Summit publishes preclinical data on utrophin modulation in DMD

Upon modulation of utrophin protein with the second-generation utrophin modulator SMT022357, in-vivo models of DMD showed significantly improved muscle stability and a marked reduction of the muscle regeneration, necrosis and fibrosis that are at the core of DMD pathology. Among the findings of the research published in the Aug. 1, 2015, issue of Human Molecular Genetics was that utrophin was expressed across the entire length of the muscle fiber, likely contributing to its ability to significantly reduce disease progression in animal models.

“These data strongly support utrophin modulation as a potentially valuable mechanism to treat DMD and highlight the importance of the continued development of second-generation, orally available utrophin modulator candidates,” according to Prof. Dame Kay E. Davies of the University of Oxford. “There is tremendous therapeutic potential for utrophin modulation in this devastating disease because there is currently no approved disease-modifying therapy applicable to all patients with DMD, and many other candidates in clinical development are restricted to a single mutation.”

In the published report, titled “Second-generation compound for the modulation of utrophin in the therapy of DMD,” the authors write that “DMD is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD, although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration, leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile.

“These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fiber, not just at the synapse, and is fiber-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction-induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease-modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.”

Utrophin is structurally and functionally similar to dystrophin, the protein which is lacking in boys with DMD, and is normally present during muscle development and repair. By modifying utrophin to be continuously produced in boys with DMD, this potentially disease-modifying approach could circumvent the need for dystrophin in all patients with this devastating disease.

In the reported study, SMT022357 treatment for five weeks resulted in increased utrophin expression, localized along the entire length of the muscle fiber membrane in both slow- and fast-twitch muscles. This addressed the primary cause of fiber degeneration and increased muscle stability in hind-limb muscles of the mdx mouse, which resulted in reduced regeneration and necrosis, enhanced protection of the muscle against contraction-induced damage and improved muscle function. Utrophin expression in the heart and diaphragm is highly desirable in DMD as loss of function in these organs is life-limiting. Treatment with SMT022357 resulted in significant increases in utrophin expression in both the heart and diaphragm. Notably SMT022357 treatment resulted in reduced fibrosis in the diaphragm, a significant observation due to the disease pathology in the diaphragm of the mdx model closely resembling that of DMD patients. These data suggest that SMT022357 results in significant improvement in the pathology of DMD and could represent a disease-modifying therapeutic strategy for all patients with DMD.

DMD is a progressive muscle-wasting disease that affects around 50,000 boys in the developed world. The disease is caused by different genetic faults in the gene that encodes dystrophin, a protein that is essential for the healthy function of all muscles, and life expectancy is typically only into the late 20s.

The researchers believe that utrophin modulation has the potential to slow down or even stop the progression of DMD, regardless of the underlying dystrophin mutation. It is also expected that utrophin modulation could potentially be complementary to other therapeutic approaches for DMD.