Duchenne Regulatory Science Consortium

Overview

The Problem

Duchenne Muscular Dystrophy (DMD) is a life-threatening disease caused by a genetic mutation in the DMD gene, leading to loss of ambulation, loss of upper limb function, and respiratory and cardiac failure. 

A major hurdle in improving treatments for DMD is the disease’s complexity, including its wide variety of genetic mutations. Researchers must consider factors such as the specific mutation type, disease stage, and patient age. Additionally, variable disease progression and the lack of standardized indicators complicate treatment assessment. 

The rarity of DMD, with approximately 20,000 new diagnoses per year, mostly in boys, further challenges clinical trials. The small patient population and the growing number of drugs in development make it difficult to recruit enough participants, leading to long trial durations and limited statistical power, which hinders the detection of treatment effects. 

The Solution

To combat these challenges, D-RSC has created an integrated database of patient-level clinical data from DMD studies. This database is partially available for analysis by the Duchenne community, as permitted by the dataset owners. Created by the Critical Path Institute (C-Path) and Parent Project Muscular Dystrophy (PPMD), D-RSC has developed standard terminology to integrate data and authored the CDISC Duchenne Muscular Dystrophy Therapeutic Area User Guide, which is available to the community. Utilizing its extensive database, D-RSC has developed a clinical data-sharing platform with improved semantic interoperability and completed the development of the first Clinical Trial Simulation tool for DMD, featuring five endpoints, and recently received a Letter of Support from the EMA, with additional regulatory review processes ongoing. 

In collaboration with C-Path’s Predictive Safety Testing Consortium, we are developing glutamate dehydrogenase (GLDH) as a safety biomarker for liver toxicity in patients with underlying muscle damage and have received a formal “letter of support” from EMA and positive response to the Qualification Plan for GLDH from the FDA. Future projects may include supporting the regulatory acceptance of other DMD-relevant biomarkers and patient reported outcomes or development of additional models to be leveraged for drug development. 

The Impact

The D-RSC team works every day to mitigate the effects of DMD and to bring new treatments to market faster. To do so, D-RSC provides: 

• The development of disease progression models of five endpoints to integrate into a quantitative solution – a Clinical Trial Simulation (CTS) tool
• Qualification of glutamate dehydrogenase as a liver safety biomarker in trials involving patients affected by muscle disorders. 
• Regulatory acceptance of Clinical Outcome Assessments (COAs) for DMD 
• Regulatory acceptance of quantitative tools based on MRI biomarkers for DMD and their relationship to disease progression 
• Models of additional endpoints as data become available 

How to Share Data with D-RSC

Share Data Here: https://portal.rdca.c-path.org/contribute-data

D-RSC promotes the sharing of patient-level data and encourages the standardization of new data collection. All shared rare disease data, including DMD and BMD, are collected in the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP®). By integrating data in a format suitable for analytics, RDCA-DAP accelerates the understanding of disease progression (including sources of variability to optimize the characterization of subpopulations), clinical outcome measures and biomarkers, and facilitates the development of mathematical models of disease and innovative clinical trial designs.

C-Path RDCA-DAP Portal: https://portal.rdca.c-path.org

D-RSC efforts and solutions are all data driven and the precious data shared become part of sophisticated regulatory ready solutions that are provided back to the community in form of freely available drug development tools to advance drug development in DMD and other dystrophinopathies.

D-RSC Database

The Duchenne Regulatory Science Consortium Database is open to non-consortium members if approved by a data use committee consisting of neutral members of the consortium. By sharing this resource, D-RSC aims to extend and amplify the availability of data to accelerate drug development for Duchenne muscular dystrophy. The database includes data from DMD clinical trials, natural history studies, and clinical data collections.

DMD Clinical Trial Simulation Tool

What is the DMD Clinical Trial Simulation Tool?

• A model-based clinical trial simulation platform aimed at optimizing clinical trial design of efficacy studies of potential therapies for Duchenne muscular dystrophy (DMD). 
• The D-RSC team developed models of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb and 10meter walk/run test or 30-foot walk/run test), as well as the longitudinal changes in forced vital capacity (FVC) and North Star Ambulatory Assessment total score (NSAA). 
• The longitudinal models incorporate relevant sources of variability, such as baseline severity at study start, age, steroid use (at baseline or naïve), genetic mutation, study type (clinical trial vs. observational), and race. 
• The EMA has issued a Letter of Support to encourage the further development and validation of the DMD Clinical Trial Simulation Platform, as well as encouraging sponsors to share patient-level data with the D-RSC team. 

Regulatory Successes & Publications

Regulatory Successes

• 2018: EMA Letter of Support for glutamate dehydrogenase, a biomarker of hepatocellular liver injury: in collaboration with the Predictive Safety Testing Consortium (PSTC) at C-Path 
• 2020: FDA accepted Letter of Intent submitted in collaboration with PSTC for clinical qualification of four skeletal muscle injury biomarkers (TNNI2, MYL3, FABP-3, CK-MM) 
• 2021: Led a Type B meeting with the FDA to discuss Master protocol development of a Master Protocol for the Duchenne Adaptive Platform Trial 
• 2022: EMA Letter of support on “A model-based clinical trial simulation tool to optimize clinical trial design of studies to investigate efficacy of potential therapies for Duchenne muscular dystrophy”  
• 2023: Submitted final briefing package to FDA for endorsement of two model based clinical trial simulation tools under the Fit-for-Purpose Initiative   
• 2024: Submitted response to two FDA Information Request letters on the final briefing package under review for endorsement of two model based clinical trial simulation tools under the Fit-for-Purpose Initiative   

Publications

• Published paper on “A Computational Tool to Optimize Clinical Trial Parameter Selection in Duchenne Muscular Dystrophy: A Practical Guide and Case Studies” (2024).   
• Published paper on “A model-informed clinical trial simulation tool with a graphical user interface for Duchenne muscular dystrophy” (2024).
• Published protocol entitled “A systematic review of the body of evidence for the use of protein biomarkers of muscular damage and disease progression in Duchenne and Becker Muscular Dystrophy” in PROSPERO (2024). 
• Published CDISC Duchenne Muscular Dystrophy Therapeutic Area User Guide v1.0 – Cardiac Imaging Supplement (2024). 
• Published paper on “Transforming Drug Development for Neurological Disorders: Proceedings from a Multidisease Area Workshop” (2023).
• Published paper on “Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials” (2023).
• Published paper on “Development of a model-based clinical trial simulation platform to optimize the design of clinical trials for Duchenne muscular dystrophy” (2021).
• Published paper on “Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy” (2020).
• Published paper on “Serum Glutamate Dehydrogenase Activity Enables Early Detection of Liver Injury in Subjects with Underlying Muscle Impairments” in partnership with the Predictive Safety Testing Consortium (2020).
• Published paper on “Seeking a Better Landscape for Therapy Development in Neuromuscular Disorders” (2018).
• Published CDISC Duchenne Muscular Dystrophy Therapeutic Area User Guide Version 1.0 (2017).

Collaborators

Founding Members

• Critical Path Institute
• Parent Project Muscular Dystrophy

Pharmaceutical Industry Members

• Dyne Therapeutics
• Edgewise Therapeutics
• Italfarmaco
• NS Pharma
• PepGen
• REGENXBIO
• Roche
• Sarepta Therapeutics
• Vertex
• Wave Life Sciences

Nonprofit Members

• CureDuchenne

Academic Advisor Institutions

• Binghamton University
• Children’s Hospital of Philadelphia
• Children’s National Health System
• Children’s National Heart Institute
• Cincinnati Children’s Hospital Medical Center
• Hadassah Medical Center
• Icahn School of Medicine at Mount Sinai
• Indiana University School of Medicine
• KTH–Royal Institute of Technology
• Leiden University Medical Center
• Nationwide Children’s Hospital
• Oregon Health & Science University
• Paris Cité University
• Stanford University
• UMass Memorial
• University of Arizona
• University of California, Davis
• University of Florida
• University of Leicester, UK
• University of Messina, Italy
• University of Oxford
• Vanderbilt University Medical Center

Patient Advocate Advisors

• Mindy Cameron, AdvocacyWorks
• Ryan Russell, Life on Positivity
• Adith Thummalapalli, Parent Project Muscular Dystrophy
• Colin Werth, Parent Project Muscular Dystrophy

Government and Regulatory Advisors

• Pavel Balabanov, EMA
• Atul Bhattaram, FDA
• Michelle Campbell, FDA
• Emily Freilich, FDA
• Ami Mankodi, FDA
• Veneeta Tandon, FDA
• Emily Carifi, NIH/NIAMS

Team

Co-Directors

C-Path Team