of the Project This project is proposing a Phase I clinical study in pediatric and adolescent patients with Congenital Muscular Dystrophy (CMD). It is a randomized, open-label, sequential group, ascending oral dose, cohort study assessing pharmacokinetics (PK), safety and tolerability of omigapil in up to 20 patients. Rationale of the proposed study No medicine is currently approved for CMD or in advanced clinical development and therapeutic strategies are largely restricted to the management of symptoms by physiotherapy, nocturnal ventilation and surgery. The rationale for undertaking this clinical development programme in CMD is based on the antiapoptotic mechanism of action of omigapil. Apoptosis is involved in the death of muscle cells in several types of CMD, and beneficial effects were demonstrated in animal models of CMD treated with omigapil. Omigapil has been used in over 1100 adult healthy volunteers and patients. However, for development of this compound in CMD it is important to study the PK and safety profile (i) in children and adolescents, (ii) in patients with CMD and (iii) in a liquid formulation suitable for this patient population. Study objectives The primary objective of this study in paediatric and adolescent patients with CMD is to establish the PK profile of omigapil at a range of potentially therapeutic doses. The secondary objective is to evaluate the safety and tolerability and the tertiary objective is to establish the feasibility of conducting disease-relevant clinical assessments to aid the design of future studies. Methods The study is conducted in 3 cohorts each of which is assessing the PK profile at a different dose and which start sequentially after safety assessment of the previous dose. Safety and tolerability are assessed at every visit by evaluation of adverse events, physical examination, vital signs, ECG, pulse oximetry, liver ultrasound, laboratory assessments as complete blood cell counts (CBC), comprehensive metabolic panel (CMP) and urine analysis. The feasibility of using efficacy assessments for future studies will be evaluated through the following tests: hospital and home-based pulmonary function, motor function and functional scales, time tests and hospital-based evaluation of muscle strength and function.
Congenital Muscular Dystrophy (CMD) is a devastating condition characterized by progressive loss of muscle tissue starting at birth. Furthermore, severe forms of CMD cause immobility frequently at a young age and reduced life expectancy. There is no approved pharmaceutical treatment or in advanced clinical development. Available supportive treatment is only symptomatic and most patients do not survive to adolescence. Apoptosis has been demonstrated to be involved in the loss of muscle cells in CMD and omigapil has been shown to have antiapoptotic effects. Beneficial effects due to this mechanism were demonstrated in animal models of CMD treated with omigapil and therefore is it proposed to test omigapil for the treatment of patients with CMD. This project is focussing in particular on establishing the pharmacokinetics, how the drug is tolerated in children and adolescents and which clinical parameters are suitable in this patient population. The outcome of this study will form an essential basis for future efficacy studies with omigapil in CMD in order to make a potential treatment available to these severely affected patients.
