Disease Modifying Therapy for DMD:
Utrophin Modulation Programme
PPMD Connect, June 2014
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Dystrophin or Utrophin Protein:
Maintaining Integrity of Muscle Fibres
Muscle fiber
membrane
Extracellular
matrix
Actin
cytoskeleton
Dystrophin or Utrophin
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Dystrophin or utrophin protein
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Utrophin Modulation:
A Disease-Modifying Approach for DMD
Time to Develop
•  Utrophin is functionally equivalent to
dystrophin in both fetal and repairing
muscle
•  Utrophin is continually expressed at
specialized sites in normal mature muscle
fibers
•  Utrophin modulation is a diseasemodifying strategy of potential utility for all
DMD patients (independent of dystrophin
mutation)
•  Only normal utrophin levels required for
DMD muscle recovery
•  SMT C1100 designed to increase and
maintain utrophin transcription
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Fetal
(repairining)
Fetal/
Immature
Mature
Normal
Fiber
DMD
Fiber
Degeneration
DMD
+
SMT C1100
Fiber
utrophin
dystrophin
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SMT C1100 Increased Utrophin Levels in Muscle
Fibers Improves Disease Biomarkers In Vivo
tibialis
anterior
extensor digitorum
longus
Reduced Fiber Regeneration (%CNFs)
Reduced Muscle Leakiness (blood CK levels)
mdx
mdx + SMT C1100
• Increased utrophin at the sarcolemma
significantly reduces secondary
disease effects
• 28 days of oral dosing (50mk/kg, QD)
in mdx mice (n=5)
mdx vehicle
Source: PLoS ONE, Vol 6, Issue 4, May 2011
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mdx+SMT C1100
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UTROPHIN MODULATION PROGRAMME
Clinical Data
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Summary of Phase 1 Healthy Volunteer Trial
•  Repeat dose Phase 1 healthy volunteer trial conducted in 2012 showed
–  SMT C1100 was safe and well tolerated at all doses tested
–  Achieved levels expected to increase utrophin expression for at least 14 hours/day
–  Higher plasma levels achieved when SMT C1100 taken with food
SMT C1100 taken with food v SMT C1100 taken after 12h fasting
(same individuals after washout)
200mg/kg
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Phase 1b Trial: Overview
•  UK-based study
–  4 sites: London, Liverpool, Birmingham, Manchester
•  12 ambulatory DMD patients aged 5 to 11 years old
•  3 escalating dose cohorts, 4 patients per cohort:
–  50mg/kg BID, 100mg/kg BID, 100mg/kg TID
•  10 days of oral dosing
•  Dosing to occur “ideally within 10 minutes of consuming food”
•  Primary endpoint:
Tolerability & Safety
•  Secondary endpoint:
PK levels of SMT C1100 and metabolites
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Phase 1b Trial: Safety and PK
•  First ever utrophin modulator trial in patients
Safety: Primary endpoint of trial achieved
–  SMT C1100 safe and well-tolerated in patients at all doses tested
–  No apparent issues with patient compliance
Variable Plasma levels of drug
–  2/12 boys had good SMT C1100 plasma levels appropriate for activating utrophin
modulation
–  10/12 boys plasma levels were similar to fasted healthy adult volunteers
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Phase 1b Trial: CK Observation
Reduction in enzyme related to muscle damage
•  Serum creatine kinase (CK) is an enzyme associated with muscle fibre damage
and serum levels are elevated in DMD patients
•  Reduced serum CK levels seen in non-clinical efficacy studies in mdx model after
15 days treatment with SMT C1100
Phase 1b data
•  CK levels were reduced during dosing in the majority of boys
•  Result is consistent with mdx data
•  Consistent with reduction in muscle membrane damage
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Next Steps: Targeting all Patients with DMD
•  Future clinical trials of SMT C1100 to be modified to reflect our greater
understanding of the importance of diet and other potential disease related factors
•  Will seek to determine the optimal way to address drug exposure variability
–  Dietary means and/or
–  Drug formulation change
•  Formulations already identified that increase exposure in animal studies
•  Next patient study now expected to start in Q4 2014
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•  Alliance represents a multi-year strategic collaboration that combines
extensive utrophin biology, chemistry and drug discovery expertise
•  Commitment to build on the results obtained with SMT C1100
•  Aim to deliver first in-class and best in-class utrophin modulators for the
therapy of DMD
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Utrophin Modulation Programme
DISCOVERY
OPTIMISATION
PRECLINICAL
PHASE 1
PHASE 2
Lead:
SMT C1100
SMT C1100
related
Next
Generation
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UTROPHIN MODULATION PROGRAMME
Next Generation and Biomarkers
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Next Generation Utrophin Modulators
1.  Structurally Related to SMT C1100
Rat In vivo PK Study
–  Similar in vitro potency to SMT C1100,
enhanced PK properties
–  Clean safety/off target profile
2.  New structures, new mechanism
Utrophin Levels in DMD patient Myoblasts
–  New screening technology identifying
differentiated utrophin modulators
–  Potential new mechanism of action
–  Increased in vitro activity compared to SMT C1100
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Biomarker Development Programme
Utrophin /
Mechanism Related
• UTRN localisation by
quantitative IF
• UTRN mRNA by
QPCR
• UTRN protein by
MS/MS
Muscle Health
From Muscle:
• Regeneration markers
Non-invasive
Markers
• Muscle MRI
• Inflammatory markers
From Sera:
• Membrane damage
(muscle enzymes,
MicroRNAs)
• Active fibrosis (collagen
fragments)
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Thank You to the Community
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Contact
If you have further questions, do get in contact:
Email:
dmd@summitplc.com
Phone:
+44 (0)1235 44 39 39
Web:
www.summitplc.com
Twitter:
@summitplc
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