- Email: [email protected]
Discovery of small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy (DMD)
S260
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
including those from novel biomarkers will set the scene for the pivotal clinical development of rimeporide as new therapeutic option for the treatment of patients with DMD. http://dx.doi.org/10.1016/j.nmd.2015.06.269
G.P.245 Second generation utrophin modulator for the therapy of Duchenne muscular dystrophy S. Guiraud *,1, S. Squire 1, B. Edwards 1, H. Chen 1, D. Burns 1, N. Shah 1, A. Babbs 1, S. Davies 2, G. Wynne 2, A. Russell 3, D. Elsey 4, F. Wilson 4, J. Tinsley 4, K. Davies 1 1 MRC – University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK; 2 Department of Chemistry, University of Oxford, Oxford, UK; 3 Department of Pharmacology, Department of Chemistry, University of Oxford, Oxford, UK; 4 Summit Therapeutics plc, Oxford, UK Duchenne muscular dystrophy (DMD) is a devastating, X-linked musclewasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches (e.g. stop codon readthrough, exon skipping, gene therapy) are progressing through human clinical trials. By pharmacologically modulating the dystrophin-related protein utrophin, we aim to develop a therapy applicable to all DMD patients, regardless of the underlying genetic fault in the dystrophin gene, by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit Therapeutics, we previously developed SMT C1100, an oral utrophin modulator that reduces dystrophic symptoms in the mdx mouse and successfully completed a Phase 1b trial with an excellent safety profile in DMD patients. The successful progression of SMT C1100 to date provides validation for the strategy we developed. We are now optimising second generation utrophin modulators with improved physicochemical properties and a more robust metabolism profile. Pre-clinical in vivo studies in the mdx mouse demonstrate that daily oral administration of these compounds increases utrophin expression in target muscle groups, including the diaphragm and heart. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis with no change in fibre type composition. These improvements combine to provide functional enhancement and protection of muscle from contraction induced damage. The small molecule modulation of utrophin targeting skeletal, respiratory and cardiac muscles emphasises the potential of utrophin modulation as a disease-modifying therapeutic strategy for all DMD patients, irrespective of their mutation in dystrophin. http://dx.doi.org/10.1016/j.nmd.2015.06.270
G.P.246 Utrophin modulators significantly improve muscular dystrophy in the mdx diaphragm S. Guiraud 1, H. Chen *,1, S. Squire 1, B. Edwards 1, D. Burns 1, N. Shah 1, S. Davies 2, G. Wynne 2, A. Russell 3, D. Elsey 4, F. Wilson 4, J. Tinsley 4, K. Davies 1 1 University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK; 2 University of Oxford, Department of Chemistry, Oxford, UK; 3 University of Oxford, Department of Pharmacology, Oxford, UK; 4 Summit Therapeutics plc, Abingdon, UK Duchenne muscular dystrophy (DMD) is a severe muscle degenerative disease caused by genetic mutation in the dystrophin gene resulting in the loss of dystrophin function. Affected individuals succumb to heart or respiratory failure by 30 years of age. Currently, there is no effective treatment for DMD although a number of disease-modifying drugs are progressing in clinical trials. We have previously demonstrated that the dystrophin-related protein utrophin, a structural and functional autosomal paralogue of dystrophin, can act as an
effective surrogate to compensate for the loss of dystrophin in mdx muscle. By using oral small molecules specially designed to target the muscle-specific utrophin-A promoter, we aim to develop a treatment for all DMD patients irrespective of their dystrophin mutation. In partnership with Summit Therapeutics, we previously developed SMT C1100, an oral utrophin modulator that reduces dystrophic symptoms in the mdx mouse and successfully completed a Phase 1b trial with an excellent safety profile in DMD patients. We are now conducting studies in the mdx mouse with second generation utrophin modulators with improved physicochemical properties and a more robust metabolism profile. Unlike skeletal and cardiac muscles, the mdx diaphragm exhibits a highly dystrophic pathology and closely mimics the degeneration and necrosis observed in DMD patients. The diaphragm is the most reliable indicator of damage or recovery and therefore the more stringent preclinical test to demonstrate potential therapy. Thus, by using histological and molecular methods, we evaluated and compared the benefits of second generation utrophin modulators in the mdx diaphragm. The results of these evaluations will be presented and their relevance to potential clinical development discussed. http://dx.doi.org/10.1016/j.nmd.2015.06.271
G.P.247 Discovery of small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy (DMD) N. Araujo 1, A. Vuorinen 1, R. Fairclough 2, S. Guiraud 2, J. Donald 1, C. Cairnduff 1, D. Hewings 1, F. Martinez 1, K. Csatayova 1, N. Willis 1, S. Squire 2, A. Babbs 2, B. Edwards 2, N. Shah 2, J. Tinsley 3, F. Wilson 3, S. Davies 1, G. Wynne 1, K. Davies 2, A. Russell *,4 1 University of Oxford, Department of Chemistry, Oxford, UK; 2 University of Oxford, MRC Functional Genomics Unit, Oxford, UK; 3 Summit Therapeutics plc, Abingdon, UK; 4 University of Oxford, Departments of Chemistry & Pharmacology, Oxford, UK Duchenne muscular dystrophy (DMD) is a devastating, X-linked musclewasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD, although various promising approaches (e.g. exon skipping, read through of stop codons, gene therapy) are being developed. By transcriptionally reprogramming the temporal and spatial expression of the dystrophin-related protein utrophin, we aim to develop a pharmacological therapy applicable to all DMD patients by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit Therapeutics, SMT C1100, a utrophin modulator that reduced dystrophic symptoms in the mdx mouse, has now been progressed to human clinical trials. As a potential first-in-class molecule, SMT C1100 is currently being dosed in a placebo-controlled Phase 1b trial in DMD patients. Concurrently, a multicomponent biomarker strategy is being implemented. The successful clinical progression of SMT C1100 provides crucial proof-ofconcept for the strategy, and a comprehensive pipeline of future generation utrophin modulators is now in place. Second generation utrophin modulators related to SMT C1100 with more robust physicochemical and metabolism profiles have been evaluated in the mdx mouse. In parallel, novel utrophin modulator chemotypes have been discovered using an improved in vitro screening assay based on immortalised myoblasts from the dystrophin-null, utrophin luciferase knock-in (LUmdx) mouse. Multiple structural classes which significantly increase utrophin expression in both murine and human DMD myoblasts have been identified. Importantly, evidence suggests that some of these small molecules modulate utrophin transcription through an alternative regulatory mechanism to SMT C1100. These new compounds exhibit favourable solubility, stability, oral absorption and are well tolerated in the mdx mouse. Structure–activity studies are underway, with the objective to improve compound effectiveness. http://dx.doi.org/10.1016/j.nmd.2015.06.272
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
including those from novel biomarkers will set the scene for the pivotal clinical development of rimeporide as new therapeutic option for the treatment of patients with DMD. http://dx.doi.org/10.1016/j.nmd.2015.06.269
G.P.245 Second generation utrophin modulator for the therapy of Duchenne muscular dystrophy S. Guiraud *,1, S. Squire 1, B. Edwards 1, H. Chen 1, D. Burns 1, N. Shah 1, A. Babbs 1, S. Davies 2, G. Wynne 2, A. Russell 3, D. Elsey 4, F. Wilson 4, J. Tinsley 4, K. Davies 1 1 MRC – University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK; 2 Department of Chemistry, University of Oxford, Oxford, UK; 3 Department of Pharmacology, Department of Chemistry, University of Oxford, Oxford, UK; 4 Summit Therapeutics plc, Oxford, UK Duchenne muscular dystrophy (DMD) is a devastating, X-linked musclewasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches (e.g. stop codon readthrough, exon skipping, gene therapy) are progressing through human clinical trials. By pharmacologically modulating the dystrophin-related protein utrophin, we aim to develop a therapy applicable to all DMD patients, regardless of the underlying genetic fault in the dystrophin gene, by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit Therapeutics, we previously developed SMT C1100, an oral utrophin modulator that reduces dystrophic symptoms in the mdx mouse and successfully completed a Phase 1b trial with an excellent safety profile in DMD patients. The successful progression of SMT C1100 to date provides validation for the strategy we developed. We are now optimising second generation utrophin modulators with improved physicochemical properties and a more robust metabolism profile. Pre-clinical in vivo studies in the mdx mouse demonstrate that daily oral administration of these compounds increases utrophin expression in target muscle groups, including the diaphragm and heart. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis with no change in fibre type composition. These improvements combine to provide functional enhancement and protection of muscle from contraction induced damage. The small molecule modulation of utrophin targeting skeletal, respiratory and cardiac muscles emphasises the potential of utrophin modulation as a disease-modifying therapeutic strategy for all DMD patients, irrespective of their mutation in dystrophin. http://dx.doi.org/10.1016/j.nmd.2015.06.270
G.P.246 Utrophin modulators significantly improve muscular dystrophy in the mdx diaphragm S. Guiraud 1, H. Chen *,1, S. Squire 1, B. Edwards 1, D. Burns 1, N. Shah 1, S. Davies 2, G. Wynne 2, A. Russell 3, D. Elsey 4, F. Wilson 4, J. Tinsley 4, K. Davies 1 1 University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK; 2 University of Oxford, Department of Chemistry, Oxford, UK; 3 University of Oxford, Department of Pharmacology, Oxford, UK; 4 Summit Therapeutics plc, Abingdon, UK Duchenne muscular dystrophy (DMD) is a severe muscle degenerative disease caused by genetic mutation in the dystrophin gene resulting in the loss of dystrophin function. Affected individuals succumb to heart or respiratory failure by 30 years of age. Currently, there is no effective treatment for DMD although a number of disease-modifying drugs are progressing in clinical trials. We have previously demonstrated that the dystrophin-related protein utrophin, a structural and functional autosomal paralogue of dystrophin, can act as an
effective surrogate to compensate for the loss of dystrophin in mdx muscle. By using oral small molecules specially designed to target the muscle-specific utrophin-A promoter, we aim to develop a treatment for all DMD patients irrespective of their dystrophin mutation. In partnership with Summit Therapeutics, we previously developed SMT C1100, an oral utrophin modulator that reduces dystrophic symptoms in the mdx mouse and successfully completed a Phase 1b trial with an excellent safety profile in DMD patients. We are now conducting studies in the mdx mouse with second generation utrophin modulators with improved physicochemical properties and a more robust metabolism profile. Unlike skeletal and cardiac muscles, the mdx diaphragm exhibits a highly dystrophic pathology and closely mimics the degeneration and necrosis observed in DMD patients. The diaphragm is the most reliable indicator of damage or recovery and therefore the more stringent preclinical test to demonstrate potential therapy. Thus, by using histological and molecular methods, we evaluated and compared the benefits of second generation utrophin modulators in the mdx diaphragm. The results of these evaluations will be presented and their relevance to potential clinical development discussed. http://dx.doi.org/10.1016/j.nmd.2015.06.271
G.P.247 Discovery of small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy (DMD) N. Araujo 1, A. Vuorinen 1, R. Fairclough 2, S. Guiraud 2, J. Donald 1, C. Cairnduff 1, D. Hewings 1, F. Martinez 1, K. Csatayova 1, N. Willis 1, S. Squire 2, A. Babbs 2, B. Edwards 2, N. Shah 2, J. Tinsley 3, F. Wilson 3, S. Davies 1, G. Wynne 1, K. Davies 2, A. Russell *,4 1 University of Oxford, Department of Chemistry, Oxford, UK; 2 University of Oxford, MRC Functional Genomics Unit, Oxford, UK; 3 Summit Therapeutics plc, Abingdon, UK; 4 University of Oxford, Departments of Chemistry & Pharmacology, Oxford, UK Duchenne muscular dystrophy (DMD) is a devastating, X-linked musclewasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD, although various promising approaches (e.g. exon skipping, read through of stop codons, gene therapy) are being developed. By transcriptionally reprogramming the temporal and spatial expression of the dystrophin-related protein utrophin, we aim to develop a pharmacological therapy applicable to all DMD patients by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit Therapeutics, SMT C1100, a utrophin modulator that reduced dystrophic symptoms in the mdx mouse, has now been progressed to human clinical trials. As a potential first-in-class molecule, SMT C1100 is currently being dosed in a placebo-controlled Phase 1b trial in DMD patients. Concurrently, a multicomponent biomarker strategy is being implemented. The successful clinical progression of SMT C1100 provides crucial proof-ofconcept for the strategy, and a comprehensive pipeline of future generation utrophin modulators is now in place. Second generation utrophin modulators related to SMT C1100 with more robust physicochemical and metabolism profiles have been evaluated in the mdx mouse. In parallel, novel utrophin modulator chemotypes have been discovered using an improved in vitro screening assay based on immortalised myoblasts from the dystrophin-null, utrophin luciferase knock-in (LUmdx) mouse. Multiple structural classes which significantly increase utrophin expression in both murine and human DMD myoblasts have been identified. Importantly, evidence suggests that some of these small molecules modulate utrophin transcription through an alternative regulatory mechanism to SMT C1100. These new compounds exhibit favourable solubility, stability, oral absorption and are well tolerated in the mdx mouse. Structure–activity studies are underway, with the objective to improve compound effectiveness. http://dx.doi.org/10.1016/j.nmd.2015.06.272