source: American Academy of Neurology
Jon Tinsley, Neil Robinson, Francis Wilson, Graeme Horne, Kay Davies
To progress SMT C1100, Summit’s utrophin upregulator molecule into DMD clinical trials. This is the first disease modifying approach potentially benefiting all DMD patients regardless of dystrophin mutation.
DMD is the most common form of muscular dystrophy due to an inability to make dystrophin, resulting in loss of skeletal muscle. During foetal muscle development utrophin takes the functional role of dystrophin. Continual muscle expression of utrophin can functionally replace dystrophin potentially overcoming the dystrophin deficit in DMD. In animal studies, daily SMT C1100 treatment significantly reduced muscle pathology leading to better muscle function. A Phase 1, double-blind, placebo-controlled study has been completed in healthy male subjects. The data were supportive of SMT C1100 moving into DMD patient trials.
Plans for the first patient trials of SMT C1100 have been developed consisting of two components; a safety and dose finding study in DMD boys in late 2013 followed by a proof of concept study in 2014. In order for proof of concept to be demonstrated in patients, a multicomponent biomarker strategy has been implemented that comprises of two modules. We aim to quantify utrophin RNA, total utrophin protein and utrophin fibre localisation derived from pre- and post-dose biopsies. To determine a reduction in the rate of degeneration, i.e. increase in mature fibre survival, changes in the percentage of newly regenerating fibres will be calculated from the biopsies. Using serum and urine samples we will quantify the levels of specific miRNAs associated with fibre leakage and protein markers of fibrosis and inflammation.
Preliminary data from the Phase 1b safety and PK study will be discussed. The rationale for the choice of exploratory biomarkers proposed for the Phase 2 proof of concept trial will be described.
This is the first example of a utrophin upregulation therapy to enter the clinic with the potential to treat all DMD patients.
Department of Physiology Anatomy and Genetics Oxford, UK; Summit plc, UK