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SMT C1100 Utrophin Modulator Novel oral compound with potential to treat all genetic forms of DMD

CONNECT2013 ANNUAL CONFERENCE

Jon Tinsley PhD jon.tinsley@summitplc.com

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FORWARD LOOKING STATEMENTS

This Document contains forward-looking statements. These statements relate to, among other things, analysis and other information that are based on forecasts of future results and estimates of amounts not yet determinable. These statements also relate to the Company’s future prospects, developments and business strategies. Forward-looking statements are identified by their use of terms and phrases such as “believe”, “could”, “envisage”, “estimate”, “expect”, “intend”, “may”, “plan”, “will” or the negative of those, variations or comparable expressions, including references to assumptions. The forward-looking statements in this Document are based on current expectations and are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by those statements. Given the risks and uncertainties associated with a company of this nature, potential investors should not place reliance on forward-looking statements. These forward-looking statements speak only as at the date of this Document.

The Company does not undertake any obligation to update forward-looking statements or risk factors other than as required by any relevant regulations, whether as a result of new information, future events or otherwise.

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Muscle Design – Built not to fail

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Muscle Integrity – Repeated anchor points

Contractile apparatus

Dystrophin or

Utrophin

Costamere

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Section through a muscle fibre

More springs, greater the weight capacity Contraction and relaxation stress transmitted through more anchor sites Finite number of sites

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Utrophin is the Functional Replacement for Dystrophin

•  Utrophin functional equivalent to dystrophin in both fetal and regenerating muscle

•  Utrophin is continually expressed at specialized sites in normal mature muscle fibers

•  Dystrophin can be replaced by increased utrophin

•  Utrophin replacement can “cure” dystrophin deficient (mdx) mice

•  Only normal utrophin levels required for DMD muscle recovery

•  Utrophin muscle-specific promoter can be manipulated to increase utrophin RNA levels

•  SMT C1100 designed to maintain utrophin transcription

Normal Fiber

DMD Fiber

DMD +

SMT C1100 Fiber

Fetal Fetal/ Immature Mature

utrophin dystrophin

Degeneration

Time to Develop

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Constitutively Expressed Utrophin Prevents Muscular Dystrophy in mdx Mouse

Nature Medicine, 4, 1441-1444 (1998)

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Summit’s Utrophin Modulation Programme

•  Developing a franchise in utrophin modulation

•  Pipeline includes lead candidate SMT C1100 and next generation molecules

Lead: SMT C1100

Next Generation

DISCOVERY (1-4 Years)

OPTIMISATION (1-2 Years)

PRECLINICAL (1-2 Years)

PHASE 1 (1 Year)

PHASE 2 (1-2 Years)

•  Utrophin programme builds on the academic 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

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Development of SMT C1100

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SMT C1100 Nonclinical Summary

•  Only disease modifying treatment in clinical development for all genetic forms of DMD –  Designed to maintain utrophin transcription

•  Activity demonstrated in target the cells: myocytes / myotubes from DMD patients

•  Established proof-of-concept in dystrophin deficient animal model –  Forced exercise worsened phenotype

•  Orally bioavailable small molecule drug appropriate for the pediatric population

•  Clean in regulatory preclinical safety and toxicology studies

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Overview of Key Efficacy Data

P=0.019

SMTC1100 Vehicle

2.4

2.0

1.6

1.2

0.8

2.8

Fold

incre

ase i

n Utro

phin

RNA

Increases utrophin RNA from skeletal muscle

Quantitative increase in utrophin protein levels

0.3

0.5

0.7

0.9

1.0

Heart Diaphragm

Utro

phin

prote

in lev

el*

vehicle

P<0.05 P<0.01

SMTC1100

Source: PLoS ONE, Volume 6, Issue 4, May 2011

* corrected for α-actinin

Exer mdx+ SMTC1100

Vehicle

2.0

1.5

1.0

0.5

0

2.5

Norm

alise

d For

ce In

creme

nt

mdx Exermdx

Protection against loss of forelimb grip strength

1. Utrophin RNA Increase 2. Utrophin protein Increase 3. Improves Muscle Function

•  Increase in utrophin staining at skeletal muscle sarcolemma observed confirming correct localisation for function

•  Oral daily dosing (50mg/kg) for 28 or 35 days in mdx mouse

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SMT C1100 Phase 1 Trial Sponsors

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Successful Phase 1 Trial Completed in 2012

•  Was afe 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

•  Repeat dose Phase 1 healthy volunteer trial showed a paediatric formulation of SMT C1100:

Blood level required for activity in mdx and cell models

Based on these data, SMT C1100 progressing into patient clinical trials

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SMT C1100: Clinical Development Plans

H2 2013 2014

PHASE 1b • SAD, MAD study in UK • Ambulatory DMD patients • 10 days dosing • Tolerability & Safety • Measure plasma levels of SMT

C1100 •  Identify doses for Phase 2

PHASE 2* • Proof of concept trial in US/EU • Ambulatory DMD patients • 24 weeks dosing • Pre and post muscle / plasma

biomarker quantification • 6MWT & 2o muscle function

tests • Open label extension

Biomarker programme

Long-term toxicology

Drug product manufacture

Clinical Trials

Additional planned activities

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*Plans are still to be finalized and remain subject to review by the various regulatory authorities and other clinical experts

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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

Non-invasive Markers: e.g.

1. Electrical Impedance

Myography (CMS)

2. Muscle MRI

3. Ultrasound

• Initiation of collaborations

• Access biobank materials

• Assay development

2013 • Tech transfer to clinical CROs

• Assay validation • Publication

2014

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Next Steps…

•  Advance SMT C1100 into first patient trials of a utrophin modulator drug:

–  Phase 1b safety and dose finding study in H2 2013, results H1 2014

–  Phase 2 patient proof of concept study expected to start in 2014

–  Novel biomarker program underway, includes collaboration with Children’s National Medical Centre in Washington DC

–  Scale-up and manufacture of drug product on-going for clinic and tox: completion Q1 2014

–  Long-term regulatory toxicology studies to be conducted: completion 2014 to support Phase 2 trial

•  Development of next generation utrophin modulators continuing in parallel

–  Identify candidates with enhanced pharmacokinetic properties and complimentary mechanisms

–  Collaboration with Oxford University

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THANK YOU

Ø  Remember Sign Up To The Patient Registries

Ø  For more info on SMT C1100; –  Visit: www.summitplc.com –  Email: DMD@summitplc.com

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