duchenne muscular dystrophy program developing utrophin modulator therapies for the potential...

Duchenne Muscular Dystrophy Program

Developing utrophin modulator therapies for the potential treatment of all DMD patients

Action Duchenne "A Brave New World"2

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Statements in this presentation, other than statements of historical facts, constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include statements regarding Summit’s clinical trials supporting the safety and efficacy of its product candidates and the potential novelty of such product candidates as treatments for disease, plans and objectives for clinical trials and product development, strategies, future performance, expectations, assumptions, financial condition, liquidity and capital resources. These forward-looking statements may be preceded by, followed by or otherwise include the words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions. Actual results or events may differ materially from those expressed or implied in any forward-looking statements due to various factors, including the risks and uncertainties inherent in clinical trials and product development and commercialization, such as the uncertainty in results of clinical trials for product candidates, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, the risk of failure of the third parties upon whom Summit relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials and the timing, cost and design of future clinical trials and research activities, the timing of expected filings with the FDA or other regulatory agencies; and the other risks and uncertainties described in Summit’s public filings with the Securities and Exchange Commission.

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November 2015


Thank you to the patients and their families, and the organisations who have supported our program

November 2015


Utrophin and Dystrophin

Two proteins, one major function – stabilise muscle fibre membranes

• Description of hypothesis

• Confirmation of approach in vivo

• Utrophin modulator pipeline

November 2015


Comparison Between Dystrophin and Utrophin Function

November 2015

Dystrophin Utrophin

Muscle specific transcripts

Early foetal muscle expression

Mature muscle expression

Mature fibre localisation Complete length NMJ, MTJ

Fibre repair

Specific fibre binding sites Costamere Costamere

Protein binding partners

Dystrophin Protein Complex

nNOS Microtubules Actin


Dystrophin or Utrophin Protein: Maintaining the Function of Muscle Fibers

Contractile apparatus

Dystrophinor

Utrophin

Costamere

Section through a muscle fibreFinite number of springs

Finite number of binding sites

Contraction and relaxation stress transmitted through costamere anchor sites

Muscle fibre membrane

November 2015

No springsStructural failure

No dystrophin(Duchenne)Structural failure

Fewer springsStill functional but lower weight capacity

Less dystrophin(Becker)Still functional but lower stress tolerance


Utrophin is Functionally Equivalent to Dystrophin in Developing and Repairing Muscle

> Modulation of utrophin protein has potential to compensate for lack of dystrophin

November 2015


Summit’s Utrophin Modulation Approach

• Utrophin gene expression is switched off in myonuclei once repair to a damaged region of the fibre has been made

• Exactly same mechanism operating in DMD muscle

• Development of an oral drug treatment where the drug enters muscle fibre myonuclei, via blood circulation, to switch on and maintain utrophin gene expression continuously

• Mouse dosed orally with SMT C1100

• Each “dot” radiolabelled SMT C1100

• * Example positive C1100 myonuclei

November 2015

*

*


Utrophin Modulators Increase Utrophin Expression Along Muscle Fibres in mdx Models

> Utrophin localised along the entire length of the membrane with drug treatment> Reconstruction of the dystrophin protein complex> Stabilises membrane reducing rate of degeneration

mdx control mdx + SMT C1100 mdx + 2nd Generation

β-dystroglycan (EDL)

Utrophin (TA)

November 2015

Source: Human Mol Genet, (2015), 24 (15) 4212-4224


Increased Resistance to Muscle damage

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Series1

% D

ecre

ase

in f

orce

dro

p

November 2015

Source: Human Mol Genet (2015), 24 (15), 4212-4224: PLoS ONE (2011), 6 (5), e19189

Utrophin Modulation Protected Against Loss of Muscle Function in mdx Disease Model

Control Exercised mdx Exercise mdx + SMT C1100

0

0.5

1

1.5

2

Fore Limb Strength Assessment

Nor

mal

ized

For

ce I

ncre

men

t


Utrophin Modulator Pipeline

November 2015


Our Utrophin Development Pipeline

DiscoveryClinical Trial Preparation Phase 1 Phase 2

SMT C1100

Second Generation

Future Generations

PRODUCT

> Disease modifying approach

> Potential to treat all DMD patients regardless of the dystrophin mutation

November 2015


SMT C1100 Overview

Molecule: First-generation, small molecule utrophin modulator

Status:

> Met primary objective in Phase 1b modified diet clinical trial

> Received Orphan Drug Designation from the FDA and Orphan Medicinal Product Designation from the EMA

Clinical Data-to-Date:

> Well-tolerated in ~100 healthy volunteers and 24 DMD patients

> Phase 1b modified diet clinical trial demonstrated improved drug exposure in patients following specific dietary guidance

November 2015

>>> Next Milestone: Phase 2 proof of concept trial expected to start Q4 2015


Phase 1b Modified Diet Trial Design

Evaluated plasma levels of SMT C1100 in DMD patients following specific

dietary guidance providing for a balanced diet of fats, proteins and carbohydrates

Study Design: > 12 ambulatory DMD patients aged 5-13 years old

> Placebo controlled, dose escalating trial

> 14 days of oral dosing

Primary Objective: > PK of SMT C1100

Secondary Objectives: > Safety/tolerability of SMT C1100

> Evaluate variability in steady state PK

> Evaluate CK levels as a potential biomarker of SMT C1100 activity

November 2015


Modified Diet Phase 1b Results: Increased Exposure in Patients who had Participated in First Phase 1b Trial

> All seven patients who participated in previous Phase 1b trial had increased exposures when following dietary guidance

> Seven of the 12 patients had higher exposure after Day 14 compared to Day 1, which was not observed in previous trials of SMT C1100

November 2015

>>> Potential for all DMD patients to benefit from continued utrophin production

>>> Data support advancement to Phase 2 proof of concept trial

02 Study-Day 11 (50 mg/kg)

03 Study-Day 140

100

200

300

400

500

600

700

800

Comparison of Plasma Levels in Pa-tients who Participated in

the 02 and 03 Trials*

28 mg/kg44 mg/kg51 mg/kg52 mg/kg55 mg/kg57 mg/kg

SM

T C

1100

Pla

sma

Lev

els

(AU

C n

g.h/

mL

)

*

(Fixed Dose)

* Excludes 1 patient who had AUC >1215 in both studies


Next Steps: Phase 2 Proof of Concept Trial

> Trial to evaluate clinical benefit of SMT C1100 in patients with DMD

> Expected initiation Q4 2015

> Plan to report interim data periodically

Planned Study Design: • Open label trial expected to enrol up to 40 ambulatory DMD patients aged 5-10 years old

• 48 week trial

• Sites in Europe and US

• PK not part of inclusion criteria

November 2015


Phase 2 Proof of Concept Trial: Range of Mechanism and Efficacy Measures Planned

MECHANISM• Utrophin protein levels• Muscle fibre regeneration

MUSCLE HEALTH• Magnetic Resonance Imaging (MRI)• Serum biomarkers

FUNCTION• Six minute walk test• North Star Ambulatory Assessment

November 2015

duchenne muscular dystrophy program developing utrophin modulator therapies for the potential...

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