Expert Consensus on Dystrophin and Creatine Kinase as Predictors of Clinical Benefit in Duchenne Muscular Dystrophy: a RAND/UCLA Modified Delphi Panel

Topic:

Clinical Management

Poster Number: 29 S

Author(s):

Edward Smith, MD, Rare Disease Research, Lindsay Alfano, PT, DPT, PCS, Nationwide Children's Hospital, John Brandsema, MD, Children's Hospital of Philadelphia, Tina Duong, PT, PhD, Stanford University School of Medicine, Katherine Mathews, MD, University of Iowa, Iowa City, Iowa, USA, Leigh Ramos-Platt, MD, Children’s Hospital Los Angeles, Aravindhan Veerapandiyan, MD, Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US, Brenda Wong, MD, Duchenne Muscular Dystrophy Program, UMass Chan Medical School, Craig M. Zaidman, MD, Department of Neurology, Washington University in St Louis, St Louis, MO, USA, Justin Weiss, MPH, ADVI Health, Irina Yermilov, MD, ADVI Health

Background: Duchenne muscular dystrophy (DMD) is characterized by reduced dystrophin protein leading to muscle destruction evidenced by elevated creatine kinase (CK) levels. This leads to progressive motor and cardiopulmonary dysfunction. However, data quantitatively linking changes in dystrophin and CK levels to long-term outcomes–particularly in exon-skipping therapies–remain limited. We aimed to develop consensus on how changes in these biomarkers may predict functional and clinical outcomes.
Methods: We used a double-blinded RAND/UCLA modified Delphi method with nine US panelists (seven pediatric neurologists, two physical therapists). Panelists reviewed 376 hypothetical scenarios across disease stages (early/late ambulatory, early/late non-ambulatory) with specified dystrophin and CK levels 3 months after exon-skipping initiation. Panelists rated predicted impacts on motor, cardiac, and pulmonary outcomes at 3 years on a 1-9 scale before and after a virtual meeting. Confidence was scored from 1 to 9. Disagreement was defined as >2 panelists rating a scenario on the extremes of the scale (1-3 and 7-9).
Results: Panelists disagreed on <1% of scenario ratings following the meeting, compared with 34% prior. The panel predicted the greatest impact when substantial biomarker changes (>21% dystrophin and a >75% decrease in CK levels) occur during earlier stages of disease. Increases in dystrophin and reductions in CK were predicted to most strongly influence motor function, with smaller and more uncertain effects on pulmonary and cardiac outcomes.
Conclusion: This expert panel reached strong consensus that DMD clinical outcomes favor patients with greater increases in dystrophin and larger reductions in CK during earlier disease stages. These findings support the clinical relevance and utility of dystrophin and CK as early biomarkers of treatment benefits in patients receiving exon-skipping therapies.