Utrophin modulators to treat Duchenne muscular dystrophy (DMD): Phase 1b Clinical Trial Results of SMT C1100 (P2.006)

Objective: To assess the safety, tolerability and pharmacokinetics of SMT C1100; the first ever utrophin modulator molecule to enter clinical trials for Duchenne muscular dystrophy (DMD) patients. Background: In DMD skeletal muscle is lost due to an inability to produce dystrophin. During foetal muscle development utrophin takes the functional role of dystrophin. Continuous muscle expression of utrophin could functionally replace dystrophin and potentially overcome the dystrophin deficit in DMD. In dystrophic animal studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. A Phase 1, double-blind, placebo-controlled study has been completed in healthy male subjects with data supportive of SMT C1100 moving into DMD patient trials. Design/Methods: This was a multi-centre Phase 1, open-label, single and multiple oral dose, safety, tolerability and pharmacokinetic study in 12 male DMD patients aged between 6 and 11 years. A sequential group design was chosen and three groups consisting of 4 patients were sequentially dosed at 50 mg/kg bid, 100mg/kg bid and 100mg/kg tid orally. Results: All oral doses of SMT C1100 were safe and well tolerated in paediatric DMD patients. The most frequently reported adverse events following dosing was pale faeces, considered related to study drug and mild in severity. There were no clinically significant findings in laboratory evaluations, vital signs, ECGs or physical examinations during the study. SMT C1100 was rapidly absorbed, but exhibited high between-patient variability with a number of boys achieving lower systemic exposures than anticipated. In the majority of the boys, serum biomarkers indicative of muscle damage decreased during the dosing phase. Conclusion: Data from this trial has helped to design the next SMT C1100 trial in DMD boys which looks at the effect of diet on drug absorption and allows muscle damage biomarker observations to be assessed under placebo controlled conditions. Disclosure: Dr. Tinsley has received personal compensation for activities with Summit PLC as an employee. Dr. Tinsley holds stock and/or stock options in Summit PLC. Dr. Muntoni has received personal compensation for activities with AVI BioPharma as an advisory board member. Dr. Spinty has received research support from Summit plc. Dr. Roper has received research support from Summit plc. Dr. Hughes has received research support from Summit plc. Dr. Ricotti has nothing to disclose. Dr. Bracchi has received personal compensation for activities as an employee. Dr. Tejura has received personal compensation for activities with Summit plc as an employee. Dr. Roblin has received personal compensation for activities with Summit plc as a consultant. Dr. Layton has received personal compensation for activities with Summit plc as a consultant. Dr. Davies has received personal compensation for activities with Summit plc as a consultant. Dr. Davies holds stock and/or stock options in Summit plc.