London-based orphan drug developer AMO Pharma’s drug AMO-02 has been granted FDA fast track status as treatment for congenital myotonic dystrophy, a sub-indication muscular dystrophy.
AMO-02 (tideglusib), an inhibitor of glycogen synthase kinase 3 beta (GSK3beta), is currently undergoing Phase II safety testing in adolescents and adults with myotonic dystrophy. The form of the inherited defect, apparent at birth, is termed congenital DM1. It leads to weak muscle tone (hypotonia), an inward- and upward-turning foot, breathing problems, delayed development, and intellectual disability in newborns.
Myotonic dystrophy, the most common form of muscular dystrophy, is caused by a mutation in the dystrophia myotonica protein kinase (DMPK) gene that results in an expanded CTG triple (trinucleoide) repeat. The severity of the condition varies with the number of these repeats. The usual form of the DMPK gene has five to 30 repeat copies. Mildly affected individuals have from 50 to 80 repeats and children with the severe congenital form of the condition have 2,000 or more copies of the repeat. The mutant DMPK mRNA transcripts containing the repeats change the regulation and activity of RNA binding proteins, such as CUG-binding protein 1 (CUBP1), in the affected cells, leading to the DM1 pathology.
In cellular and animal models of congenital DM1 and Duchenne muscular dystrophy, as well as in muscle biopsies from patients, activity of GSK3beta is increased. Inhibitors of the enzyme have been shown to correct the activity of RNA binding proteins, such as CUGBP1, in animal models of DM1. AMO-02 has shown pre-clinical efficacy in transgenic animals and reversal of muscle cell differentiation deficits in ex vivo tissue samples derived from patients with congenital DM1.
“Our ongoing phase 2 clinical trial for AMO-02 in the UK is the first sponsor-led clinical study in the treatment of congenital myotonic dystrophy and represents a historic milestone in research and a new era of hope for patients and their families affected by this serious condition,” said AMO Pharma’s CEO and co-founder, Mike Snape.