Second-generation compound for the modulation of utrophin in the therapy of DMD

Abstract

Duchenne muscular dystrophy (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 fibre, not just at the synapse, and is fibre-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.

The Pathogenesis and Therapy of Muscular Dystrophies

“…Clinical trials of SMT C1100 in boys with DMD are ongoing to confirm appropriate levels of exposure (ClinicalTrials.gov identifier NCT02383511). Preclinical studies of the compounds chemically related to SMT C1100 suggest that these second-generation molecules lead to increased utrophin expression in skeletal, respiratory, and cardiac muscles, resulting in improved sarcolemmal stability (93). These results endorse the therapeutic potential of utrophin modulation as a disease-modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.…”

Identification of serum protein biomarkers for utrophin based DMD therapy

“…Glucocorticoid treatment is the current standard of care which delays the loss of ambulation by 3-4 years 7,8 but shows no long treatment benefit and is often associated with debilitating side effects [9][10][11] . The urgency to seek a therapy for DMD has resulted in parallel efforts to develop exon skipping 12,13 , termination codon read through 14 , dystrophin gene replacement or editing therapies 15,16 and non-dystrophin strategies [17][18][19] such as utrophin modulation 20,21 . However, despite the recent accelerated approval of Exondys 51 (eteplirsen) in US, disappointing clinical trials results 22 and failure of approval from the FDA for Ataluren 23 and Kyndrisa 24 drugs rekindle discussions about clinical trials designs and endpoints.…”

Advances in the Treatment of Duchenne Muscular Dystrophy: New and Emerging Pharmacotherapies

“…Utrophin is localized to the neuromuscular and myotendinous junctions and upregulated only when a muscle is being repaired . The expression and prevalence of utrophin is increased in DMD but not to the extent that would decrease dystrophic symptoms . Considering the similarity between utrophin and dystrophin, ongoing studies are evaluating whether utrophin is an effective substitute for dystrophin in patients with DMD.…”

“…In addition to ezutromid, another utrophin modulator is in development. SMT022357 is an oral second‐generation utrophin modulator that decreased muscle damage in mdx mice …”