World Muscle Society Poster Sessions

WMS Berlin continues to deliver evolving data and novel insights into the treatment, study and diagnosis of Duchenne Muscular Dystrophy.  The location in one of the historical districts for Berlin and German medicine has offered a unique and appropriate setting for keynotes, oral reviews and poster presentations.

Some highlights from the posters over the last two days:

• Summit PLC continues to move forward their lead oral utrophin modulator, SMT C1100
  • The company will initiate another clinical trial in Q4 2014 while developing additional formulations in parallel to increase exposure
  • Phase ib safety data were as expected and consistent with previously reported animal data; safe and well-tolerated
  • 2/12 patients had a greater than 2-fold activation of utrophin; 10/12 lower than expected
• Summit PLC, UtroDMD and the University of Oxford UK also exhibited a poster highlighting new orally available utrophin modulators structurally related to SMT C1100, SMT 1 and 2
  • Both compounds increase utrophin protein expression, protect muscle and demonstrate improved systemic exposure when compared to SMT C1100; additionally, both modulate utrophin in mdx mice diaphragm and heart
• Taiho shared data from their ongoing work with a novel inhibitor of hematopoietic prostaglanding D synthase (HPGDS), TAS-205
  • Prostaglandin D₂, synthesized by HPGDS, is involved in the progression of muscular necrosis (death) in DMD
  • Preclinical data suggest TAS-205 may improve or recover muscle locomotor activity by reducing the amount of necrotic muscle fibers
  • TAS-205 is in a phase 1 clinical trial in Japan (not yet enrolling)
• Catabasis is developing a novel anti-inflammatory agent, CAT-1004
  • CAT-1004 inhibits NF-kappaB and could be used in place of steroids to manage chronic inflammation the occurs as a result of muscle degeneration
  • Phase 1 data indicate CAT-1004 is safe and reduced NF-kappaB land target gene evels in patients
  • Phase 2 studies are planned to develop CAT-1004 as a steroid-sparing therapy
• PTC Therapeutics presented a poster on their early stage screening work to identify novel, orally available exon skipping compounds for DMD
  • While the company has identified novel small molecule chemotypes, early studies are ongoing to optimize drug-like properties prior to naming a drug candidate
• The University of Messina, Italy, presented a pilot clinical study with the marketed product flavocoxid (Limbrel®) in ambulant DMD patients
  • Flavocoxid has anti-inflammatory properties, including reducing NF-kappaB
  • While the drug was safe, a number of patients demonstrated a negative functional trend at the end of the study
• The University of Bari, Italy (supported by Servier, as part of a collaboration with ARMGO Pharma Inc.) exhibited a poster on the effects of S48168/ARM210, a new Rycal® compound, in mdxmice
  • Dystrophin-lacking muscle fibers suffer from a chronic Ca²⁺ overload, leading to multiple pathological events and fiber necrosis (death)
  • Modifications to the Ryanodine receptor (RyR1) stabilizes the closed state of the receptor, contributing to Ca²⁺ leakiness
  • Drugs able to prevent the formation of the closed state, such as S48168/ARM210, may be able to prevent the downstream necrosis
  • Data indicate modest improvements in exercised mdx mice suggesting the need for longer treatment (which will be explored)
• Investigators at the University of Geneva presented a poster demonstrating the amelioration of the DMD phenotype in a mouse model with diapocynin, an NADPH oxidase inhibitor
  • Multiple molecular events lead to DMD pathogenesis and muscle death, including the production of reactive oxygen species (ROS)
  • In preclinical studies, diapocynin improved multiple functional measures associated with DMD pathology
• Multiple organizations continue to explore the potential of gene therapy for DMD
  • Genethon exhibited a poster of their ongoing work with a recombinant AAV carrying an exon skipping sequence; the company saw no difference between 3 and 6 months for vector stability
  • Investigators at INSERM utilized an AAV8 vector to demonstrate penetration into DMD myoblasts (muscle cells)
  • University of Washington presented a poster of their micro-dystrophin cassettes for AAV gene therapy; a number of novel clones were identified and will undergo further characterization