Benitec Biopharma Inc. · NASDAQ:BNTC
Benitec Biopharma — 2017 ESGCT Conference
17 slides from Benitec Biopharma's conference presentation, Oct 18, 2017
Slide 1: Towards Development of a 'Silence and Replace' Based Approach for the Treatment of OPMD
Towards Development of a ‘Silence and Replace’ Based Approach for the Treatment of Oculopharyngeal Muscular Dystrophy Vanessa Strings‐Ufombah Research Scientist 2017 ESGCT Conference
Slide 2: Safe Harbor Statement
Safe Harbor Statement This presentation contains "forward‐looking statements" within the meaning of section 27A of the US Securities Act of 1933 and section 21E of the US Securities Exchange Act of 1934. Benitec has tried to identify such forward‐looking statements by use of such words as "expects,"
Slide 3: Permanent Gene Silencing via DNA-Directed RNA Interference (ddRNAi)
Permanent Gene Silencing via DNA‐Directed RNA Interference (ddRNAi) • Combines RNA interference Transient gene silencing ‐ siRNA Permanent gene silencing ‐ ddRNAi with gene therapy delivery • Long term therapeutic potential from a single administration • Constant, steady state levels of shRNA expres
Slide 4: Diverse Program Pipeline
Diverse Program Pipeline IND‐ Early stage clinical Late stage clinical Commercial Program Delivery Discovery Preclinical Enabling (IND – Phase 2) (Phase 2 – Phase 3) Rights Oncology – head and neck squamous cell carcinoma (HNSCC) HNSCC Plasmid • global BB‐401 Intratumoral HNSCC ddRNAi • global BB‐50
Slide 5: Oculopharyngeal Muscular Dystrophy
Oculopharyngeal Muscular Dystrophy Disease: • Rare autosomal dominant inheritance • 1:100,000 (Europe) • As high as 1:600 in specific populations • Typical age of onset is in 50’s or 60’s Characterized by: • Eyelid drooping (ptosis) • Swallowing difficulty (dysphagia) • Proximal limb weakness • Deat
Slide 6: Genetic Basis of OPMD: Expansion of the Poly-Alanine Tract Within PABPN1
Genetic Basis of OPMD: Expansion of the Poly‐Alanine Tract Within PABPN1 PABPN1: • A ubiquitous factor that promotes interaction between the poly(A) polymerase and CPSF (cleavage and polyadenylation specificity factor) and thus controls the length of mRNA poly(A) tails, mRNA export from the nucleus,
Slide 7: A Dual Vector Approach for a ddRNAi Treatment Against OPMD
A Dual Vector Approach for a ddRNAi Treatment Against OPMD Promoter PABPN1 Promoter PABPN1 Promoter PABPN1 “Silence” ITR A shRNA‐1 B shRNA‐2 C shRNA‐3 ITR REP/CAP removed and MYC “Replace” ITR Muscle Specific Promoter Codon replacedoptimized wildtype with expression PABPN1 cassette ITR MYC Insensiti
Slide 8: BB-301: A Single Vector 'Silence and Replace' Approach to Treat OPMD
BB‐301: A Single Vector ‘Silence and Replace’ Approach to Treat OPMD Muscle Specific REP/CAP removed and PABPN1 PABPN1 BB‐301 ITR Promoter Codon replacedoptimized wildtype with expression PABPN1 cassette shRNA‐1 shRNA‐2 ITR “Replace” “Silence” 8
Slide 9: Pre-Clinical Model of OPMD: The 'A17' Mouse
Pre‐Clinical Model of OPMD: The ‘A17’ Mouse • Transgenic mouse: express a mutated bovine PABPN1 driven by the human skeletal actin promoter in addition to the endogenous PABPN1 • Recapitulates severe muscle atrophy • Mimics many of the disease pathologies: ‐ Progressive muscle weakness/ atrophy ‐ Fi
Slide 10: BB-301: Use of AAV / Intramuscular Injections
BB‐301: Use of AAV / Intramuscular Injections 10
Slide 11: BB-301 Treatment Inhibits Diseased Gene Expression & Restores Wildtype PABPN1 Levels in A17 Mice
BB‐301 Treatment Inhibits Diseased Gene Expression & Restores Wildtype PABPN1 Levels in A17 Mice SILENCE: Inhibition of PABPN1 Expression REPLACE: Codon‐Optimized PABPN1 Expression 100.0 1.00 88% 91% 90.0 Inhibition Replacement 0.90 Relative Expression ((coPABPN1/GAPDH)/A17 Saline) 80.0 0.80 70.0 0.
Slide 12: BB-301 Treatment Resolves Intranuclear Inclusions in A17 Mice
BB‐301 Treatment Resolves Intranuclear Inclusions in A17 Mice 40 Wildtype + Saline A17 + Saline *** *** % Cells PABPN1 Intranuclear Inclusions 30 PABPN1/Laminin/DAPI 20 A17+ BB‐301 High Dose A17 + BB‐301 Low Dose 10 0 Mouse WT A17 A17 A17 Treatment WT Saline A17 saline BB‐301 BB‐301 High Dose Low Do
Slide 13: BB-301 Treatment Reduces Fibrosis in Transverse Muscle Section of A17 Mice
BB‐301 Treatment Reduces Fibrosis in Transverse Muscle Section of A17 Mice 16 Wildtype + Saline A17 + Saline 14 12 10 % %Fibrosis Fibrosis 8 A17+ BB‐301 High Dose A17 + BB‐301 Low Dose 6 4 2 0 Mouse WT A17 A17 A17 Treatment Saline Saline BB‐301 High BB‐301 Dose Low Dose 13
Slide 14: BB-301 Treatment Restores Muscle Force and Muscle Weight in A17 Mice
BB‐301 Treatment Restores Muscle Force and Muscle Weight in A17 Mice Restoration of Muscle Force Restoration of Muscle Weight 2000 2 ** ** * ** ** ** ** ** * ** * * Muscle weight/final body weight (mg/g) 1.6 1600 * WT Saline A17 BB‐301 Low A17 BB‐301 High 1.2 1200 Force (mN) A17 Saline 0.8 800 0.4 4
Slide 15: Summary
Summary Developed a single vector “silence and replace” based approach to treat OPMD • Uses a bi‐functional RNA to produce shRNA to inhibit PABPN1 including the expanded PABPN1 protein as well as expresses a codon optimized normal copy of PABPN1 • Simplifies the manufacturing and clinical developmen
Slide 16: OPMD Clinical Candidate BB-301: Product Overview
Oculopharyngeal Muscular Dystrophy Clinical Candidate BB‐301: Product Overview • Rare, autosomal dominant, monogenic disease Oculopharyngeal • Estimated 12,000 patients in Western countries Muscular Dystrophy • Characterized by eye lid drooping, swallowing difficulties, proximal limb weakness, death
Slide 17: Acknowledgments
Acknowledgments Benitec Biopharma Centre for Biomedical Myology Research Center, Sciences UMRS974 (Paris) Sonal Harbaran Dr. Michael Graham Dr. Alberto Malerba Fanny Roth Dr. Peter Roelvink Dr. Ngoc Lu‐Nguyen Prof. Arnaud Ferry Dr. Houria Bachtarzi Dr. Pierre Klein Dr. David Suhy Dr. Susan Jarmin Dr