Slide 1: Biotech Showcase
NASDAQ: BNTC ASX: BLT Biotech Showcase 9th January 2017 Copyright © Benitec Biopharma Ltd www.benitec.com
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: Company overview
Company overview Novel application of gene silencing technologies to build a focused product pipeline to address unmet medical needs across numerous indications NOVEL GENE SILENCING ddRNAi combines RNA interference (RNAi) with gene therapy delivery to TECHNOLOGY change the way patients are treated a
Slide 4: Gene therapy approach to silence disease-associated genes
Gene therapy approach to silence disease-associated genes Copyright © Benitec Biopharma Ltd www.benitec.com
Slide 5: Benitec technology platform: DNA-directed RNAi (ddRNAi)
Benitec technology platform: DNA-directed RNAi (ddRNAi) Benitec technology • Combines RNA interference with siRNA ddRNAi gene therapy delivery • Long term therapeutic potential from a single administration • Steady state levels of shRNA expression • Silence a single gene or target multiple genes sim
Slide 6: Business Model
Business Model ddRNAi Technology Pipeline Business Outcomes Partnering of Pipeline programs (e.g. co-develop or license) Prioritizing ddRNAi pipeline Internal Product opportunities by: Pipeline Product Franchise spinout and/or - identifying unmet medical needs commercialization - optimized delivery
Slide 7: Pipeline Programs
Pipeline Programs IND- Program Discovery Preclinical Phase I/II Status Enabling Oncology Head and Neck • Sublicense signed December 2016 Cancer (HNSCC) • Phase 1 clinical POC completed in patients with HNSCC BB-401 (EGFR-AS ) • Follow-on PII/III trial design under review ddRNAi for Head and Neck Can
Slide 8: New ddRNAi Applications
New ddRNAi Applications IND- Program Discovery Preclinical Phase I/II Phase III Status Enabling Immunotherapy CAR-T • In vitro POC completed New Technologies Non-Viral Delivery • In vitro POC underway Copyright © Benitec Biopharma Ltd 8 www.benitec.com
Slide 9: Strategic Collaboration with NantWorks
Strategic Collaboration with NantWorks Copyright © Benitec Biopharma Ltd www.benitec.com
Slide 10: Strategic Engagement With NantWorks
Strategic Engagement With NantWorks Highlights: • Two phased investment by NantVentures with oncology focused R&D collaboration • Returns Benitec to the clinic through in-licensing of a Phase II ready gene silencing asset for the treatment of head and neck squamous cell carcinoma (HNSCC) • Follow-on
Slide 11: NantWorks Vision and Focus
NantWorks Vision and Focus ‘The Cognitive Age’: Convergence of Science, Technology and Communication • Nantworks: founded by Patrick Soon Shiong in 2011 • Shiong is pioneer of novel therapies for diabetes and cancer (e.g. Abraxane) and prolific innovator • Ecosystem of companies to create transforma
Slide 12: Head and Neck Squamous Cell Carcinoma (HNSCC)
Head and Neck Squamous Cell Carcinoma (HNSCC) Anatomical sites of HNSCC Incidence and patient mortality: • Circa 64,000 patients diagnosed annually in US • 50% of patients expected to develop recurrent or metastatic disease • 13,000 deaths annually in the US Unmet need: • Significant patient morbidi
Slide 13: Framework for Benitec / Nant Research Collaboration
Framework for Benitec / Nant Research Collaboration Gene silencing treatments directed against HNSCC targeting EGFR RNA antisense program for continued clinical development HNSCC ddRNAi Program • DNA plasmid to produce antisense RNA • Follow-on program for durable gene silencing of (EGFR-AS) EGFR vi
Slide 14: EGFR-AS clinical studies compare favorably to other EGFR treatments evaluated in HNSCC
EGFR-AS clinical studies compare favorably to other EGFR treatments evaluated in HNSCC Phase I study Follow on Phase 1 Clinical Study 17 patients with advanced, refractory HNSCC * 6 patients with advanced HNSCC evaluate improvement to multi treatment regimen: • Safety and Efficacy evaluated followin
Slide 15: HNSCC Program Highlights
HNSCC Program Highlights EGFR-AS • Direct intra-tumoral injection indicates an effective method of administration for a gene- silencing treatment modality • No concerning adverse events have been reported • Clinical efficacy observed in combination study point to potential improved clinical outcomes
Slide 16: BB-102 and BB-103 Hepatitis B
BB-102 and BB-103 Hepatitis B Copyright © Benitec Biopharma Ltd www.benitec.com
Slide 17: Hepatitis B: Market size
Hepatitis B: Market size • Hepatitis B is a DNA virus with an unmet medical need • 240 million infected worldwide, resulting in up to 780,000 deaths per year • Hepatitis B virus causes 60-80% of the world’s primary liver cancers • Existing therapies have low cure rates • Current standard of care in
Slide 18: BB-102/BB-103: Mechanism of Action
BB-102/BB-103: Mechanism of Action Copyright © Benitec Biopharma Ltd 18 www.benitec.com
Slide 19: BB-102 vs BB-103: A Difference in Expression Cassettes
BB-102 vs BB-103: A Difference in Expression Cassettes Copyright © Benitec Biopharma Ltd 19 www.benitec.com
Slide 20: In Vivo Infectious HBV Studies Using PXB Mice
In Vivo Infectious HBV Studies Using PXB Mice 2. Incubate mice for 4 3. Transduce mice with BB-102 or BB-103 weeks, establish baseline HBV infection, randomize Chimeric mouse with HBV infected Chimeric mouse humanized liver 1. Infect chimeric PXB mice 4. Administer Entecavir (Daily) or Pegasys (twic
Slide 21: BB-102 and BB-103 Monotherapy vs Entecavir: Reduction of Serum HBV DNA Levels
BB-102 and BB-103 Monotherapy vs Entecavir: Reduction of Serum HBV DNA Levels 1.0E+09 Untreated, HBV infected PXB mice 1.0E+08 Serum HBV DNA (copies/ml) 1.34 log drop BB-102 (*max 1.87 Day 63) 1.0E+07 1.34 log drop BB-103 (*max 2.17 Day 63) * * 1.0E+06 2.63 log drop ETV 1.0E+05 LLOQ – 4e4 DNA copies
Slide 22: BB-102 and BB-103 Combos with Entecavir: Reduction of Serum HBV DNA Levels
BB-102 and BB-103 Combos with Entecavir: Reduction of Serum HBV DNA Levels 1.0E+09 Untreated, HBV infected PXB mice 1.0E+08 Serum HBV DNA (copies/ml) 1.34 log drop BB-102 (*max 1.87 Day 63) 1.0E+07 1.34 log drop BB-103 (*max 2.17 Day 63) * * 1.0E+06 2.63 log drop ETV 1.0E+05 LLOQ – 4e4 DNA copies ml
Slide 23: Activity of combinations of BB-102 and BB-103 with SOC on HBV Parameters
Activity of combinations of BB-102 and BB-103 with SOC on HBV Parameters Log Reduction of Log Reduction Log Reduction Treatment Serum HBV DNA of HBsAg of HBeAg entecavir (ETV) 2.63 0.46 0.37 6 mg/kg daily Control groups pegylated interferon 30 mg/kg twice 2.41 0.96 1.09 weekly BB-102 1.87 max 1.75 m
Slide 24: HBV Program Highlights
HBV Program Highlights • Development BB-102/BB-103 leverages existing safety and efficacy data in HCV using similar molecular construct and delivery • Superior Significant and sustained drop of serum HBV levels, HBsAg levels and HBeAg levels with single doses of BB-103 and BB-102 in combination with
Slide 25: BB-201 Age-related macular degeneration
BB-201 Age-related macular degeneration Copyright © Benitec Biopharma Ltd www.benitec.com
Slide 26: Dry and Neovascular (Wet) Age-related Macular Degeneration (AMD)
Dry and Neovascular (Wet) Age-related Macular Degeneration (AMD) • AMD is the leading cause of irreversible vision loss in the U.S. • 196M people affected worldwide by 2020 • Ranibizumab (Lucentis) /Aflibercept (Eylea) act as molecular sponges to mop up secreted VEGF-a, (as well as VEGF-b and PlGF)
Slide 27: BB-201: Clinical Construct
BB-201: Clinical Construct VEGFb shMir VEGFa shMir PlGF shMir ITR U6-9 U6-1 U6-8 ITR • An AAV-encapsidated construct that expresses a single shRNA modeled into a miRNA backbone that inhibits the expression of VEGF-a, VEGF-b and PGF • Molecular targets are treated with protein-based current SOC that
Slide 28: BB-201: Mechanism of Action
BB-201: Mechanism of Action Copyright © Benitec Biopharma Ltd 28 www.benitec.com
Slide 29: BB-201: In vitro Knockdown of VEGF-a, VEGF-b and PlGF
BB-201: In vitro Knockdown of VEGF-a, VEGF-b and PlGF VEGF-a VEGF-b PlGF 100 1.0E+05 100 7.0E+05 100 15000 mRNA mRNA mRNA Protein VEGFb-sh1 PGF -sh7 VEGFa-sh8 80 8.0E+04 80 5.6E+05 80 12000 Anti-VEGF-b shMir copies / cell anti-PlGF shMir copies / cell Anti-VEGF-a shMir copies / cell Percent Inhibiti
Slide 30: Modified AAV vectors for Intravitreal Delivery
Modified AAV vectors for Intravitreal Delivery • BB-201 is being developed for intravitreal route of delivery • Intravitreal is more commercially viable than a subretinal injection (typically used by most gene therapy vectors for ocular diseases) • Vectors developed through 4DMT’s ‘therapeutic evolu
Slide 31: 4DMT Collaboration: NHP Screen for AAV Variants with Pan-Retinal Expression
4DMT Collaboration: NHP Screen for AAV Variants with Pan-Retinal Expression • Benitec has an exclusive license to ocular vectors from 4D Molecular Therapeutics for use in RNAi applications as well as in ‘silence & replace’ strategies • Novel evolution selection in non human primates (complex eye wit
Slide 32: Therapeutic Evolution Yields AAV Variants with Optimal Tissue Distribution (Round 6)
Therapeutic Evolution Yields AAV Variants with Optimal Tissue Distribution (Round 6) Copyright © Benitec Biopharma Ltd 32 www.benitec.com
Slide 33: AMD Program Highlights
AMD Program Highlights • Demonstrated knockdown of of clinically validated targets in an in vitro model • Completed ‘Therapeutic evolution’ selection of AAV variants validating biodistribution in the back of the eye • Next steps: efficacy model utilizing laser induced choroidal neovascularization in
Slide 34: BB-301 Oculopharyngeal muscular dystrophy (OPMD)
BB-301 Oculopharyngeal muscular dystrophy (OPMD) Copyright © Benitec Biopharma Ltd www.benitec.com
Slide 35: Clinical Features of OPMD
Clinical Features of OPMD Rare autosomal dominant inheritance • 1:100,000 (Europe) • As high as 1:600 in specific populations • Founder effect in Quebec, Canada Typically age onset occurs in subjects 50’s or 60’s Raz et al., BMC Neurology 2013, 13:70 Characterised by: • eyelid drooping (ptosis) • sw
Slide 36: 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: • Ubiquitous factor that promotes interaction between the poly(A) polymerase and CPSF (cleavage and polyadenylation specificity factor) In OPMD: • Genetic mutation results in trinucleotide repeat expansion results in an
Slide 37: BB-301: 'Silence and Replace' Approach
BB-301: ‘Silence and Replace’ Approach Wildtype AAV (4.7 Kb packaging capacity) REP/CAP removed and replaced with expression cassette Codon optimized wildtype PABPN1 PABPN1 PABPN1 BB-301 ITR Muscle Specific Promoter (insensitive to PABPN1 shRNA cleavage) shRNA-2 shRNA-1 ITR Recombinant AAV “Replace”
Slide 38: BB-301: Mechanism of Action
BB-301: Mechanism of Action Copyright © Benitec Biopharma Ltd 38 www.benitec.com
Slide 39: An Animal model of OPMD: The 'A17' mouse
An Animal 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 - Fibro
Slide 40: Muscle Atrophy and Restoration of Specific Force Treated A17 mice
Muscle Atrophy and Restoration of Specific Force Treated A17 mice Muscle weight Specific Force Reduced Fibrosis + Specific force calculated by normalizing Partial Reversal of Atrophy maximal force for muscle weight Copyright © Benitec Biopharma Ltd 40 www.benitec.com
Slide 41: OPMD Program Highlights
OPMD Program Highlights • Rare orphan indication, potentially accelerates clinical development and commercialization • ddRNAi construct design highlights unique ‘silence and replace’ therapeutic strategy for monogenic disease • In vivo study demonstrates correction of disease phenotype • Next steps:
Slide 42: Financial and News flow
Financial and News flow Copyright © Benitec Biopharma Ltd www.benitec.com
Slide 43: Company financial snapshot
Company financial snapshot ASX: BLT Key Financial Details NASDAQ: BNTC NASDAQ: BNTCW BNTC Share Price as of 31st Dec, 2016: USD 1.53 Market Capitalization as of 31st Dec, 2016: USD 14.1M Issued Securities as of 31st Dec, 2016: Ordinary shares 175,834,915 Options 34,626,202 Cash Balance as of 30th Se
Slide 44: Multiple Shots on Goal Expected Milestones 2017-2019
Multiple Shots on Goal Expected Milestones 2017-2019 2017 2018 2019 Hepatitis B • Pre-IND meeting • Phase 1/2 initiation • Phase 1/2 BB-103 • IND-enabling studies AMD • Preclinical POC • IND enabling studies • Phase 1/2 BB-201 • Pre-IND meeting • Phase 1/2 initiation OPMD • Preclinical POC • IND ena
Slide 45: Investment Highlights
Investment Highlights Novel application of gene silencing technologies to build a focused product pipeline to address unmet medical needs across numerous indications NOVEL GENE SILENCING ddRNAi has demonstrated broad applicability to address high unmet needs TECHNOLOGY Superior efficacy in preclinic
Slide 46: Cliff Holloway CBO/COO
NASDAQ: BNTC ASX: BLT Cliff Holloway CBO/COO cholloway@benitec.com Copyright © Benitec Biopharma Ltd www.benitec.com