Date: 2015-07-13
Type of information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of results in Human Molecular Genetics
Company: Summit Therapeutics (UK)
Product: SMT022357
Action
mechanism: utrophin modulator. SMT022357 is a small molecule drug that works by increasing production of a similar, naturally occurring protein called utrophin to replace the missing dystrophin. 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.
Disease: Duchenne muscular dystrophy
Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases
Country:
Trial details:
Latest
news: * On July 13, 2015, Summit Therapeutics, a drug discovery and development company advancing therapies for Duchenne muscular dystrophy (‘DMD’) and C. difficile infection, announced the publication of preclinical data on the disease-modifying
potential of utrophin modulation in the treatment of 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 muscle
regeneration, necrosis and fibrosis, the hallmark of DMD pathology. Interestingly, researchers found that utrophin was expressed across the entire length of the muscle fibre, likely contributing to its ability to significantly reduce disease progression in animal models. The data were published in the August 1, 2015 issue of Human Molecular Genetics. The paper, “Second-generation compound for the modulation of utrophin in the therapy of DMD,” describes the significant diseasemodifying
potential of SMT022357, a structurally related compound to SMT C1100, which has enhanced pharmaceutical properties.
In the reported study, SMT022357 treatment for five weeks resulted in increased utrophin expression, localized along the entire length of the muscle fibre membrane in both slow- and fast-twitch muscles. This addressed the primary cause of fibre 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 in DMD. 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.
The paper was authored by Simon Guiraud, Sarah E. Squire, Benjamin Edwards, Huijia Chen, David T. Burns, Nandini Shah, Arran Babbs, Stephen G. Davies, Graham M. Wynne, Angela J. Russell and Kay E. Davies of the University of Oxford, and David Elsey, Francis X. Wilson and Jon M. Tinsley of Summit Therapeutics (reference: Hum. Mol. Genet. (2015) 24 (15): 4212-4224).
