SMTC1100: Progressing to Patient Clinical Trials Action Duchenne Conference 9 th November 2013
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Muscle Integrity Repeated anchor points Finite number of springs Section through a muscle fibre Finite number of binding sites Less springs Still functional but lower weight capacity Costamere Contractile apparatus Contraction and relaxation stress transmitted through costamere anchor sites Less dystrophin (Becker) Still functional but lower stress tolerance No springs Structural failure Dystrophin or Utrophin No dystrophin (Duchenne) Structural failure 3 Utrophin Modulation Programme Action Duchenne 2013
Utrophin: A Replacement for Dystrophin Normal muscle fibre MATURING MUSCLE FIBRE Foetal Foetal/Immature Mature DMD muscle fibre DMD + utrophin drug muscle fibre Utrophin: Dystrophin: DEGENERATION 4 Utrophin Modulation Programme Action Duchenne 2013
Continual Expression of Utrophin Prevents Muscular Dystrophy in mdx Mouse Nature Medicine, 4, 1441-1444 (1998) 5 Utrophin Modulation Programme Action Duchenne 2013
Summit s Utrophin Modulation Programme Developing first and best in class medicines for utrophin modulation Includes lead candidate SMT C1100 and next generation molecules: DISCOVERY (1-4 Years) OPTIMISATION (1-2 Years) PRECLINICAL (1-2 Years) PHASE 1 (1 Year) PHASE 2 (1-2 Years) Lead: SMT C1100 Next Generation Utrophin programme builds on the research from Oxford University: Utrophin biology: Prof Kay Davies group (MRC Functional Genomics Unit) Medicinal chemistry: Prof Steve Davies group (Dept of Chemistry) Co-founders of Summit 6 Utrophin Modulation Programme Action Duchenne 2013
Development of SMT C1100 7 Utrophin Modulation Programme Action Duchenne 2013
SMT C1100 Nonclinical Summary Only disease modifying treatment for DMD regardless of the dystrophin mutation Designed to modulate utrophin transcription Activity demonstrated in target the cells: DMD myoblasts / developing myotubes Established proof-of-concept in dystrophin deficient animal model Effective in worsened disease caused by forced exercise Orally taken drug appropriate for the pediatric population No problems in regulatory preclinical safety and toxicology studies to date 8 Utrophin Modulation Programme Action Duchenne 2013
Overview of Key Efficacy Data 1. More Utrophin Fibres 2. Reduced Muscle Damage 3. Improves Muscle Function Mdx Mdx + SMT C1100 100% 80% 60% 40% 20% 0% Regeneration Necrosis Non muscle area mdx mdx+c1100 Normalised Force Increment 2.5 2.0 1.5 1.0 0.5 0 Vehicle mdx Exer mdx Exer mdx+ SMTC1100 Daily dosing with SMT C1100 Fall in biomarkers of muscle damage; regeneration, fibrosis, fibre death Protection against loss of forelimb grip strength Source: PLoS ONE, Volume 6, Issue 4, May 2011 9 Utrophin Modulation Programme Action Duchenne 2013
Successful Phase 1 Trial Completed in 2012 Repeat dose Phase 1 healthy volunteer trial showed a paediatric formulation of SMT C1100 (100mg/kg, taken twice a day for 10 days): Safe and well tolerated Achieved stable plasma concentrations after 4 days Individuals with the lowest plasma levels still expected to modulate utrophin expression for at least 14 hours a day Blood level required for utrophin modulation activity in mdx and cell models Based on these data, SMT C1100 is progressing into patient clinical trials 10 Utrophin Modulation Programme Action Duchenne 2013
Current and Future Activities 2013 2014 Phase 1b Biomarker Programme Long-term Toxicology Drug Product Manufacture Phase 2 11 Utrophin Modulation Programme Action Duchenne 2013
Biomarker Programme Utrophin / Mechanism Related: 1. UTRN localisation by quantitative IF 2. Total utrophin protein 3. Total utrophin mrna Muscle Health: Regeneration & Inflammation From Muscle: 1. Muscle regeneration markers 2. Inflammatory markers From Plasma: 3. mirnas 4. Active Fibrosis Supported by 12 Utrophin Modulation Programme Action Duchenne 2013
Phase 1b DMD Patient Trial 12 ambulatory DMD patients aged 5 to 11 years old Three escalating dose groups 10 days of oral dosing Tolerability & Safety PK levels SMT C1100 and metabolites Identify doses for Phase 2 Proof of Concept (PoC) trial UK-based study (4 sites) Ethics and regulatory approval granted 13 Utrophin Modulation Programme Action Duchenne 2013
On-Going Activities Phase 1b Clinical Trial Opening of trial sites and the start of patient recruitment Preparation for Phase 2 DMD proof of concept trial Double blind PoC trial ~40-50 ambulatory DMD patients At least 24 weeks dosing International study Development of next generation utrophin modulators Identify candidates with enhanced pharmacokinetic properties and complimentary mechanisms Collaboration with Oxford University Subject to review by advisers and regulators 14 Utrophin Modulation Programme Action Duchenne 2013
Thank you to the Community 15 Utrophin Modulation Programme Action Duchenne 2013