About Myotonic Dystrophy

Myotonic dystrophy is a genetic neuromuscular disorder that affects about 1 in 8,000 people. It is the most common form of muscular dystrophy, a term used to describe a family of disorders characterized by progressive weakness and degeneration of the skeletal or voluntary muscles that control movement.

As it progresses, myotonic dystrophy can also affect many other organs and systems in the body, including cognitive function, vision, breathing, cardiovascular health, CNS function and reproduction. Myotonic dystrophy type 1, or DM1, is a more severe form of the disease. The subtypes of DM1 are often determined by the age of onset, with congenital onset occurring at birth and in early childhood, juvenile onset occurring during childhood and adult onset occurring in late adolescence or early adulthood. The predominance of symptoms such as muscle weakness, intellectual/developmental impairment or cognitive/behavioral changes is determined by a number of factors, including age at onset.

Myotonic 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 most cases disease progression is gradual and chronic; symptoms often do not appear or become severe until adulthood. As a result, DM1 is often not diagnosed until later in life. Genetic testing along with a physical examination and review of family medical history are used to confirm a diagnosis of myotonic dystrophy.

The prognosis for people living with myotonic dystrophy will depend on the type and severity of the disease. Increased risk of death associated with DM1 is most often caused by related respiratory and cardiac diseases. Disease progression and the impact on both physical and cognitive function can make it difficult or impossible for many people living with DM1 to work, handle day to day responsibilities, or live independently. There are currently no approved therapies to treat DM1. Patients are typically treated with therapies to control certain symptoms including daytime sleepiness and myotonia.

About AMO-02

AMO-02 (tideglusib) is in development for the treatment of congenital myotonic dystrophy and has potential for use in additional CNS, neuromuscular and oncology indications. AM0-02 is positioned to enter clinical stage development for the treatment of the severe form of congenital myotonic dystrophy known as DM1 or Steinert disease. In cellular and animal models of DM1 and Duchenne muscular dystrophy, as well as in muscle biopsies from patients, activity of glycogen synthase kinase 3 beta (GSK3ß) has been shown to increase. Inhibitors of GSK3ß have been shown to correct the activity of RNA binding proteins, such as CUGBP1 in animal models of DM1. AMO-02 is an inhibitor of GSK3ß that has demonstrated pre-clinical efficacy in transgenic models and reversal of muscle cell deficits in ex vivo tissue samples in patients with DM1.

Inhibition of increased levels of GSK3ß is known to reverse cognitive and behavioral deficits in transgenic models of syndromic autism, a developmental disorder characterized by social communication deficits and repetitive behaviors.

Jones, Timchenko, et al. 2012. J. Clin. Invest. 122(12), 4461-4472.
Jones, Timchenko et al. 2015. PNAS 112 (26), 8041-8045.

Development & Clinical Trial Update

AMO has initiated a phase 2 clinical study in the United Kingdom for AMO-02 (tideglusib) for the treatment of congenital myotonic dystrophy. This phase 2 exploratory study focuses on patients with congenital and juvenile onset myotonic dystrophy. This is the first sponsor-led clinical study evaluating an investigational therapy in this patient group as part of a development program. Earlier in 2016 AMO Pharma completed discussions with the U.S. Food and Drug Administration (FDA) for a planned investigational new drug (IND) application for AMO-02. AMO is planning additional global studies of AMO-02 in both congenital and adult onset myotonic dystrophy. Based on FDA feedback, AMO Pharma is currently working to finalize plans to advance its clinical development program.

More information on the Phase 2 clinical trial for AMO-02 in congenital myotonic dystrophy can be found at https://clinicaltrials.gov/ct2/show/NCT02858908.