VBP15 in Duchenne muscular dystrophy Rationale for anti-inflammatory therapy in DMD Action Duchenne Conference 2015 Michela Guglieri JWMDRC Newcastle upon Tyne Michela.guglieri@Newcastle.ac.uk Co-applicant for H2020 grant for VBP15 development program

Why is anti-inflammatory therapy important for DMD Normal muscle Action Duchenne Conference 2015 DMD Action Duchenne Conference 2015

Corticosteroids: mechanism of action Cytoplasam Membrane Stabilization Beneficial Effects p65 p50 IkB Anti-inflammatory Effects Protein Interference Mechanisms GR C-Jun Fos NFĸB Response Element 3 Plasma membrane GR 2 Nucleus DNA-Dependent Regulation Glucocorticoid Responsive Element GR Metabolic Side Effects The Anti-inflammatory activities via inhibition of NF-κB pathways seems to be of particular importance to DMD treatment Other immunosuppressive compounds reduce inflammation in DMD but fail to increase patient strength 1 Reeves, et al. Bioorganic & Medicinal Chemistry 2013. Baudy, et al. International Immunopharmacology 2009. Action Duchenne Conference 2015

Corticosteroids in Duchenne Muscular Dystrophy Side effects Weight gain Growth restriction Bone fragility Adrenal suppression Adrenal failure Delayed puberty Immune suppression ………………………. Action Duchenne Conference 2015

Action Duchenne Conference 2015 VBP15 Glucocorticoids have many different activities Efficacy (good layers) Anti-inflammatory NFkB inhibition Side effects (bad layer) Mineral-corticoid agonist Peel away layers Keep or enhance the ‘good layers’ Reduce or remove the ‘bad layers’ Action Duchenne Conference 2015

VPB15 Scaffold Discovery Efficacy: Retention of NF-kB inhibition Can increase dose Efficacy: Gain of membrane stabilization Changes pred damage to VBP15 protection Safety: Loss of transactivation Loss of some GRE-mediated activities relative to pred Safety: MR antagonist (instead of agonist) Loss of growth stunting, Cushingoid Prednisolone VBP-15 Action Duchenne Conference 2015

Action Duchenne Conference 2015 VPB15: mdx mouse Action Duchenne Conference 2015

Action Duchenne Conference 2015 VPB15: Clinical program Phase 1 study: Healthy adult volunteers. August 2015-November 2015 Single Ascending Dose (SAD) 0.1, 0.3, 1.0, 3.0, 8.0, 8.0 fed, 20.0 mg/kg Multiple Ascending Dose (MAD) 1.0, 3.0, 9.0, 20.0 mg/kg/day 2 weeks Action Duchenne Conference 2015

Phase 1 data through SAD Cohort 4 (3.0 mg/kg) Excellent dose proportionality Short half-life (2 hrs) – similar to pred Consistent findings between subjects No adverse events reported through 8.0 mg/kg Action Duchenne Conference 2015

VPB15: DMD Clinical program Phase 2a and 2a extension studies (1Q 2016) CINRG international trials group (Paula Clemens) US Phase 2b and 2b extension (4Q 2016-1Q 2017) Newcastle Team (Kate Bushby and Michela Guglieri) EU, Israel, (Australia) VBP15 – Verolone: Oral syrup suspencion Once daily administration Action Duchenne Conference 2015

Action Duchenne Conference 2015 Phase 2a and 2a extension 10 US CINRG sites Dose escalation study (4 doses) Subjects: 3-12 subjects per cohort Duration of treatment: 2 weeks Primary outcome: PK and safety Inclusion criteria: 4-7 year old, steroid naïve Start date: 1Q 2016 (February 2016) Action Duchenne Conference 2015

Action Duchenne Conference 2015 Phase 2b and 2b extension 30 sites (EU, Israel, Australia) Double-blind, prednisolone-placebo-control study, two doses of Verolone Primary outcomes: Efficacy (versus placebo) Safety (versus daily prednisolone) Subjects: 100 subjects (25 per cohort) Duration of treatment: 6 months Inclusion criteria: 4-7 year old, steroid naïve, able to stand from the floor Start date: 4Q 2016 – 1Q 2017 Action Duchenne Conference 2015

Pharmacodynamic biomarkers Objective measures (blood not subject to placebo effect) Possibly an acute read out (changes in blood seen before clinical changes) SAFETY Steroid related side effects Insulin resistance Adrenal suppression Bone remodeling EFFICACY Exploratory Pro-inflammatory proteins Should help build ‘compelling case’ for regulators: accelerated approval Action Duchenne Conference 2015

Pharmacodynamic biomarkers Should support and extend clinical outcomes Should help build ‘compelling case’ for regulators: accelerated approval Could allow clinical trials in populations where there are no strong clinical outcomes (young boys and older, non- ambulant subjects) Action Duchenne Conference 2015

Action Duchenne Conference 2015 VBP15: Timelines 2016 2017 2018 2019 2020 Phase 2a 4-7 yr old DMD Phase 2b 1-3 yr old DMD 0-1 yr old DMD 7-18 yr old DMD 3-17 yr old Pediatric Ulcerative Colitis Phase 2b, Phase 2b Extension Phase 2a, Phase 2a Extension Phase 1 Aug 2015 2016 2017 2018 FDA/EMA NDA Action Duchenne Conference 2015

Action Duchenne Conference 2015 VBP15: Innovation Venture philanthropy - Sustainable drug Reduce costs To build a compelling case that ‘drug works’ Accelerated approvals Action Duchenne Conference 2015

VBP15:Made possible by…… the community National Institutes of Health; NCATS, TRND; SBIRs US Department of Defense (CDMRP DMDRP) National Institute on Disability and Rehabilitation Research (NIDRR) NIH NICHD RPDP U54 Foundation to Eradicate Duchenne (FED) (USA) MDA (USA) Joining Jack (UK) Duchenne Research Foundation (UK) Duchenne Children’s Trust (UK) PPMD (USA) Clark Charitable Foundation (USA) ActionDuchenne (UK) DuchenneAlliance (Michael’s Cause- USA, Pietro’s Fight - USA, Alex’s Wish - UK, Ryan’s Quest - USA, Save Our Sons - AUS)

National Institutes of Health; NCATS, TRND; SBIRs US Department of Defense (CDMRP DMDRP) National Institute on Disability and Rehabilitation Research (NIDRR) NIH NICHD RPDP U54 Foundation to Eradicate Duchenne (FED) (USA) MDA (USA) Joining Jack (UK) Duchenne Research Foundation (UK) Duchenne Children’s Trust (UK) PPMD (USA) Clark Charitable Foundation (USA) ActionDuchenne (UK) DuchenneAlliance (Michael’s Cause- USA, Pietro’s Fight - USA, Alex’s Wish - UK, Ryan’s Quest - USA, Save Our Sons - AUS) Michela.guglieri@ncl.ac.uk