Quantitative Muscle Analysis in FSHD using Whole-Body MRI: Composite Muscle Measurements for Cross-Sectional Analysis

Topic:

Clinical Trials

Poster Number: 72

Author(s):

Per Widholm PhD, Markus Karlsson PhD, Andre Ahlgren , Olof Dahlqvist Leinhard PhD, Rabi Tawil MD, Kathryn Wagner MD, PhD, Jeffery Statland MD, Leo Wang MD, Perry Shieh MD, PhD, Baziel Van Engelen MD, PhD, Diego Cadavid MD, Lucienne Ronco PhD, Adefowope Odueyungbo PhD, Jay Han MD, Maya Hatch PhD, Michelle Mellion MD

Institutions:

1. AMRA Medical AB, 2. AMRA Medical AB, 3. AMRA Medical AB, 4. AMRA Medical AB, 5. University of Rochester, 6. Kennedy Krieger Institute & Johns Hopkins School of Medicine, 7. University of Kansas Medical Center, 8. University of Washington, 9. University of California, Los Angeles, 11. Fulcrum Therapeutics, 12. Fulcrum Therapeutics, 14. UC Irvine, School of Medicine, Department of Physical Medicine and Rehabilitation, 15. University of California Irvine, 16. Fulcrum Therapeutics

Objective: Develop an optimized whole-body MRI protocol and composite analysis that correlates with clinical outcome assessments in Facioscapulohumeral Muscular Dystrophy (FSHD).

Background: Functional assessments show limited sensitivity in detecting slowing or arrest of disease progression in FSHD. MRI can potentially detect pathological changes in muscle prior to changes in clinical outcome assessments (COA). Several groups have observed correlations between MRI skeletal muscle fat fraction (MFF) and COAs.

Fulcrum is developing losmapimod, a small molecule inhibitor of p38 MAPK α/β, to reduce DUX4 expression with the intent to decrease/arrest replacement of muscle by fat.

Methods: This was a prospective, longitudinal, observational, multicenter study. Seventeen adults with FSHD1, aged 18 to 65, were enrolled at 6 sites, imaged at baseline and 4 to 12 weeks later. Volumetric analysis of 36 muscles included the shoulder girdle and upper arm (upper extremity (UE)), torso, and lower extremities (LE). Muscles were identified by an automated atlas-based segmentation that was manually verified. Composite scores were generated for muscles associated with COAs including LE for timed up and go (TUG), UE/LE and torso for FSHD-TUG, and UE and trunk muscles for reachable workspace (RWS). MRI endpoint measures included MFF, muscle fat infiltration (MFI) and lean muscle volume (LMV).

Results: Total LMV (Pearson’s r=0.9984), MFI (r=0.9845) and MFF (r=0.9918) showed strong correlations between the two timepoints. The composite total MFF and MFI (MFFtot and MFItot) for the LE muscles (10 total) correlated with TUG, 0.72 and 0.83 respectively; UE/LE and trunk muscles (36 total) for FSHD-TUG, 0.73 in both measures and composite total MFF for the UE and trunk muscles (26 total) with RWS (r=0.85).

Conclusions: There was strong cross-sectional correlation between whole-body MRI- composite measurements and COAs. MRI measurements can potentially provide important information about disease severity and progression as it correlates with FSHD relevant clinical endpoints.