Advancing New Treatments for DMD and C. difficile Infection

Transcription

1 Advancing New Treatments for DMD and C. difficile Infection 34 th Annual Canaccord Genuity Growth Conference August 13, 2014

2 Legal Disclaimer 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. 2 Company Presentation August 2014

3 Corporate Overview Focused on two areas of high unmet clinical need Duchenne Muscular Dystrophy (DMD): Novel utrophin modulator approach targets 100% of patient population Technology developed at University of Oxford Potential to be monotherapy or complementary to other therapies C. difficile Infection (CDI): Differentiated antibiotic for treatment of initial infection and significantly reduced disease recurrence U.K./U.S. team based out of Oxfordshire, U.K. and Cambridge, MA Completed $35 million equity capital raise in March 2014 Publicly traded on AIM Exchange, London 3 Company Presentation August 2014

4 Our Pipeline DISCOVERY OPTIMIZATION PRECLINICAL PHASE 1 PHASE 2 CDI SMT19969 SMT C1100 DMD Next Generation University of Oxford technology 4 Company Presentation August 2014

5 Dystrophin and Utrophin Proteins Maintain Integrity of Muscle Fibers Dystrophin or utrophin protein provides the link between the actin cytoskeleton and cell membrane Provides stability and elasticity in muscle fibers Bundle of muscle fibers Dystrophin or utrophin Muscle cell membrane Dystrophin Utrophin Individual fiber Actin Protein complex 5 Company Presentation August 2014

6 Utrophin Modulation: Novel Disease-Modifying Approach for DMD Utrophin is functionally equivalent to dystrophin in both developing and repairing muscle Utrophin is continually expressed at specialized sites in normal mature muscle fibers Normal fiber MUSCLE FIBER DEVELOPMENT OVER TIME Developing/ repairing Maturing Mature Utrophin modulation is a disease-modifying strategy of potential utility for all DMD patients (independent of dystrophin mutation) DMD fiber DEGENERATION Only normal utrophin levels required for DMD muscle recovery DMD fiber + Utrophin modulator utrophin dystrophin 6 Company Presentation August 2014

7 Utrophin Modulation: Targeting 100% of DMD Population Dystrophin disease modifying approaches in clinical trials only treat sub-sets of patients Dystrophin Approaches* Exon 51 (13%) Exon 44 (6%) Exon 45 (8%) Exon 53 (6%) Nonsense (13%) Untreated (54%) Utrophin modulation is independent of gene mutation and can potentially treat 100% of DMD population Potential for combination use with dystrophin approaches Utrophin Modulation SMT C1100 (100%) Potential to treat Becker MD and other muscle wasting disorders 7 Company Presentation August 2014 * Treatments in clinical trials shown

8 SMT C1100 Increased Utrophin Levels in Muscle Fibers & Improves Disease Biomarkers In Vivo Reduced Fiber Regeneration (%CNFs) tibialis anterior extensor digitorum longus Reduced Plasma Creatine Kinase Levels mdx Increased utrophin at the sarcolemma significantly reduces secondary disease effects 28 days of oral dosing (50mk/kg, QD) in mdx mice (n=5) Source: PLoS ONE, Vol 6, Issue 4, May 2011 mdx + SMT C1100 mdx vehicle mdx+smt C Company Presentation August 2014

9 SMT C1100 Protects 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 completely protects against the loss of function otherwise seen with exercise Source: PLoS ONE, Vol 6, Issue 4, May Company Presentation August 2014

10 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 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 August 2014

11 Phase 1b Trial: Safety and PK in DMD Boys 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 100% patient compliance PK: Variable plasma levels Inter-individual variation in plasma levels 2/12 boys had SMT C1100 plasma levels appropriate for > 2x increase in utrophin levels based on in vivo data 10/12 boys plasma levels were similar to fasted healthy adult volunteers 11 Company Presentation August 2014

12 Phase 1b Trial: Significant Reduction in Plasma Markers of Muscle Damage Reduction in creatine kinase (CK), alanine transferase (ALT) and aspartate transferase (AST) levels during dosing Levels of these enzymes are typically elevated in DMD patients Levels increased once dosing with SMT C1100 had stopped Plot of average reduction from baseline (Estimate, square) with upper and lower 95% CI (diamond) for each time point after dosing (Day 7, Day 12) and follow-up (3 Days post completion of dosing SMT C1100) 12 Company Presentation August 2014

13 Phase 1b: Enzyme Changes by Patient CK, ALT and AST markers of muscle damage, GGT is a non-muscle marker % Change from Baseline Change in CK Levels at Day mg/kg BID 100mg/kg BID 100mg/kg TID % Change from Baseline Change in AST Levels at Day mg/kg BID 100mg/kg BID 100mg/kg TID % Change from Baseline Change in ALT Levels at Day mg/kg BID 100mg/kg BID 100mg/kg TID % Change from Baseline Change in GGT Levels at Day mg/kg BID 100mg/kg BID 100mg/kg TID 13 Company Presentation August 2014

14 Next Generation Utrophin Modulators 1.Structurally Related to SMT C1100 Equivalent in vitro potency to SMT C1100, enhanced PK properties Clean safety/off target profile In vitro genotox, herg, CYP inhibition; GPCR/ion channel screens In vivo PK Study Exposure: ~10-fold improvement 2.New structures, new mechanism New screening technology identifying differentiated utrophin modulators Potential new mechanism of action Increased in vitro activity compared to SMT C1100 Developed as part of collaboration with University of Oxford to strengthen long-term utrophin pipeline Utrophin Levels in DMD patient Myoblasts 14 Company Presentation August 2014

15 Biomarker Development Program Utrophin / Mechanism Related UTRN localisation by quantitative IF UTRN mrna by QPCR Regeneration, Inflammation & Fibrosis From Muscle: Muscle regeneration markers Inflammatory markers From Sera: mirnas Active Fibrosis Non-invasive Markers Muscle MRI 15 Company Presentation August 2014

16 DMD Program Summary Utrophin modulation is a novel disease modifying approach targeting 100% of the DMD population Innovative science from University of Oxford Conventional oral pharmacological approach Expected to be complementary with other disease modifying approaches Strong data package generated on first-in-class candidate SMT C1100 Potential indicators of activity in Phase 1b clinical trial in DMD boys Increase in utrophin protein levels, improvement in muscle function and secondary disease markers from in vivo studies Excellent safety profile Next clinical trial in patients expected to start in Q Next generation utrophin modulators and extensive biomarker program being developed in parallel 16 Company Presentation August 2014

17 C. DIFFICILE INFECTION PROGRAM SMT Company Presentation August 2014

18 CDI: A Significant Healthcare Problem Significant increase in global prevalence CDI Cases and Mortality in USA EUCLID Study: CDI 25% underdiagnosed Hyper-virulent strains Established ribotypes 027 (US) and 078 (EU) Emerging ribotypes include 244 Significant impact on healthcare resource US: $4.8bill in acute care direct cost Secondary CDI 3.5 fold increase in cost and length of stay Recurrent disease of particular concern Cost ($) 31,500 Length of Stay (days) % after initial episode 9, >60% after third episode Healthcare Cost and Utilization Project CDC NVSR Reports; J Pharm Pract 2013 p464 No CDI CDI No CDI CDI 18 Company Presentation August 2014

19 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 complete SMT19969 considered safe and 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 19 Company Presentation August 2014

20 SMT19969: Targeted Spectrum of Activity Potent bactericidal inhibition of C. difficile growth 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 Bacteroides spp. > >512 >8, Bifidobacterium spp. > >32 Lactobacillus spp. >512 >512 >512 > >32 Eggerthella lenta > Peptostreptococcus spp Staphylococcus aureus >512 > * Published data 20 Company Presentation August 2014

21 SMT19969: A Selective Therapy for CDI Treats initial infection and prevents recurrence in key disease model Oral, small molecule with low propensity for resistance Drug dosing Recurrent Disease Phase 21 Company Presentation August 2014

22 Phase 1: Gut Flora Fecal samples from MAD phase analyzed for gut flora composition SMT19969 shown to be highly sparing of the groups analyzed Total Clostridia only group where marked changes in counts were seen Group Median Changes 200mg BID Group Median Changes 500mg BID Log CFU/mL Log CFU/mL Day Day 22 Company Presentation August 2014

23 Phase 2 Proof of Concept Trial 100 subjects ~30 US/Canadian sites First subjects recruited Primary outcome parameter: Sustained Clinical Response (SCR) Clinical cure and absence of recurrence within 30 days of EOT Secondary outcome parameters: Clinical response at TOC Recurrence of CDI Time to resolution of diarrhea Group Design Group N Agent Regimen 1 50 SMT 2 50 VAN 200mg BID 10 days 125mg QID 10 days 23 Company Presentation August 2014

24 Outlook DMD utrophin modulation program Small molecule approach with potential to treat all DMD patients Phase 1b clinical trial on lead candidate SMT C1100 reported in May 2014 Next patient trial expected to start Q SMT19969: A novel antibiotic for C. difficile infections Exquisitely selective activity seen in human gut flora Safe and well tolerated in Phase 1 healthy volunteer trial Phase 2 PoC trial recruiting patients, top-line data expected H Phase 2 PoC for both programs expected in 2015/early Company Presentation August 2014

25 Contact Phone: +44 (0) Web: Twitter: 85b Park Drive Milton Park Abingdon Oxfordshire UK. OX14 4RY 25 Company Presentation August 2014