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Multicenter Study
. 2025 Jun;12(6):1179-1186.
doi: 10.1002/acn3.70049. Epub 2025 Apr 16.

Clinical Trial Readiness in Limb Girdle Muscular Dystrophy R1 (LGMDR1): A GRASP Consortium Study

Stephanie M Hunn  1 , Lindsay N Alfano  2   3 , Aileen Jones  4 , Amanda Butler  4 , Linda P Lowes  2   3 , Megan A Iammarino  2 , Natalie F Reash  2 , Lindsay Pietruszewski  2 , Sandhya Sasidharan  5 , Melissa Currence  5 , Jeffrey M Statland  5 , Talia Strahler  6 , Robert Will  6 , Matthew Wicklund  6 , Stacy Dixon  6 , Renee Augsburger  7 , Tahseen Mozaffar  7 , Katie M Laubscher  8 , Shelley R H Mockler  8 , Katherine D Mathews  8 , Nikia Stinson  9 , Doris G Leung  9 , Molly M Stark  10 , Rebecca A Horton  10 , Peter B Kang  10 , Meredith K James  11 , Amanda Clause  1 , Conrad C Weihl  1 , Nicholas E Johnson  4 ; GRASP‐LGMD Consortium
Affiliations
Multicenter Study

Clinical Trial Readiness in Limb Girdle Muscular Dystrophy R1 (LGMDR1): A GRASP Consortium Study

Stephanie M Hunn et al. Ann Clin Transl Neurol. 2025 Jun.

Abstract

Objective: Identifying functional measures that are both valid and reliable in the limb girdle muscular dystrophy (LGMD) population is critical for quantifying the level of functional impairment related to disease progression in order to establish clinical trial readiness in the context of anticipated therapeutic trials.

Methods: Through the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Consortium, 42 subjects with LGMDR1 were enrolled in a 12-month natural history study across 11 international sites. Each subject completed a battery of clinical outcome assessments (COA), including the North Star Assessment for Limb Girdle-Type Dystrophies (NSAD), 10-m walk/run, and Performance of the Upper Limb (PUL), in addition to several patient-reported outcome measures (PROM).

Results: In this baseline cross-sectional analysis, significant correlations were found between COAs and PROMs, with significant differences in the performance of assessments based on subjects' ambulatory status and genetic variant classification.

Interpretation: The study has determined that the NSAD and other assessments are valid and reliable measures for quantifying the level of disease impairment in individuals with LGMDR1.

Keywords: limb girdle muscular dystrophy; natural history; outcome measures.

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Conflict of interest statement

Dr. Hunn has received a travel award from Coalition to Cure Calpain 3 (C3). Dr. Alfano received consultant fees from Amicus Therapeutics and Asklepios Biopharmaceutical and receives funding via her institution and royalties from Sarepta Therapeutics. Dr. Lowes has joined Sarepta Therapeutics since the completion of this study. Dr. Iammarino serves as a consultant for ATOM international and receives salary support to her institution from Sarepta Therapeutics. Dr. Reash serves as a consultant for ATOM International and receives salary support to her institution from Sarepta Therapeutics. Dr. Statland has received grant funding from the NIH, MDA, CDC, FSHD Society, Friends of FSH Research, FSHD Canada, and ALSA; he is on the advisory board or serves as a consultant for Dyne, Avidity, Fulcrum, Roche, Kate, Sanofi, Epic Bio, ML Bio, Vertex, MireCule, and Merck. Dr. Dixon has served on advisory boards for Sarepta, Biogen, Genetech, Argenx, Alexion, Immunovant, and CSL Behring. Dr. Mozaffar has received research funding from ML Bio. He has consulted for Ask Bio. Dr. Laubscher receives support through her institution via funding from Edgewise Therapeutics, Italfarmaco, MLBio Solutions, Pfizer, Sarepta Therapeutics, and Virginia Commonwealth University. She is a paid consultant for ATOM International. Dr. Mockler receives funding from NIH grant 2 U54 NS053672‐11. She provides consultation services for ATOM International Limited, which includes consultation for Edgewise Therapeutics, Italfarmaco SpA, MLBio, NS Pharma, Pfizer, PTC Therapeutics Inc., Sarepta Therapeutics Inc., Capricor Therapeutics, AskBio, Biohaven, Dyne Therapeutics, PepGen, REGENXBIO Inc., Entrada Therapeutics, and Vertex Pharmaceuticals. Dr. Leung's institution has received research funding from Asklepios BioPharmaceutical Inc., Avidity Biosciences, Cumberland Pharmaceuticals, Edgewise Therapeutics, F. Hoffmann‐La Roche AG, Fulcrum Therapeutics, Harmony Biosciences, ML Bio Solutions Inc., Pfizer Inc., Sarepta Therapeutics, Seattle Children's Research Institute, the University of Kansas Medical Center Research Institute, and Virginia Commonwealth University. Dr. Kang has received research funding from Sarepta Therapeutics and ML Bio. He has served on advisory boards for ITF Therapeutics and Lupin Pharmaceuticals, and has consulted for Neurogene. Dr. James provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd., Ascendis Pharma, Biomarin, Edgewise, Genethon, Italfarmaco, MLBio, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics, Sarepta Therapeutics). Meredith has participated on Advisory Boards for F. Hoffman La Roche AG, Sarepta Therapeutics, and consultancies with Sarepta Therapeutics, Amicus, and Sanofi with fees paid to Newcastle University, and received fee support for PhD studies from the Jain Foundation. Dr. Clause has received consulting fees from Sarepta. Dr. Weihl has received funding and consulting fees from MLBio and Sarepta. Dr. Johnson has received research funds from Novartis, Takeda, PepGen, Sanofi Genzyme, Dyne, Vertex Pharmaceuticals, Fulcrum Therapeutics, AskBio, ML Bio, and Sarepta. He has provided consultation for Arthex, Angle Therapeutics, Juvena, Rgenta, PepGen, AMO Pharma, Takeda, Design, Dyne, AskBio, Avidity, and Vertex Pharmaceuticals. He has stock options from Myogene Therapies, Repeat RNA therapeutics, Angle therapeutics, and Juvena.

Figures

FIGURE 1
FIGURE 1
Inter‐visit reliability: Bland–Altman plots of variability in scoring between Baseline Day 1 and Baseline Day 2 of the NSAD (A), 10 m (B), and 9HPT (C) to evaluate inter‐visit reliability of individual COAs. Data points outside of allowed scoring ranges are considered unreliable. The NSAD (A) demonstrated random individual patient variability within the acceptable range while the 10 m (B) shows acceptable individual variability with a trend toward decreasing performance over the visits. The 9HPT (C) demonstrated significant individual variability despite high group reliability measured by ICC.
FIGURE 2
FIGURE 2
NSAD and PUL Comparison: Linear regression models of NSAD and PUL comparing performance between Cohort A and Cohort B (A, B) and between variant classification groups (C, D). Both the NSAD (A) and PUL (B) show a significant difference between Cohorts A and B, with higher scores seen in Cohort A indicating stronger functional abilities. There was no detectable difference in the performance of variant groups of the NSAD (C) or PUL (D).
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