 – 0.8mg/kg); Taper start d 10  Sirolimus (target trough 4-8 ng/mL)  RP-A501  RP-A501  n=2 grade 3 steroid myopathy  n=1 grade 3 steroid myopathy  n=1 grade 4 TMA   SAEs of Interest  none  Platelets  n=2,  Grade 1   decrease(to LLN range)  n=1,  Grade 4 decrease  Remain in   normal range  Steroid (prednisone 1mg/kg)  Pt  Age  Wt  1006  21.1  82.7  1007b  20.7  96.7  Pt  Age  Wt  1008  12.3  70.5  1009  11.7  55.7  a Corticosteroid compliance uncertain  b This patient underwent heart transplant due to DD progression five months post RP-A501 infusion; both because this patient would no longer be eligible for future studies based on revised eligibility criteria and because long-term RP-A501 effect is not evaluable, data for this patient are not shown. He is currently stable.  Rituximab   (2 doses)  Daily, real-time monitoring of labs & clinical status  Day -14  Month 3  Day 14  d, day; LLN, lower limit of normal; Pt, patient; SAE, serious adverse event; TMA, thrombotic microangiopathy; Wt, weight.​  Age in years at RP-A501 infusion; weight in kg.​  RP-A501: Danon Disease 
 
 RP-A501 Was Generally Well Tolerated in Pediatric Cohorton Enhanced Immunomodulation  Minimal complement activation  No complement-related clinical or laboratory AEs  All AEs were transient and reversible  No treatment-related SAEs  Steroid     (prednisone 0.5 – 0.8mg/kg and tapered starting  day 10)  Sirolimus       (target trough 4-8 ng/mL)  Rituximab   (2 doses)  RP-A501  Pediatric immunomodulation protocol  Daily, real-time monitoring of labs & clinical status  Day -14  Month 3  Day 14  Platelets remained within normal range  No reported skeletal myopathy or late transaminitis with initial steroid dose-reduction and more rapid taper, and introduction of sirolimus  sC5b9 Evaluation Post RP-A501  AE, adverse event; SAE, serious AE; ULN, upper limit of normal.  Data cut-off September 27, 2022 with source data verification through July 11, 2022.  All AEs were Transient and Reversible with 6 and 11 month follow up in 1008 and 1009, respectively  1008  1009  1000  750  500  250  0  0  30  60  90  ULN  sC5b9 (ng/mL)  Days Post Dose  RP-A501: Danon Disease 
 
 Early Pediatric Data are Encouraging and Consistent with Adult Efficacy Data at Similar Timeframe  Variable​​​​  Baseline2  Most Recent Follow-up​​​  LAMP2 protein3 (%)   2.6  354  Troponin-I (ng/mL)  0.67  0.07  BNP (pg/mL)​​​  297​  113  KCCQ-overall scale  52  815  NYHA Class  II  I  6 months  AGE AT INFUSION 11.7 years  ICD no    WPW no  Patient ID: A501-008-1008  Patient ID: A501-008-1009  AGE AT INFUSION 12.3 years  ICD yes1  WPW yes  Variable​​​​  Baseline2​​​  Most RecentFollow-up​​​  LAMP2 protein3 (%)  0.5  214  Troponin-I (ng/mL)  1.89  0.28  BNP (pg/mL)​​​  1837  406  KCCQ-overall scale  50  93  NYHA Class  II  I  9 months  MAX LV WALL THICKNESS 41.9 mm, z-score +32   6MWT   438 meters      MAX LV WALL THICKNESS 19.8 mm, z-score +12  6MWT   553 meters  Baseline Characteristics  Baseline Characteristics  6MWT, 6-minute walk test; BNP, brain natriuretic peptide; ICD, implantable cardioverter defibrillator; KCCQ, Kansas City cardiomyopathy questionnaire; LAMP2, lysosome-associated membrane protein 2; LV, left ventricle; NYHA, New York Heart Association; WPW, Wolff-Parkinson-White syndrome.   Data cut-off September 27, 2022 with source data verification through July 11, 2022.  1 Recommended prior to enrollment; ICD implanted 3 months after RP-A501 infusion  2 Baseline values for troponin-I and BNP are the mean values from all pre-dose visits   3 All biopsies stained for LAMP2 were compared to normal controls. Data is quantitated in a blinded fashion from ~3-5 sections   4 Most recent biopsy data available from 6 month visit for 1008 and 3 month visit for 1009  5 Most recent KCCQ data available from 3 month visit for 1009   RP-A501: Danon Disease 
 
 Early Pediatric LAMP2 Expression are Encouraging and Consistent with Adult Data   LAMP2, lysosome associated membrane protein 2.  IHC, immunohistochemistry.  Cohort  Patient ID  Initial Biopsy  Post Infusion  Pediatric - Low Dose  1008  Month 3:   18.5%*  1009  Month 3:   34.7%  Adult - Low Dose   1001  Month 2:      7.3%  1002  Month 2:   36.9%  1005  Month 2:   17.6%  Adult - High Dose  1006  Month 2:      5.0%  1007  Month 2:      6.9%  All biopsies stained for LAMP2 were compared to normal control samples. Data is quantitated in a blinded fashion from ~3-5 sections.   * 1008 Month 6 biopsy: 21% as noted in previous slide  Adapted from Oldfors 2015.   A: IHC of an explanted heart of a younger female Danon disease patient with extremely patchy, nonhomogenous LAMP2 staining.   C: IHC of an explanted heart of an older female Danon disease patient with more homogenous LAMP2 staining  Quantified LAMP2 protein expression by immunohistochemistry (IHC)  RP-A501: Danon Disease 
 
 LAMP2 Myocardial Protein Expression and Histologic Improvement in the Pediatric Cohort  EMB, endomyocardial biopsy; H&E, hematoxylin & eosin stain; LAMP2, lysosome associated membrane protein 2.  A501-008-1008 Endomyocardial Biopsy (EMB) Images  LAMP2 protein expression assessed (relative to normal human controls) by core lab in a blinded fashion of entire tissue sample  Electron Microscopy  Immunohistochemistry  Baseline  Month 3  Month 6  Hematoxylin & Eosin  Grade 0  Grade 2  Grade 2  Percentages reflect estimated extent of LAMP2 staining  Grade 0 negative staining   Grade 1 ≤25%  Grade 2 26%-50%   Grade 3 51%-75%   Grade 4 >75%  H&E images captured at 20x magnification, presented digitally zoomed  Arrows indicate autophagic vacuoles   Similar findings on EMB from patient 1009 at Baseline and Month 3  RP-A501: Danon Disease 
 
 Pediatric LAMP2 Protein and DNA Suggests Durable Expression As Demonstrated in Adult Cohort  *LAMP2 protein expression assessed (relative to normal human controls) by core lab in a blinded fashion of entire tissue sample; Percentages reflect estimated extent of LAMP2 staining:    Grade 0=negative staining; Grade 1 ≤25%; Grade 2 =26%-50%; Grade 3 =51%-75%; Grade 4 >75%.  1001  1002  1005  1006  1008  1009  4  3  2  1  0  Pre  M3  M6  M12  M24  Pre  M3  M6  M12  M24  Pre  M3  M6  M12  M24  Pre  M3  M6  M12  M24  Pre  M3  M6  M12  M24  Pre  M3  M6  M12  M24  M36  Grade 0  Grade 0  Grade 0  Grade 0  No Data  Grade 0  No Data  Grade 0  Grade 0  Oct 2022  Oct 2023  Grade 0  Data Pending  March 2023  March 2024  LAMP2 Grade* by IHC  Patient ID   Predose  Month 6  Month 12  Month 36    1001a  0  0.384  0.197  0.120  1002  0  ND  0.575  0.590c  1005  0  0.583  ND  1.228c  1006  0  2.693  1.131  -  1007  0  RV: 6.77b  LV: 9.15b  Post heart transplant  1008  0  0.492  -  -  1009  0  Data pending  -  -  LAMP2, lysosome associated membrane protein 2; M, month.  LAMP2 Protein Expression   Cardiac LAMP2 DNA by qPCR (vector copies per diploid nucleus)  LV, Left ventricle and RV, Right ventricle at 5 months from explanted heart; ND.  not done, -, visit pending.   a Corticosteroid compliance uncertain. b Assessment from explanted heart tissue at 5 months. c Month 30 visit.  RP-A501: Danon Disease 
 
 n=1  15  n=6  n=3  n=3  n=2  10  5  0  Predose  Month 6  Vacuole Area/Tissue Area (%)  Month 12  Month 24  Month 36  Restored Autophagy Sustained Following RP-A501  M, month; X, data not assessed  B.  1001  1002  1005  1006  1008  M12  M24  M36  M6  M12  M24  M24  M6  M12  M6  M6  25  0  -25  -50  -75  -100  Improvement  Vacuole Area/Tissue Area  % Change from Baseline  X  X  X  A.  Vacuolar Area of Endomyocardial Tissue  Restored autophagy indicated by attenuation of vacuolar area  B.  Vacuolar Area Decreases with Treatment  Bars denote minimum and maximum range, and line within each bar represents the mean value within study population.  Light microscopy images at 20X;  Autophagic vacuoles are depicted by yellow arrows.    RP-A501: Danon Disease 
 
 Sustained Improvement or Stabilization of Biomarkers of Myocardial Injury and Stress Following RP-A501  Brain Natriuretic Peptide (BNP)  1001  1002  1005  1006  High Sensitivity Troponin I (hsTnI)  25  0  -25  -50  -75  -100  M18  M24  M30  M36  X  X  X  M18  M24  M30  M12  M18  M30  M18  M24  M12  Improvement  hsTroponin I   % Change from Baseline  25  0  -25  -50  -75  -100  M18  M24  M30  M36  M12  M18  M24  M30  M12  M18  M30  M18  M24  M12  Improvement  BNP   % Change from Baseline  X  X  M, month; X, data not assessed  RP-A501: Danon Disease 
 
 Sustained Improvement or Stabilization of LV HypertrophyFollowing RP-A501  LV, left ventricle; LVPWd, LV posterior wall end diastole; M, month; X, data not assessed  LV hypertrophy is assessed via LV posterior wall at end diastole (LVPWd) and LV mass.  LV Posterior Wall Thickness  LV Mass  M18  M24  M30  M36  M12  M6  M18  M24  M30  M18  M9  M18  M12  M9  M6  25  0  -25  -50  Improvement  X  X  X  X  X  X  X  X  LVPWd   % Change from Baseline  LV Mass   % Change from Baseline  M18  M24  M30  M36  M12  M6  M18  M24  M30  M18  M9  M18  M12  M9  M6  Improvement  X  X  X  X  X  X  X  X  25  0  -25  -50  1001  1002  1005  1006  RP-A501: Danon Disease 
 
 Sustained Improvement or Stabilization of  Functional Cardiac StatusFollowing RP-A501  Cohort​​​  Patient ID​​​  Baseline​​​  Month 12  Most Recent Follow-up  Time of Most Recent   Follow-up  Low Dose​ Adult  1001​​​a  II​​​​  II  II  36 months  1002​​​​  II​​​​  III  I  30 months  1005​​​  II​​​​  II  I​  30 months  High Dose Adult  1006​​​​  II​​​​  I​​​  I​​​  24 months  Low Dose Pediatric  1008  II​​​​  October 2022  I  9 months  1009​​​  II​​​​  March 2023  I  6 months  New York Heart Association Class  100  75  50  25  0  KCCQ-Overall Score  1001  1002  1005  1006  1008  M, month; X, data not assessed.  a Corticosteroid compliance uncertain  Pre  M3  Pre  M9  X  Pre  M24  X  Pre  M24  X  X  X  X  Pre  M30  X  X  Pre  M3  M6  M12  M18  M24  M30  M36  X  1009  Kansas City Cardiomyopathy Questionnaire Overall Score  RP-A501: Danon Disease 
 
 Summary of Results  PEDIATRIC COHORT   ADULT COHORT  Low-dose continues to be generally well tolerated at 2-3 years post-treatment  Increased LAMP2B protein expression was associated with durable disease improvement or stabilization including clinical status (NYHA class, KCCQ), LV hypertrophy (LV wall thickness and mass), biomarkers of myocardial injury and stress (hsTroponin I and BNP), and cardiac histology   All patients are alive in their early 20s, whereas median survival in DD males is 19 years old*  RP-A501 was well tolerated  No immediate, early or delayed RP-A501 related SAEs observed to date with enhanced immunomodulation   Minimal complement activation  Platelets remained within normal range  Absent or limited worsening of skeletal myopathy with reduced steroid dose and more rapid taper, and introduction of sirolimus  Increased LAMP2B protein expression was associated with early signals of improved cardiac histology, as well as serological evidence of decreased myocardial injury and stress  Early improvement in NYHA class and KCCQ for both patients   BNP, brain natriuretic peptide; hs, high sensitivity; KCCQ, Kansas City cardiomyopathy questionnaire; LAMP2B, lysosome-associated membrane protein 2B; LV, left ventricle; NYHA, New York Heart Association; SAE, serious adverse event.  *Except for patient 1007 who received a heart transplant at 5 months due to Danon Disease progression. He is currently stable. Brambatti M et al. Int J Cardiol. 2019;286:92-98  Data cut-off September 27, 2022 with source data, verification through July 11, 2022.  RP-A501: Danon Disease 
 
 Connecting Surrogate Endpoints to Functional Outcomes for Pivotal Study*   Molecular Expression   Cellular Structure   Cardiac Structure and Function   Cardiac Structure and Function   Clinical Status   Endomyocardial Bx:   LAMP2 protein expression  Endomyocardial Bx:   Vacuolar area   Serology:   Troponin-I  BNP   Echo Parameters:   Wall thickness (LVPWd, MLVWT)  LVEF  LV mass   Hemodynamics:   PCWp  Cardiac output  Functional parameters:    NYHA Class  KCCQ Overall Score  Patient Screening  Predose  Month 3  Month 6  Month 12  Month 24  Month 36  RP-A501  Post Gene Therapy  BNP, brain natriuretic peptide; Bx, biopsy; KCCQ, Kansas City cardiomyopathy questionnaire; LAMP2, lysosome-associated membrane protein 2; LV, left ventricle; LVEF, LV ejection fraction; LVPWd, LV posterior wall end diastole; MLVWT, maximal LV wall thickness; NYHA, New York Heart Association; PCWp, pulmonary capillary wedge pressure.  *Pending regulatory feedback  RP-A501: Danon Disease 
 
 Summary of Results  Phase 1 enrollment and treatment are complete  The enhanced immunomodulatory regimen was generally well tolerated and has mitigated adverse events in the pediatric cohort, who are currently 6 and 11 months post treatment  The early LAMP2 expression data from the pediatric cohort are encouraging and consistent with that seen in the adult patients at the same timepoints  The early clinical trends for the pediatric cohort are encouraging and consistent with the sustained clinical responses seen in the adults at 24-36 months   Study design and endpoints have been identified for the planned Phase 2 pivotal study* and endorsed by an International Scientific and Clinical Advisory Board; FDA discussion planned at the end of this year  *Pending regulatory feedback  RP-A501: Danon Disease 
 

 Development Plan  Moving toward pivotal Phase 2 study  PLANNED GLOBAL  REGISTRATIONAL PHASE 2 STUDY  Expanded natural history study  End of Phase 1 regulatory meeting with FDA  Initiate Phase 2 global pivotal study activities  Initiate female study  PLANNED  Phase 1 treatment completed in males  Orphan Drug, Rare Pediatric and Fast Track designations in the US (eligible for PRV, if approved)  Initiated in-house manufacturing to support Phase 2 product  CURRENT  FDA, Food and Drug Administration; H2, second half of the year; PRV, priority review voucher.  Data on file. Rocket Pharmaceuticals. 2022.  RP-A501: Danon Disease