Gene Therapy for Male Patients With Danon Disease (DD) Using RP-A501; AAV9.LAMP2B

NCT03882437 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: RP-A501-0219
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 3

Brief Summary

This is a non-randomized open-label Phase 1 study to evaluate the safety and toxicity of gene therapy using a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene (investigational product (IP), RP-A501) in male patients with Danon Disease (DD).

Conditions

Danon Disease

Keywords

hypertrophic cardiomyopathy; HCM; X-linked disease; LAMP 2A; Pediatric; Skeletal myopathies

Outcome Measures

Primary Outcomes (4)

• Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE)

  Evaluation of safety associated with RP-A501

  3 years

• Number of participants within each dose level cohort with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE)

  Assessment of safety at both doses (single IV administration)

  3 years

• Evaluation of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy

  Assessment of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy

  3 years

• Preliminary evaluation of clinical stabilization of cardiomyopathy following administration of RP-A501 via cardiopulmonary testing

  Assessment of clinical stabilization of cardiomyopathy following infusion of RP-A501 via cardiopulmonary testing

  3 years

Secondary Outcomes (5)

• Determination of the percentage of patients in whom RP-A501 resulted in a sustained improvement or stabilization in cardiovascular pathophysiology

  3 years

• Determination of the percentage of patients in whom cardiomyocytes corrected LAMP2B gene and/or protein

  3 years

• Determination and characterization of immunologic response to RP-A501

  3 years

• Determination of the percentage of patients who require and/or receive treatment for heart failure following RP-A501

  3 years

• Evaluation of overall survival

  3 years

Study Arms (1)

RP-A501

EXPERIMENTAL

RP-A501 is a gene therapy product consisting of a rAAV9 capsid containing the human LAMP2B transgene which will be administered as a single intravenous (IV) infusion. Subjects will receive one of three dose levels depending on the cohort.

Biological: RP-A501

Interventions

RP-A501 BIOLOGICAL

RP-A501 is a gene therapy product consisting of a rAAV9 capsid containing the human LAMP2B transgene which will be administered as a single IV infusion.

RP-A501

Eligibility Criteria

• Age: 8 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• The study will enroll adult and pediatric males with a confirmed diagnosis of DD. Patients may be of any race or ethnicity. Patients and/or competent custodial parents must provide informed written consent and meet all of the enrollment criteria as detailed subsequently to be eligible to participate.
• DD diagnosis with any confirmed LAMP2 mutation(s).
• Cardiac involvement as documented by at least one abnormal finding on electrocardiogram (ECG), echocardiogram, gadolinium-enhanced cardiac magnetic resonance imaging (MRI), or electrophysiology study.
• Age ≥15 years for cohorts 1 and 2; 8-14 years for cohorts 1A.
• Male gender.
• New York Heart Association (NYHA) Class II or III.
• Adequate hematologic function as defined by hemoglobin, absolute neutrophil count (ANC), and platelet count ≥ lower limit of normal (LLN).
• Adequate hepatic function as defined by:
• AST and ALT ≤10.0×ULN or GGT ≤2.0×ULN (transaminase elevations in DD are considered extensively to result from muscle injury; hence the relatively high upper limit for transaminases and consideration of GGT level, and the presence of additional hepatic eligibility markers of bilirubin and PT/INR).
• Serum bilirubin ≤1.2×ULN (i.e., Grade ≤1 bilirubin increase).
• PT/INR ≤1.2×ULN (in the absence of anticoagulation).
• Absence of cirrhosis or other signs of inflammation on liver ultrasound
• Adequate renal function as defined by creatinine ≤ULN.
• Ability to provide informed consent (for adult patients and parents/legal guardians of pediatric patients) and assent (for patients age 15-17).
• Ability to comply with study procedures including investigational therapy and follow-up evaluations.

You may not qualify if:

• Patients meeting any of the following criteria are not eligible for study participation:
• I.V. therapy with positive inotropes, vasodilators, or diuretics within the 30 days prior to enrollment (i.e., patient must be stable on oral medical therapy).
• Prior cardiac transplantation or prior transplant of other organ (lung, liver, other).
• Prior cardiac surgery and/or percutaneous cardiac intervention for arteriothrombotic complications, or valvuloplasty.
• Presence or requirement of a Left Ventricular Assisted Device (LVAD).
• History of intracardiac thrombosis or arteriothromboembolic events including stroke or transient ischemic attack (TIA).
• Left ventricular ejection fraction (LVEF) \<40% at baseline.
• History of the following prior arteriothromboembolic complications: myocardial infarction or unstable angina.
• Significant (greater than moderate) valvular stenosis or regurgitation on echocardiogram.
• Requires mechanical ventilation.
• Anti-AAV9 neutralizing antibody titer \>1:40.
• Concurrent enrollment in any other clinical investigation involving use of an investigational agent for the treatment of CHF or cardiomyopathy.
• Active hepatitis B or C infection (including patients with positive hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B core antibody (HBcAb), or detectable hepatitis B virus (HBV) or hepatitis C virus (HCV) viral load). Patients with previous, adequately resolved HBV or HCV are eligible.
• Significant medical conditions including documented human immunodeficiency virus (HIV) infection, active viral or other hepatitis, poorly-controlled hypertension or diabetes, poorly controlled cardiac arrhythmia, or uncontrolled viral, bacterial, or fungal infection.
• Any concomitant medical or psychiatric condition that in the opinion of the Investigator renders the patient unfit for study participation or at higher than acceptable risk for study participation.

Sponsors & Collaborators

• Rocket Pharmaceuticals Inc.: lead

Study Sites (3)

University of California, San Diego

La Jolla, California, 92037, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (3)

• Greenberg B, Taylor M, Adler E, Colan S, Ricks D, Yarabe P, Battiprolu P, Shah G, Patel K, Coggins M, Carou-Keenan S, Schwartz JD, Rossano JW. Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease. N Engl J Med. 2025 Mar 6;392(10):972-983. doi: 10.1056/NEJMoa2412392. Epub 2024 Nov 18.

  PMID: 39556016 DERIVED

• Grisorio L, Bongianino R, Gianeselli M, Priori SG. Gene therapy for cardiac diseases: methods, challenges, and future directions. Cardiovasc Res. 2024 Nov 25;120(14):1664-1682. doi: 10.1093/cvr/cvae207.

  PMID: 39302117 DERIVED

• O'Neil EC, Uyhazi KE, O'Connor K, Aleman IA, Pulido JS, Rossano JW, Aleman TS. DANON DISEASE: A MODEL OF PHOTORECEPTOR DEGENERATION SECONDARY TO PRIMARY RETINAL PIGMENT EPITHELIUM DISEASE. Retin Cases Brief Rep. 2022 Nov 1;16(6):707-713. doi: 10.1097/ICB.0000000000001125.

  PMID: 36288619 DERIVED

MeSH Terms

Conditions

Glycogen Storage Disease Type IIb; Cardiomyopathy, Hypertrophic

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Glycogen Storage Disease; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases

Study Officials

• Joseph Rossano, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

• Matthew Taylor, MD, PhD

  University of Colorado, Anschutz Medical Ctr

  PRINCIPAL INVESTIGATOR

• Barry Greenberg, MD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Evaluation of RP-A501 in pediatric patients (ages 8-14) will commence only pending determination of safety in the older (adult and age 15-17) population. In Phase 1, RP-A501 will be investigated in three treatment cohorts, as follows with a single cohort currently recruiting: Cohort 1: Adult and age 15-17: 6.7 × 1013 GC/kg (n=3-4) Cohort 2: Adult and age 15-17: 1.1 × 1014 GC/kg (n=2 \[patients already treated; closed for current enrollment\]) Cohort 1A: Pediatric age 8-14: 6.7 × 1013 GC/kg (n=2-4)

Study Record Dates

• First Submitted: March 12, 2019
• First Posted: March 20, 2019
• Study Start: April 17, 2019
• Primary Completion: March 24, 2025
• Study Completion: March 24, 2025
• Last Updated: March 3, 2023

Record last verified: 2023-02

Locations

US (3)