Development and Evaluation of a whole-body MRI imaging protocol and analysis algorithms to measure changes in skeletal muscle in FSHD


Preclinical Trial Design & Biomarker Development

Poster Number: 142


Diego Cadavid, MD, Michelle Mellion, MD, Shane Raines, PhD, Per Widholm, Olof Dahlqvist Leinhard


1. Fulcrum Therapeutics, 2. Fulcrum Therapeutics

Objective: Establish a whole-body MRI imaging protocol and analysis algorithms to measure replacement of skeletal muscle tissue by fat in FSHD.
Background: FSHD is caused by loss of repression at the D4Z4 locus resulting in aberrant expression of the homeobox transcription factor DUX4. DUX4 activates a downstream transcriptional program resulting in skeletal muscle loss and motor disability characterized by slowly progressive descending weakness. Clinical severity, ambulation, and muscle strength are strongly correlated with muscle fat fraction (MFF) as measured by musculoskeletal fat-water separated MRI (MSK-MRI). There is little established consensus on standards for repeatability, reproducibility, and measurement error in whole-body MSK-MRI (WB-MSK-MRI) of individual muscles for multicenter trials.
Fulcrum Therapeutics is developing losmapimod, a selective small molecule inhibitor of p38α/β, to reduce DUX4 expression. An effective treatment for FSHD is expected to reduce or arrest the progression of muscle replaced by fat. A preparatory biomarker study was performed to evaluate, optimize and standardize a WB-MSK-MRI protocol for losmapimod trials.
Methods: 17 adults with FSHD1 aged 18 to 65 were enrolled at 6 sites. 16 patients completed the study and were imaged twice 4 to 12 weeks apart. Volumetric analyses of 18 different individual muscles or muscle groups from shoulder, proximal arm, trunk and legs were performed bilaterally. Outcomes included MFF, lean muscle volume (LMV), and muscle fat infiltration (MFI).
Results: All but one patient tolerated the repeated MRI protocol well. Measurement of total MFF (r=0.992), LMV (Pearson’s r=0.998) and MFI (r=0.985) and showed strong correlations between the two timepoints.
Conclusions: An optimized WB-MSK-MRI protocol feasible for repeated quantification of MFF, LMV, and MFI in most muscles and muscle regions in FSHD has been developed. These efficacy MRI measures are currently being used in losmapimod clinical trials.