To identify a panel of DUX4-regulated gene transcripts pathologically expressed in FSHD muscle biopsies to measure treatment effect of losmapimod on the root cause of the disease. 

Both genetic types of FSHD are caused by the pathogenic expression of the homeobox transcription factor DUX4.  Aberrant DUX4 expression in skeletal muscle results in profound transcriptional dysregulation and a characteristic DUX4-regulated transcriptional signature leading to myofiber death and the replacement of muscle with fat.

Clinical evaluation of the p38a/b inhibitor losmapimod is ongoing in FSHD including assessment of efficacy for inhibition of DUX4 expression in affected skeletal muscle. While pharmacodynamic detection of DUX4 protein and DUX4 mRNA in FSHD muscle is challenging, this is not the case for DUX4-regulated gene transcripts which are readily detected at sites of active disease (Wang, 2018). To support the development of a molecular efficacy endpoint for the treatment of the root cause of FSHD, we completed a preparatory biomarker study (FIS-002-2018) that included examination of repeated muscle biopsies from affected muscle tissue for evidence of DUX4 activity.

17 subjects were enrolled and 16 completed the FIS-002-2018 study.  The mean (SD) age was 49 (13) and 70% were males with a mean CSS of 3. Muscle needle biopsies were well tolerated.  Using published RNA sequencing data from a previous study (Wang, 2018) and new RNAseq data from this study, a subset of DUX4-regulated gene transcripts was identified based on consistent expression in repeated skeletal muscle needle biopsies of affected muscles identified by MRI.  

DUX4-regulated gene transcripts provide a pharmacodynamic biomarker endpoint to measure treatment effect for the root cause of FSHD in therapeutic clinical trials.  We have identified a panel of such transcripts that will be used to measureDUX4 activity in affected skeletal muscles from FSHD patients.