Enzalutamide treatment with SMT C1100 significantly reduces this damage by virtue of the reduced fibre regeneration. Blinded analysis by a boardcertified veterinary pathologist of muscle sections from mdx mice dosed with either ABT-263 vehicle or SMTC1100 demonstrated a significant reduction in both inflammation and fibrosis. Whole muscle sections were rated with a pathology score on a scale from normal �C mild �C moderate �C severe. Pooled averages of total scoring from the TA, EDL and soleus are shown. A qualitative example of the extent of inflammation from a SMT C1100-dosed EDL or vehicle dosed EDL is shown where the SMT C1100 section was scored as mild and the mdx as moderate. This data confirms the concept of reduced fibre damage due to utrophin localization leading to reduced inflammation and fibrosis. A forced exercise regime of chronic exercise was used as a strategy to worsen the murine pathology. Five week old mdx mice underwent forced treadmill exercise twice a week and the effects of daily SMT C1100 treatment under this exercise regime were then evaluated. This exercise protocol significantly worsens in vivo parameters readily evaluated by non-invasive approaches, such as fore limb grip and endurance tests. In particular, the exercise protocol induced the typical decrease of fore limb force in vivo over time; a reduction which is seldom observed in sedentary mdx. SMT C1100-treated mdx showed a significant protection against exercise-induced fore limb weakness, as demonstrated by both the maximal strength achieved and the increase in strength after four weeks of dosing. After four weeks of dosing both values from the SMT C1100-dosed mdx were equivalent to those observed in sedentary mdx and wild type mice. Data with direct relevance to DMD treatment was generated using a fatigue assessment of the mice which underwent forced exercise. Fatigue was assessed in an acute endurance test and estimated as the maximal distance run before exhaustion. Sedentary mdx mice, although run for a shorter distance than wild type, maintain the same exercise performance over time, whilst the exercised mdx demonstrate a dramatic increase in fatigability between the start and the fourth and fifth week of training. A partial restoration of the resistance to fatigue was observed in SMT C1100-dosed mice, with an increase in distance travelled of around 50% compared to vehicle only after 5 weeks of dosing. Interestingly, this effect was similar to that observed in the exercised mdx mice treated with PDN; which is currently the gold standard in clinical treatment for Duchenne patients. Significant synergy was observed when SMT C1100 was co-administered with PDN for five weeks. The forced exercise mdx were completely resistant to fatigue and were able to continue running as far as the sedentary mdx. This equated to an increase in distance travelled of around 350% compared to the vehicle-treated forced exercise mdx.