Natural History of Danon Disease

A Retrospective, Multicenter, International Study to Characterize the Natural History of Danon Disease

This is a multicenter, international, non-interventional, natural history study designed to collect longitudinal retrospective clinical information on patients with Danon disease (DD). This study is composed of 2 parts:

• Feasibility study: to identify participating sites, assess site and team capabilities, confirm the site and investigator qualification for taking part in the study,
• Retrospective chart review: Data will be collected retrospectively by means of a chart review of living and/or deceased DD patients with a confirmed lysosome associated membrane protein-2 gene (LAMP2) mutation, and,
• For living patients (who have not undergone heart transplantation or placement of a cardiac assist device), availability of at least 6-month cardiology follow-up data,
• For living patients who underwent heart transplantation or placement of a cardiac assist device, and for deceased patients, at least 1 MRI or echo assessment prior to heart transplantation/cardiac assist device placement or death.

Study Overview

• Status: Completed
• Conditions: Danon Disease
• Intervention / Treatment: Procedure: Heart Transplant; Device: Cardiac Assistive Device

Detailed Description

Danon disease (DD) is a rare X-linked dominant genetic disorder characterized by cardiomyopathy, skeletal myopathy, and neurocognitive deficits. The disease is caused by a mutation in the lysosome associated membrane protein-2 gene (LAMP2). LAMP2 functions as a lysosomal membrane receptor in autophagy. Most men and many women with LAMP2 gene mutations will develop cardiac disease that includes hypertrophic cardiomyopathy and/or dilated cardiomyopathy, cardiac pre-excitation syndrome, and a propensity for arrhythmias. The prognosis is directly related to the severity of the cardiac disease, and many patients will die from sudden cardiac death. Males are typically more severely affected than females.

There is currently no therapy available to cure, or even prevent disease progression. DD treatment is thus primarily supportive therapy, and survival beyond 25 years without a cardiac transplantation is improbable for afflicted male patients.

Rocket Pharmaceuticals, a clinical-stage company advancing an integrated and sustainable pipeline of genetic therapies for rare pediatric disorders, is developing Rocket Pharmaceuticals Adeno-associated- vector-501 (RP-A501) (AAV9.LAMP2B), an investigational gene therapy product for DD and the first potential gene therapy for monogenic heart failure.

This retrospective, multicenter, international, longitudinal, non- interventional study of DD patients with confirmed LAMP2 mutation aims at characterizing the Natural History of disease in males and females. The Real-world data collected from patients in this natural history study will help support the overall development and protocol design of the RP-A501 gene therapy pivotal trial to be submitted to the health authorities.

Additionally, this study will allow identification of the core centers managing DD patients in several countries as well as the description of the disease characteristics, diagnosis pathway and disease progression. This will inform the development of patient profiles for future studies, including a potential prospective observational study to investigate the burden of disease among DD patients and an international patient registry for Danon disease.

The overarching goal of this retrospective, multicenter, international study is to gain a better understanding of the Natural History of Danon disease, by collecting de-identified information from patients with this condition treated.

Primary objective: Determine how specific cardiac manifestations in patients diagnosed with Danon disease change over time. Essential echocardiography and/or MRI-based parameters include: thickness of the Left Ventricular Posterior Wall at end-diastole (LVPWd); thickness of the Interventricular Septum at end-diastole (IVSd); Left Ventricular mass (LVmass); Left Ventricular Ejection Fraction (LVEF).

Secondary objectives: Describe the progression of other cardiac and extracardiac manifestations in patients diagnosed with Danon disease, including, but not limited to: serologic markers of heart failure, serologic markers of muscle injury, risk and frequency of arrhythmias, comprehensive echocardiogram and MRI-based assessments of cardiomyopathy, overall survival, and event-free survival (as defined subsequently).

Exploratory objectives:

1. Describe the diagnostic pathway of Danon disease, therapeutic management and local centers' approaches to genetic testing for LAMP2 mutations.
2. Identify key Natural History trends to inform a prospective European Union (EU) natural history study and plan for a potential gene therapy trial for DD patients in the EU.

• Study Type: Observational
• Enrollment (Actual): 59

Contacts and Locations

• Study Contact: Name: Rocket Pharma Patient Advocacy; Phone Number: +1-646-627-0033; Email: clinicaltrials@rocketpharma.com

Study Locations

• Czechia
  • Prague, Czechia, 14021
    • Institut klinické a experimentální medicíny (IKEM)- Institute for Clinical and Experimental Medicine
    • Contact: Milos Kubanek; Phone Number: +420 737 205 964
• France
  • Nantes, France, 44800
    • CHU de Nantes, Hôpital Laennec
    • Contact: Jean-Noel Trochu; Phone Number: +33 02 40 08 33 33
  • Paris, France, 75013
    • APHP, Hôpital de la Pitié Salppêtrière - Charles Foix
    • Contact: Philppe Charron; Phone Number: +33 01 42 16 13 46
  • Rennes, France, 35033
    • CHU de Rennes, Hopital Pontchaillou
    • Contact: Erwan Donal; Phone Number: +33 02 99 28 25 25
• Ireland
  • Dublin, Ireland, D07 R2WY
    • Mater Misericordiae University Hospital
    • Contact: Joseph Galvin; Phone Number: +353 1 803 2000
• Italy
  • Bergamo, Italy, 24127
    • Ospedale Papa Giovanni XXIII di Bergamo ASST Pap Giovanni XXIII Hospital
    • Contact: Attilio Iacovoni; Phone Number: +39 035 267 111
  • Florence, Italy, 50134
    • University of Florence Dept. of Experimental and Clinical Medicine
    • Contact: Iacopo Olivotto; Phone Number: +39 333 331 4844
  • Trieste, Italy, 34137
    • IRCCS Burlo Garogolo- Hospital Burlo Garofolo
    • Contact: Irene Bruno; Phone Number: +390403785111
• Spain
  • Barcelona, Spain, 08907
    • Hospital Clínic de Barcelona - Barnaclínic+
    • Contact: Ana Garcia-Alvarez; Phone Number: +34 932 27 54 00
  • Barcelona, Spain, 08907
    • Hospital Universitario de Bellvitge- Bellvitge University Hospital
    • Contact: Carles Diaz-Lopez; Phone Number: +34 932 60 79 31
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz - La Paz University Hospital
    • Contact: Luis Garcia Guereta; Phone Number: +34 630 02 45 78
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro Majadahonda Puerta de Hierro Majadahonda - University Hospital
    • Contact: Pablo Garcia Pavia; Phone Number: +34 911 91 72 97
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria- Virgen de la Victoria University Hosptial
    • Contact: Jose Manuel Garcia-Pinilla; Phone Number: +34 951 03 25 60
  • Pontevedra, Spain, 326312
    • Hospital Álvaro Cunqueiro
    • Contact: David Dobarro; Phone Number: +34 986 82 55 64
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe, Instituto De Investigación Sanitaria La Fe, La Fe University and Polytechnic Hospital
    • Contact: Esther Zorio Grima; Phone Number: +34 961 24 58 49

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Female and male patients with confirmed diagnosis of Danon disease based on a genetic test positive for a mutation in LAMP2

Description

Inclusion Criteria:

1. Patients older than 6 years old and any sex.

2. Patients with a confirmed genetic mutation in LAMP2. 3a. Living patients (who have not undergone heart transplantation or placement of a cardiac assist device):

   • A minimum of 6 months of longitudinal data, including at least 2 echocardiograms or MRIs at least 6 months apart, prior to most recent follow-up visit or enrollment in Sponsor's gene therapy clinical trial.

     3b. Deceased patients or living patients who underwent heart transplantation or cardiac assist device placement:

   • At least 1 echocardiogram or MRI assessment prior to heart transplantation/ cardiac assist device placement or death

4. Informed consent/assent by the patient and/or their legally authorized representative (if the patient is living at the time of enrollment).

Exclusion Criteria:

1. Diagnosis of Danon disease without genetic testing confirmation.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Heart Transplant or Cardiac Assist Device; Female and male patients with confirmed diagnosis of Danon disease based on a genetic test positive for a mutation in LAMP2 For living patients who underwent heart transplantation or placement of a cardiac assist device, and for deceased patients, at least 1 MRI or echo assessment prior to heart transplantation/cardiac assist device placement or death.	Procedure: Heart Transplant; Patients who have undergone a heart transplant as standard of care (SOC) procedure; Device: Cardiac Assistive Device; Patients who have undergone a placement of a cardiac assistive device
No Intervention; Female and male patients with confirmed diagnosis of Danon disease based on a genetic test positive for a mutation in LAMP2 for living patients (who have not undergone heart transplantation or placement of a cardiac assist device), availability of at least 6-month cardiology follow-up data

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac Manifestations- LVPWd	Descriptive analysis will be conducted to characterize specific cardiac manifestations in patients diagnosed with Danon disease, and changes over time. Data collected will be analyzed by 6-month intervals and by the changes from initial evaluation over each 6-month interval. This includes the following cardiac parameters obtained from echocardiogram and/or MRI assessments: thickness of the left ventricular posterior wall end diastole and end systole (LVPWd).	Retrospective minimum of 6 months
Cardiac Manifestations- lVSd	Descriptive analysis will be conducted to characterize specific cardiac manifestations in patients diagnosed with Danon disease, and changes over time. Data collected will be analyzed by 6-month intervals and by the changes from initial evaluation over each 6-month interval. This includes the following cardiac parameters obtained from echocardiogram and/or MRI assessments including thickness of the left ventricular systolic dysfunction (IVSd).	Retrospective minimum of 6 months
Cardiac Manifestations- LVmass	Descriptive analysis will be conducted to characterize specific cardiac manifestations in patients diagnosed with Danon disease, and changes over time. Data collected will be analyzed by 6-month intervals and by the changes from initial evaluation over each 6-month interval. This includes the following cardiac parameters obtained from echocardiogram and/or MRI assessments including left ventricular mass (LVmass).	Retrospective minimum of 6 months
Cardiac Manifestations - LVEF	Descriptive analysis will be conducted to characterize specific cardiac manifestations in patients diagnosed with Danon disease, and changes over time. Data collected will be analyzed by 6-month intervals and by the changes from initial evaluation over each 6-month interval. This includes the following cardiac parameters obtained from echocardiogram and/or MRI assessments including left ventricular ejection fraction (LVEF).	Retrospective minimum of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serologic Markers & Imaging - BNP	Mean values, standard deviations, medians and changes in means will be provided for serologic markers of heart failure which include B-type natriuretic peptide (BNP).	Retrospective minimum of 6 months
Serologic Markers & Imaging Pro-BNP	Mean values, standard deviations, medians and changes in means will be provided for serologic markers of heart failure which include Pro- B-type natriuretic peptide (Pro-BNP).	Retrospective minimum of 6 months
Serologic Markers & Imaging- CK-MB	Mean values, standard deviations, medians and changes in means will be provided for serologic markers of heart failure which include creatine kinase - MB (CK-MB).	Retrospective minimum of 6 months
Serologic Markers & Imaging- Troponin	Mean values, standard deviations, medians and changes in means will be provided for serologic markers of heart failure which include Troponin	Retrospective minimum of 6 months
Serologic Markers & Imaging- CPK	Mean values, standard deviations, medians and changes in means will be provided for serologic markers of muscle injury, which include creatine phosphokinase (CPK).	Retrospective minimum of 6 months
Serologic Markers & Imaging- transaminases	Mean values, standard deviations, medians and changes in means will be provided for serologic markers of muscle injury, which include transaminases	Retrospective minimum of 6 months
Serologic Markers & Imaging- Echo/MRI	Mean values, standard deviations, medians and changes in means will be provided for the echocardiogram- and MRI-based assessments of cardiomyopathy, which include measures of cardiac hypertrophy or dilation	Retrospective minimum of 6 months
Serologic Markers & Imaging- BP	Mean values, standard deviations, medians and changes in means will be provided for the echocardiogram- and MRI-based assessments of cardiomyopathy, which include measures of systolic and diastolic function	Retrospective minimum of 6 months
Serologic Markers & Imaging- GLS	Mean values, standard deviations, medians and changes in means will be provided for the echocardiogram- and MRI-based assessments of cardiomyopathy, which include measures of Global Longitudinal Strain (GLS)	Retrospective minimum of 6 months
Serologic Markers & Imaging- E/A	Mean values, standard deviations, medians and changes in means will be provided for the echocardiogram- and MRI-based assessments of cardiomyopathy, which include measures of mitral inflow ratio of the early (E) to late (A) (ventricular filling velocities (E/A))	Retrospective minimum of 6 months
Arrhythmias	Time to event (risk of arrhythmia), for each of the following: supraventricular arrhythmias and non-sustained ventricular arrhythmias on Holter or similar monitoring, treatment with anti-arrhythmic medications	Retrospective minimum of 6 months
Wolf-Parkinson-White syndrome	Time to event of Wolf-Parkinson-White syndrome (WPW) on electrocardiogram	Retrospective minimum of 6 months
ICD Placement	Time to event of Implantable cardioverter-defibrillators (ICD) placement	Retrospective minimum of 6 months
Reason for ICD Placement	Reasoning for ICD placement will be summarized by frequency of the reasons	Retrospective minimum of 6 months
Overall Survival	Overall survival will be analyzed using Kaplan-Meier estimates. Patients lost to follow-up or who complete the study will be censored at the last follow-up time.	Retrospective minimum of 6 months
Event-free survival	Event-free survival (EFS) will be analyzed using Kaplan-Meier estimates. EFS will be provided for Tier 1 events, Tier 1 + Tier 2 events, and Tier 1 + Tier 2 +Tier 3 events. Patients lost to follow-up or who complete the study will be censored at the last follow-up time.	Retrospective minimum of 6 months

Collaborators and Investigators

• Sponsor: Rocket Pharmaceuticals Inc.

Publications and helpful links

Helpful Links

• Glycogen Storage Disease type IX
• Danon Disease

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2022
• Primary Completion (Actual): October 31, 2023
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: July 29, 2022
• First Submitted That Met QC Criteria: September 16, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Observational; Danon Disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Cardiomyopathies; Glycogen Storage Disease; Glycogen Storage Disease Type IIb
• Other Study ID Numbers: RP-NI-A501-0122

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No