Benitec Biopharma Inc. · NASDAQ:BNTC
Benitec Biopharma — Investor Presentation (November 2011)
54 slides from Benitec Biopharma's investor presentation, Nov 18, 2011
Slide 1: Gene silencing technology for unmet global medical conditions
Gene silencing technology for unmet global medical conditions – progress and potential Clinical Investigator Group Update 17-18 November 2011 www.benitec.com
Slide 2: Forward looking statements
This presentation contains forward looking statements that involve risks and uncertainties. Although we believe that the expectations reflected in the forward looking statements are reasonable at this time, Benitec can give no assurance that these expectations will prove to be correct. Actual result
Slide 3: Welcome
Welcome Dr Peter French, CEO Benitec Biopharma Ltd Benitec Ltd 3 www.benitec.com 3
Slide 4: Agenda
Agenda • Overview • Cancer-associated pain update • Hepatitis B update • OPMD program commencement • Lung cancer update • HIV/AIDS trial update • IP Summary • Questions Benitec Ltd 4 4 www.benitec.com
Slide 5: Benitec Background
Benitec Background DNA-directed RNA interference (ddRNAi) is a novel technology platform capable of achieving long-term targeted gene silencing. Benitec is developing a range of products that utilize the ddRNAi technology to treat and cure life threatening severe conditions in infectious disease
Slide 6: Benitec's Novel RNA Interference Technology
Benitec’s Novel RNA Interference Technology Benitec’s ddRNAi technology platform utilizes a vector to express shRNA molecules which silence a targeted gene of interest. ddRNAi Mechanism of Action ddRNAi Mechanism of ActionBenitec technology The ddRNAi-based product contains a novel ddRNAi DNA cons
Slide 7: ddRNAi Product Development Timeline
ddRNAi Product Development Timeline Benitec has a pipeline of ddRNAi-based therapeutics targeted for indications where their technology provides a significant competitive advantage. Human Collaborator/ Indication Discovery Pre- clinical Collaboration Status Clinical Licensee Cancer- University of Be
Slide 8: ddRNAi Technology for Cancer Pain Treatment
ddRNAi Technology for Cancer Pain Treatment – A New Class of Pain Therapeutics Benitec Ltd 8 www.benitec.com
Slide 9: The Problem With Cancer-Associated Pain
The Problem With Cancer-Associated Pain Approximately 65% of all cancer patients experience pain Global Incidence of Cancer-Associated Pain Among Cancer Patients Opioids are the first line of therapy for cancer pain, but their efficacy is often insufficient and their side effects can be severe. “It
Slide 10: ddRNAi can uniquely fill that need
ddRNAi can uniquely fill that need Single treatment Localised administration Specific single target Well understood mechanism of action Long term pain relief Benitec Ltd 10 www.benitec.com
Slide 11: Key Success Factors
Key Success Factors The best target Overall Opinion of the ddRNAi Product The best silencing sequence Average: 6.4 7 6 Medical acceptance 5 4 Proven safety 3 2 Proven efficacy 1 0 FDA approval US KOL EU KOL Question: On a scale of 1 to 7 (1=Very low, 7=Very high) how would you rate this product base
Slide 12: Choosing the best target
Choosing the best target In the last six months, Benitec has been examining two possible targets in a rat model of neuropathic pain – DAO and PKCg Whilst encouraging results 1 x 10E6 TU/animal 1 x 10E7 TU / animal have been achieved with DAO, data from an independent group have persuaded us to move
Slide 13: Validation of PKCg as the Best Neuropathic Pain Target
Validation of PKCg as the Best Neuropathic Pain Target PKCg is increased in the spinal cord in PKCγ-Mediated Pain Inhibition in Rats cancer pain Researchers have proven the concept in a rat model of neuropathic pain – the rats with ddRNAi silencing of PKCg showed a significant increase in pain t
Slide 14: Validation of PKCg as the Best Neuropathic Pain Target
Validation of PKCg as the Best Neuropathic Pain Target Leading clinical pain specialists strongly endorsed the mechanism of action because of the strong connection between PKCγ and neuropathic pain. “Noting the mechanism of neuropathic pain and the cascade of evidence associated with the activation
Slide 15: Potential Lead Indication for the ddRNAi Pain Product
Potential Lead Indication for the ddRNAi Pain Product KOLs saw terminal cancer patients as an ideal lead indication for the ddRNAi product due to the level of novelty of the product and the length of trials required for an indication in this patient segment. KOLs see strong potential for the ddRNA
Slide 16: Progress and Plans
Progress and Plans Feb – June 2011 Target Selection (I) • Confirmation that DAO inhibition blocks pain • DAO constructs selected • Tested in neuropathic pain model • Confirmed gene silencing achieved in vivo • Needs dose optimisation July – November 2011 Target Selection (II) • Publication of ddRNAi
Slide 17: Progress and Plans
Progress and Plans May-August 2011 Market Assessment • Product specification defined • Interviews with key pain specialists • Target market identified September 2011- May 2012 IND Package Development • Confirmation of target • Design of FDA compliant experiments • Regulatory requirements incorporate
Slide 18: Progress and Plans
Progress and Plans Overview of in vivo and laboratory testing Benitec Ltd 18 www.benitec.com
Slide 19: Cancer Pain Product Original Development Plan and Timeline
ddRNAi Cancer Pain Product Original Development Plan and Timeline ddRNAi Cancer Pain Product Clinical Development Timeline 2011 2012 2013 2014 2015 Proof of concept in pre-clinical model of pain Preclinical Studies Toxicology studies Phase I/II Trial (cancer patients IND Preparation and Submission w
Slide 20: Cancer Pain Product Updated Development Plan and Timeline
ddRNAi Cancer Pain Product Updated Development Plan and Timeline ddRNAi Cancer Pain Product Clinical Development Timeline 2011 2012 2013 2014 2015 Proof of concept in pre-clinical model of pain Preclinical Studies Toxicology studies A New Class Phase I/II Trial (cancer patients of Pain IND Preparati
Slide 21: Current ddRNAi Programs: Hepatitis B
Current ddRNAi Programs: Hepatitis B The ddRNAi technology is also being developed for HBV under collaboration with Biomics Biotechnologies in China. Hepatitis B Virus Rationale: Collaborator: Successful ddRNAi delivery to the liver has been demonstrated. The targeted enzyme is key to HBV replic
Slide 22: Summary of the Project
Summary of the Project Phase I (Biomics) - EsT libraries - In vitro screening Phase II (collaboration between Biomics & Benitec) - Convert siRNAs to shRNAs - Validate shRNAs in vitro - Design construct(s) expressing 3 active shRNAs - Validate in vivo using AAV delivery Benitec Ltd 22 www.benitec
Slide 23: HBV program: target identification
HBV program: target identification – from virus to gene to effective sequences Virus Viral Genes 14 RNA sequences identified by Biomics that 5000 potential target sequences provide ≥70% knock down of HBV gene mRNA Benitec Ltd 23 www.benitec.com 23
Slide 24: Overview of Phase II
Overview of Phase II In vitro • siRNA candidates validation • Convert siRNAs to shRNAs • Validate shRNAs in vitro • Optimize the promoters • Definite triple cassette components (specify minimal expression and full potency against HBV ) In vivo • Peak expression time and dose optimization of AAV8 • s
Slide 25: Reduction of HBV DNA Levels by Continuous Transfection of shRNAs
Reduction of HBV DNA Levels by Continuous Transfection of shRNAs 140% 5 Day DNA Level 120% 7 Day 100% 9 Day 11 Day 80% 60% 40% 20% 0% si-3 si-11 si-12 si-17 si-GL3 Untreated Continuous siRNA transfection inhibited HBV DNA levels in a time-dependent manner Benitec Ltd 25 www.benitec.com
Slide 26: Calibration of the Activity of shRNAs
Calibration of the Activity of shRNAs The relative activity of shRNA is: shRNA-8 > shRNA-12>shRNA-3>shRNA-17>shRNA-11. Benitec Ltd 26 www.benitec.com
Slide 27: Optimization of delivery vector
Optimization of delivery vector 20 days after dsAAV8-GFP treatment Few GFP positive ~20% GFP positive ~60% GFP positive Close to 100% GFP positive Benitec Ltd 27 www.benitec.com
Slide 28: Conclusions
Conclusions Achieved to date • Several shRNA constructs have been identified • Expression levels being optimised • Proof of concept of delivery to 100% liver cells achieved Next steps • Build a triple cassette construct with maximum silencing activity and minimal shRNA expression • Package into AAV8
Slide 29: Original Development Plan and Timeline for HBV Program
Original Development Plan and Timeline for HBV Program HBV Program Clinical Development Timeline Program 2011 2012 2013 2014 2015 Target Sequence Efficacy Design vector- expressed constructs Preclinical testing (in vivo models) GLP Hepatitis B Manufa cturing Toxicology studies IND Preparation Phase
Slide 30: Updated Development Plan and Timeline for HBV Program
Updated Development Plan and Timeline for HBV Program HBV Program Clinical Development Timeline Program 2011 2012 2013 2014 2015 Target Sequence Efficacy Design vector- expressed constructs Preclinical testing (in vivo models) GLP Hepatitis B Manufa cturing Toxicology studies IND Preparation Phase I
Slide 31: Oculopharyngeal Muscular Dystrophy Background
Oculopharyngeal Muscular Dystrophy Background ! " #$%#&' ( ) *" #$%# Oculopharyngeal muscular dystrophy is a rare dominant inherited genetic condition for which no effective treatment exists. Oculopharyngeal Muscular Dystrophy Incidence and Prevalence Oculopharyngeal muscular dystrophy (OPMD) is a
Slide 32: The ddRNAi OPMD Treatment Target
The ddRNAi OPMD Treatment Target A mutation in the Poly(A) Binding Protein Nuclear 1 gene (PABPN1) is known to be responsible for the onset of oculopharyngeal muscular dystrophy. OPMD is particularly adapted to gene therapy based on RNA interference since targeted cells are limited, the genetic mu
Slide 33: ddRNAi OPMD Treatment Development Plan and Timeline
ddRNAi OPMD Treatment Development Plan and Timeline ddRNAi OPMD Treatment Preclinical Development Timeline 2012 2013 2014 2015 Materials Development Lentivector studies OPMD AVV Local Delivery Studies Benitec Ltd 33 www.benitec.com
Slide 34: Current ddRNAi Programs: Drug Resistant NSCLC
Current ddRNAi Programs: Drug Resistant NSCLC Benitec is collaborating with University of New South Wales researchers to develop a ddRNAi-based therapeutic targeting a gene associated with chemotherapy resistance. Non-small Cell Lung Cancer (NSCLC) Rationale: Collaborator: βIII-tubulin has been sh
Slide 35: bIII-tubulin in lung cancer
Professor Maria Kavallaris Proof of concept Head, Pharmacoproteomics Program study: NHMRC Senior Research Fellow Director, Australian Centre for Nanomedicine, UNSW Silencing of drug resistance gene bIII-tubulin in NSCLC cells using Lung Lung cancer ddRNAi constructs in vitro and in vivo Benitec Ltd
Slide 36: Lung cancer and NSCLC treatment background
• Lung cancer is the most common cause of cancer death in the world • Majority of cases diagnosed at advanced disease stage • Treatment of NSCLC typically involves the use of surgery, radiation and chemotherapy • 2 common classes of chemotherapy agents used in NSCLC Despite advances in the treatment
Slide 37: bIII-tubulin in NSCLC overall survival
Overall survival* βIII-tubulin in NSCLC 100 Percent Disease Free 80 60 P < 0.0023 low βIII-tubulin 40 high βIII-tubulin 20 Dumontet et al, Lancet Oncol, 2008 0 0 200 400 600 800 1000 1200 1400 Time (days) Increased βIII-tubulin in NSCLC associated with clinical: • drug resistance and aggressive dise
Slide 38: Gene targeting with RNAi
Delivery into cancer cells lines Vector incorporates into bIII-tubulin shRNA vector cancer cells and expresses bIII-tubulin shRNA GENE TARGETING with RNAi Suppression of bIII-tubulin expression Benitec Ltd 38 www.benitec.com GENE SILENCING
Slide 39: bIII-tubulin Gene Silencing
Low dose chemotherapy bIII-tubulin Most cells alive expressing NSCLC Low dose chemotherapy Suppression of bIII-tubulin expression Most cells dead bIII-tubulin Gene Silencing Benitec Ltd www.benitec.com 39
Slide 40: Gene and protein silencing of bIII-tubulin using ddRNAi
Gene and protein silencing of βIII-tubulin using ddRNAi 55 KDa bIII-tubulin 32 KDa GAPDH loading control bIII tubulin PROTEIN Benitec Ltd 40 www.benitec.com Hilary Brooks
Slide 41: Chemosensitisation of NSCLC
Chemosensitisation of NSCLC Suppression of cancer gene bIII-tubulin triple cassette vector Chemotherapy Benitec Ltd 41 www.benitec.com
Slide 42: Orthotopic NSCLC mouse model
Orthotopic NSCLC mouse model Human lung cancer cells orthotopically xenografted in mouse lung bIII-tubulin lung Tumour 14 days post- X40 injection Josh McCarroll, Benitec Ltd Rafael Erlich, 42 www.benitec.com Tanya Dwarte 2X106 cells H460-luc cells
Slide 43: bIII-tubulin gene expression of tumour tissue
bIII-tubulin gene expression of tumour tissue (preliminary data) (Relative to saline control) 120 100 80 60 bIII-tubulin 40 20 0 Control bIII Benitec Vector NB: One mouse in each group (1) Saline control and (2) bIII-Triple cassette shRNA vector Received three injections of vector. Benitec Ltd 43 ww
Slide 44: Chemosensitisation of NSCLC
Chemosensitisation of NSCLC Suppression of cancer gene bIII-tubulin triple cassette vector Chemotherapy Benitec Ltd 44 www.benitec.com
Slide 45: Development Plan and Timeline for NSCLC Program
Development Plan and Timeline for NSCLC Program NSCLC ddRNAi Program Updated Clinical Development Timeline Program 2011 2012 2013 2014 Animal model (lung) In vivo NSCLC Toxicology IND Preparation and Phase I Clinical Submission Trial Benitec Ltd 45 www.benitec.com
Slide 46: Gene silencing for a potential HIV/AIDS cure
Professor John Rossi City of Hope National Medical Centre California USA Gene silencing for a potential HIV/AIDS cure Benitec Ltd 46 46 www.benitec.com
Slide 47: Why Do We Need New Therapies for HIV?
Why Do We Need New Therapies for HIV? Toxicities associated with the current drug therapies. Medications have to be taken daily (often multiple times per day) for the rest of the patient’s life. There are strains of HIV with resistance to current anti-viral drugs and there are no alternatives for th
Slide 48: Combining Small RNAs as Anti-HIV Therapeutic Agents
Combining Small RNAs as Anti-HIV Therapeutic Agents Benitec Ltd 48 www.benitec.com
Slide 49: First in man Lentivirus-shRNA Stem Cell Transplant for HIV
First in man-Lentivirus-shRNA Stem Cell Transplant for HIV Gene Modified Stem cells Benitec Ltd 49 www.benitec.com
Slide 50: HIV/AIDS Phase I results
HIV/AIDS Phase I results • ddRNAi therapy is safe and feasible • Long lasting (at least 2 years) from a single treatment • Able to rebuild a resistant immune system A. Gene Marking of Peripheral Blood Monocytes B. Gene Marking in Immune Cells 0.35 304 0.30 305 Percent Positive 0.25 306 0.20 307 0.15
Slide 51: Clinical follow up of shRNA expression
Clinical follow up at 36 months • shRNA expression still present in patient 306 CD34+ stem cells at 36 months • Number of peripheral blood cells carrying the shRNA expanded 6 fold • Professor Rossi described these results as “spectacular” Red is SD Green is BMMC and BMGC Blue is PBMC and PBGC Pink i
Slide 52: Summary and Significance
Summary and Significance • First in human trial of ddRNAi based gene therapy. • Patients are in complete remission from lymphoma, all have suppressed HIV loads. • ddRNAi expression now out to 3 years from a single treatment • The safety and feasibility of this study has opened the door for this trea
Slide 53: Benitec Biopharma Corporate Overview
Benitec Biopharma Corporate Overview Based in Sydney, Australia, Benitec is a biopharmaceutical company developing a novel Business Overview DNA-directed RNA interference (ddRNAi) platform for therapeutic use. The company is listed on the Australian stock exchange (ASX: BLT). Benitec is pursuing lic
Slide 54: Investment Opportunity Summary
Investment Opportunity Summary ddRNAi Product Asset Summary Large Market Opportunities Non-Small Cell Lung Cancer, Pain, Hepatitis Favorable KOL Responses and a plethora of other opportunities Transformational Approach Favourable preclinical data New class of therapeutics for treatment and From Exte
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