P.469 - Collection of high quality muscle biopsies for use in DMD clinical trial analysis; process development and implementation

Continuous expression of utrophin protein by a utrophin modulator has potential as a disease modifying treatment for Duchenne muscular dystrophy (DMD) patients regardless of their dystrophin mutation. Summit's lead utrophin modulator, ezutromid, is an orally administered, small molecule currently being dosed in a 48-week open label trial, PhaseOut DMD (see clintrials.gov NCT02858362). This proof of concept study includes analyses of utrophin protein (estimate of target engagement) and muscle fibre regeneration (a potential pharmacodynamic marker) from muscle biopsy samples, one taken at baseline and another at either 24 or 48 weeks. High quality muscle biopsies are essential for imaging analyses. Detailed biopsy manuals were developed for use by the surgical and laboratory teams at each site. With permission from Sarepta Therapeutics, manuals and training documents were modified to our specific clinical requirements. All sites were provided with detailed manuals and training sessions for relevant team members including surgeons and histotechnicians. One important training component involved practice of the freezing and shipping process using a beef sample. A pathologist from Flagship Bioscience then performed a quality control analysis of a beef cryosection from the shipped sample and confirmed successful site training prior to any patient biopsy. Biopsy samples from all UK and US sites were shipped to the Flagship Biosciences laboratory in the US for analysis. We have collected and assessed the quality of the biopsy samples from DMD boys in this way. In all cases, samples have been deemed of suitable quality for assay processing as confirmed by a pathologist's assessment of the stained cryosection. Using these biopsies and the recently developed validated imaging assays we expect to generate high quality data from all patients in the PhaseOut DMD study to evaluate target engagement and the effect of ezutromid on muscle fibre regeneration.