Advancing New Treatments for DMD and C. difficile Infection Oppenheimer 25 th Annual Healthcare Conference December 2014
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Corporate Overview Focused on two areas of high unmet clinical need Duchenne Muscular Dystrophy (DMD): Novel utrophin modulation approach designed to target 100% of patient population Small molecule oral delivery Potential to be monotherapy or complementary to other therapies C. difficile Infection (CDI): Differentiated antibiotic under development for treatment of initial infection and to significantly reduce disease recurrence UK/US team based out of Oxfordshire, UK and Cambridge, MA Publicly traded on AIM Exchange, London 3 Company Presentation December 2014
Our Pipeline DISCOVERY OPTIMISATION PRECLINICAL PHASE 1 PHASE 2 SMT C1100 DMD Second Generation Future Generations CDI SMT19969 4 Company Presentation December 2014
DMD PROGRAM About Utrophin Modulation 5 Company Presentation December 2014
Utrophin: A Universal Treatment for DMD DMD is a fatal disease caused by different genetic mutations in the dystrophin gene and results in progressive wasting of muscles throughout the body No cure, life expectancy around mid to late 20 s Utrophin is a structurally related protein present in developing muscle fibers Maintaining production of utrophin in mature muscle fibers has potential to maintain muscle function and prevent progression of DMD Dystrophin or utrophin Muscle cell membrane Dystrophin Individual muscle fiber Actin Protein complex Utrophin 6 Company Presentation December 2014
SMT C1100: A First-in-Class Utrophin Modulator 7 Company Presentation December 2014
tibialis anterior extensor digitorum longus SMT C1100 Increased Utrophin Levels in Muscle Fibers & Improved Disease Biomarkers In Vivo Reduced Fiber Regeneration (%CNFs) mdx mdx + SMT C1100 Increased utrophin at the sarcolemma significantly reduced secondary disease effects 28 days of oral dosing (50mk/kg, QD) in mdx mice (n=5) Reduced Plasma Creatine Kinase Levels Source: PLoS ONE, Vol 6, Issue 4, May 2011 mdx vehicle mdx+smt C1100 8 Company Presentation December 2014
SMT C1100 Protected Against Forced Exercise Changes in Mdx Disease Model Measures ability to maintain grip Exercise study measuring force grip strength in mdx model Daily dosing (50mg/kg, QD) of SMT C1100 to mdx mice for 5 weeks days (n=8) SMT C1100 protected against the loss of function otherwise seen with exercise Source: PLoS ONE, Vol 6, Issue 4, May 2011 9 Company Presentation December 2014
Phase 1 Healthy Volunteer (Trial 01): Key Results Repeat dose Phase 1 healthy volunteer trial conducted in 2012: SMT C1100 was well tolerated at all doses tested Achieved levels expected to increase utrophin expression for at least 14 hours/day after 100mg/kg twice a day dosing Strong food effect: Higher plasma levels achieved when SMT C1100 taken with food SMT C1100 taken with food v SMT C1100 taken after 12h fasting 200mg/kg 10 Company Presentation December 2014
Phase 1b in Patients (Trial 02): Safety, PK and Enzyme Marker Data Safety: Well tolerated SMT C1100 well-tolerated in patients at all doses tested 100% patient compliance PK: Variable plasma levels In majority of patients the blood plasma levels of SMT C1100 similar to levels seen in fasted healthy volunteers Indicates complex absorption profile potentially due to diet or formulation Plasma levels from preclinical studies resulting in 50% increase in utrophin levels Observed reduction in plasma markers of muscle damage Reduction in enzyme marker of muscle damage in majority of patients Potential early indication of SMT C1100 activity in DMD patients 11 Company Presentation December 2014
% Change from Baseline % Change from Baseline % Change from Baseline % Change from Baseline Phase 1b (Trial 02): Enzyme Changes by Patient CK, ALT and AST markers of muscle damage, GGT is a non-muscle marker 100 50 0-50 -100 Change in CK Levels at Day 10 20 0-20 -40-60 -80 Change in AST Levels at Day 10 50mg/kg BID 100mg/kg BID 100mg/kg TID 50mg/kg BID 100mg/kg BID 100mg/kg TID 0-20 -40-60 -80 Change in ALT Levels at Day 10 60 40 20 0-20 -40 Change in GGT Levels at Day 10 50mg/kg BID 100mg/kg BID 100mg/kg TID 50mg/kg BID 100mg/kg BID 100mg/kg TID 12 Company Presentation December 2014
Next Trial: Phase 1b Modified Diet Evaluating the current formulation in DMD boys following a balanced diet Trial to be conducted in the UK and expected to be initiated in Q4 2014 Study design: Primary endpoint: Secondary endpoints: 12 ambulatory DMD patients aged 5-13 years old Placebo controlled, dose escalating trial 14 days of oral dosing PK of SMT C1100 following a balanced diet Safety/tolerability of SMT C1100 Evaluate variability in steady state PK Evaluate CK levels as a potential biomarker of SMT C1100 13 Company Presentation December 2014
SMT C1100: Phase 2 Next Steps Phase 2 Open Label Trial 2 year study to evaluate muscle health and function and biomarkers in DMD boys Report data periodically during study and generate longer-term safety data Plan to start immediately following Phase 1b modified diet study Phase 2b Placebo Controlled Trial A randomized, placebo controlled study is expected to start early 2016. International study in US and EU. 14 Company Presentation December 2014
Second Generation Utrophin Modulators Significant improvement in systemic exposure in vivo Increased utrophin levels in skeletal muscle, including the diaphragm, and heart Protection of muscle function with increased resistance to muscle damage SG 1 SG 2 Vehicle Utrophin (EDL) β-dystroglycan (EDL) Data published: WMS 2014 15 Company Presentation December 2014
Biomarker Development Program Utrophin Measurement From Muscle: Utrophin localization by quantitative immunofluorescence Muscle Health Markers From Muscle: Muscle regeneration markers Inflammatory markers From Sera: mirnas Active Fibrosis 16 Company Presentation December 2014
C. DIFFICILE INFECTION PROGRAM SMT19969 17 Company Presentation December 2014
C. difficile Infection: A Major Healthcare Threat This bacteria is an immediate public health threat that requires urgent and aggressive action Significant increase in global prevalence $4.8bn in acute care cost in the US CDI is directly related to use of antibiotics resulting in disturbance of natural gut flora Antibiotics to treat CDI cause further disruption to gut flora leading to recurrent disease Additional episodes are more severe with increased mortality US Department for Health and Human Services, 2013 18 Company Presentation December 2014
A Selective Therapy for C. difficile Infection SMT19969 has promising profile Potent, bactericidal inhibition of C. difficile Targeted spectrum of activity Low propensity to resistance development Superior to vancomycin in the hamster model of CDI Phase 1 clinical trial conducted in 2013 SMT19969 well tolerated at all administered doses Oral dosing associated with negligible systemic exposure Minimal effects against gut flora in humans significant reductions in total Clostridia only Phase 2 clinical trial now dosing patients Top-line data expected to be reported in mid-2015 19 Company Presentation December 2014
SMT19969: Targeted Spectrum of Activity Potent bactericidal inhibition of C. difficile growth observed during in vitro studies Minimal antibiotic effect against wide panel of gut flora bacteria Superior selectivity compared to current treatment options Key Bacterial Groups Spectrum of Activity MIC 90 (µg/ml) SMT MTZ VAN FDX SUR* CAD* LFF* Clostridium difficile 0.25 2 4 0.5 0.25 0.25 0.25 Bacteroides spp. >512 2 128 >512 >8,192 4 8 Bifidobacterium spp. >512 128 1 0.125 2 0.5 >32 Lactobacillus spp. >512 >512 >512 >512 2 - >32 Eggerthella lenta >512 0.5 4 0.03 8 0.5 0.06 Peptostreptococcus spp. 64 1 0.5 0.03 0.5-0.06 Staphylococcus aureus >512 >512 1 16 1.0 1.0 0.125 * Published data 20 Company Presentation December 2014
SMT19969: A Selective Therapy for CDI Treated initial infection and prevented recurrence in key disease model Oral, small molecule with low propensity for resistance in vitro Drug dosing Recurrent Disease Phase 21 Company Presentation December 2014
Phase 1: Summary First in human Phase 1 clinical trial complete 56 healthy male volunteers - Single and multiple ascending oral doses SMT19969 well tolerated at all doses tested No clinically significant findings from biochemistry, haematology, urinalysis, vital signs, ECGs and FOB All adverse events mild in severity and resolved without intervention No dose dependent relationship between AEs and SMT19969 Comparable rate of AEs in SMT19969 and placebo groups Oral dosing associated with negligible systemic exposure 22 Company Presentation December 2014
Phase 1: Gut Flora Well tolerated at all doses SMT19969 restricted to the GI tract, the site where CDI infections occur Highly sparring of natural gut flora with reduction in total clostridia only (200mg dose BID) 23 Company Presentation December 2014
Phase 2 Proof of Concept Trial 100 patients, ~30 US/Canadian sites Recruitment and dosing underway Primary endpoint: Sustained Clinical Response (SCR) Clinical cure and absence of recurrence within 30 days of EOT Secondary endpoints: Clinical response at TOC Recurrence of CDI Group Design Group N Agent Regimen 1 50 SMT 200mg BID 10 days 2 50 VAN 125mg QID 10 days 24 Company Presentation December 2014
Outlook DMD utrophin modulation program Small molecule approach with potential to treat 100% of DMD population Initial Phase 1b clinical trial on lead candidate SMT C1100 completed Phase 1b modified diet trial expected to be initiated in Q4 2014 Phase 2 open label study to follow with data expected in early 2016 SMT19969: A novel antibiotic for C. difficile infections Selective activity seen in human gut flora Well tolerated in Phase 1 healthy volunteer trial Phase 2 PoC trial dosing patients Top line data expected in mid-2015 25 Company Presentation December 2014
Contact Email: investors@summitplc.com Phone: +44 (0)1235 44 39 39 Web: Twitter: Post: @summitplc 85b Park Drive Milton Park Abingdon Oxfordshire UK. OX14 4RY 26 Company Presentation December 2014