Benitec’s Gene SilencingPlatform Technology –An overviewNon-Confidential Presentation   Benitec Ltd                  1   w...
This presentation contains forward looking statements that involve risks and uncertainties. Althoughwe believe that the ex...
Table of Contents      ddRNAi Technology Investment Thesis       4      Benitec Corporate Overview                5      R...
ddRNAi TechnologyInvestment Thesis    DNA-directed RNA interference (ddRNAi) is a novel technology platform capable of ac...
Benitec Corporate Overview                          Based in Sydney, Australia, Benitec is a biopharmaceutical company dev...
Benitec Corporate Strategyto Build ValueBenitec has a value-building strategy based on to partnering its proprietary ddRNA...
Benitec Senior Leadership TeamBenitec’s management team has demonstrated experience and expertise in developing and licens...
ddRNAi ProductDevelopment TimelineBenitec has a pipeline of ddRNAi-based therapeutics targeted for indications where their...
RNA InterferenceTechnology BackgroundRNAi is a technology which silences targeted genes through a natural mechanism, the d...
Benitec’s NovelRNA Interference TechnologyBenitec’s ddRNAi technology platform utilizes a self-inactivating lentiviral vec...
Differences between ddRNAiand Conventional siRNAWhile siRNA has demonstrated considerable limitations for clinical use, dd...
Proof of Concept Study for ddRNAi in AIDS Lymphoma Patients (Phase I) The advantages of the ddRNAi technology were demonst...
Current ddRNAi Programs:Cancer Pain ProductUtilizing the ddRNAi platform, Benitec has developed their gene silencing techn...
Current ddRNAi Programs:Hepatitis BThe ddRNAi technology is also being developed for HBV under collaboration with Biomics....
Current ddRNAi Programs:Hepatitis CBenitec has sub-licensed its technology platform to Tacere to develop a ddRNAi-based th...
Development Plan and Timeline forCurrent ddRNAi Programs                                      Current ddRNAi Programs Clin...
Current ddRNAi Programs:Drug Resistant NSCLCBenitec is collaborating with University of New South Wales researchers to dev...
Development Plan and Timeline forNSCLC ddRNAi Program                       NSCLC ddRNAi Programs Clinical Development Tim...
Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmac...
Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmac...
Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmac...
Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmac...
Investment Opportunity Summary                                          ddRNAi Product Asset Summary            Large Mark...
Contact InformationTo respond to this introduction to the ddRNAi opportunity, please contact:                             ...
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Benitec Company Overview

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About us, our technology, our therapeutic programs and our intellectual property.

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Benitec Company Overview

  1. 1. Benitec’s Gene SilencingPlatform Technology –An overviewNon-Confidential Presentation Benitec Ltd 1 www.benitec.com
  2. 2. This presentation contains forward looking statements that involve risks and uncertainties. Althoughwe 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 resultscould differ materially from those anticipated. Reasons may include risks associated with drugdevelopment and manufacture, risks inherent in the regulatory processes, delays in clinical trials, risksassociated with patent protection, future capital needs or other general risks or factors. Benitec Ltd 2 www.benitec.com
  3. 3. Table of Contents ddRNAi Technology Investment Thesis 4 Benitec Corporate Overview 5 RNA Interference Background 9 Introduction to the ddRNAi Technology 10 Current ddRNAi Programs 13 Benitec Intellectual Property Portfolio 19 Investment Opportunity Summary 23 Contact Information 24 Benitec Ltd 3 www.benitec.com
  4. 4. ddRNAi TechnologyInvestment Thesis  DNA-directed RNA interference (ddRNAi) is a novel technology platform capable of achieving long-term targeted gene silencing.  Benitec is developing a a range of products that utilize the ddRNAi technology to treat and cure life threatening severe conditions in infectious disease, cancer and CNS areas.  Benitec’s cancer areas include drug resistant non-small cell lung cancer and relief of cancer-associated neuropathic pain.  Benitec’s infectious disease areas include programs in chronic hepatitis infection, including hepatitis B and C.  Functional gene silencing constructs for all of the programs have been created. Preclinical in vivo studies proving the safety and efficacy of the products are in progress.  Benitec’s technology platform is applicable to a large number of other therapeutic areas In which up-regulation of a gene is associated with a disease or disorder, including genetic diseases. Benitec Ltd 4 www.benitec.com
  5. 5. Benitec Corporate Overview Based in Sydney, Australia, Benitec is a biopharmaceutical company developing a novel DNA-directed RNA interference (ddRNAi) platform for therapeutic use. The company Business Overview is listed on the Australian stock exchange (ASX: BLT) with a market cap of ~AU$25M and AU$7M cash at hand. Benitec is pursuing licensing, partnering and co-development activities for its Business Strategy transformational, proprietary ddRNAi platform technology for human therapeutics and research. Benitec is currently utilising ddRNAi technology internally across multiple therapeutic areas where there is a significant unmet need to develop ddRNAi-based Product Strategy therapeutic products for a range of conditions including lung cancer, neuropathic pain, and infectious disease (hepatitis B and hepatitis C). Benitec has a robust patent portfolio protecting their platform technology across the Intellectual Property major pharmaceutical markets with patent coverage extending through 2027. Benitec has a strong management team with deep scientific and clinical resources Management Team and extensive experience with the commercialization of biological intellectual property. Benitec Ltd 5 www.benitec.com
  6. 6. Benitec Corporate Strategyto Build ValueBenitec has a value-building strategy based on to partnering its proprietary ddRNAi technology withpharmaceutical and biotechnology companies both as research tools and as potential therapeutics. ddRNAi Technology Human Therapeutics Research Tools Partner Individual Therapeutics Partner Therapeutic Platform Partner Technology For Research Develop the ddRNAi therapeutic product Partner the technology platform for a License the ddRNAi platform pipeline in-house through pre-clinical wide range of therapeutics in the near technology as a research tool to and early stage clinical studies, and term for development and research institutions, pharmaceutical potentially partner products for late- commercialization and biotech companies stage development and commercialization Benitec Ltd 6 www.benitec.com
  7. 7. Benitec Senior Leadership TeamBenitec’s management team has demonstrated experience and expertise in developing and licensing noveltherapeutic technology. CEO CFO, Company Secretary Peter French, PhD Greg West Cell and molecular biologist with an MBA in Chartered Accountant, Director and audit Technology Management. Founder of stem cell committee chairman of ITC Ltd, IDP storage company Cryosite Ltd, launched six Education Pty Ltd, Education Australia Ltd, new probiotic-based products with Probiomics. and Sydney International Film School Pty Ltd. Board of Directors Peter Francis LLB Grad Dip Mel Bridges BAppSc FAICD John Chiplin PhD Iain Ross BSc ChD (Intellectual Property) Non- Non-executive Director Non-executive Director Non-executive Director executive Chairman More than 30 years experience His most recent accomplishment Over 30 years experience in the Partner at Francis Abourizk in the global biotechnology and was the corporate reengineering international life sciences sector. Lightowlers (FAL), a legal healthcare industry. During this of Arana Therapeutics, a world Following a career with Sandoz, specialist in the areas of period, he founded and leading Antibody developer, Fisons, Hoffman La Roche, and intellectual property and licensing managed successful which resulted in the acquisition Celltech he has undertaken and and provides legal advice to a diagnostics, biotechnology and of the company by Cephalon for had input to a number of large number of corporations and medical device businesses. a significant premium to market. company turnarounds and research bodies. start‐ups Benitec Ltd 7 www.benitec.com
  8. 8. ddRNAi ProductDevelopment TimelineBenitec has a pipeline of ddRNAi-based therapeutics targeted for indications where their technology providesa significant competitive advantage. Human Collaborator/ Indication Discovery Pre- clinical Collaboration Status Clinical Licensee Cancer- University of Benitec has contracted with TetraQ to generate data to be able to associated Queensland conduct a clinical trial on terminally ill cancer patients suffering pain (Australia) from pain. Drug University of New Researchers are collaborating with Benitec to develop a ddRNAi- resistant South Wales based therapy to overcome chemotherapy resistance in non-small lung cancer (Australia) cell lung cancer. Benitec is working with Biomics to develop ddRNAi candidates for Hepatitis B Biomics (China) hepatitis B silencing for preclinical testing and a China-based clinical trial. Benitec’s preclinical hepatitis C program was outlicenced to Tacere in 2006, and then outlicensed by Tacere to Pfizer in 2008. In 2010, Pfizer exercised an option to further develop and commercialize Tacere (Pfizer) Hepatitis C Tacere’s Hepatitis C compounds as a result of favorable primate (US) and mouse efficacy and toxicity studies. The companies observed no maximum tolerated dose, no safety signals, viral inhibition and >90% penetration of human hepatocytes. Benitec funded programs Partnered program Licensed program Benitec Ltd 8 www.benitec.com
  9. 9. RNA InterferenceTechnology BackgroundRNAi is a technology which silences targeted genes through a natural mechanism, the discovery of whichearned Andrew Fire and Craig Mello the Nobel Prize in Physiology and Medicine in 2006. RNAi Mechanism Technology Background  RNA therapies can be divided into RNAi therapies, which are mediated by the RISC enzyme, and antisense therapies, The Dicer endonuclease cuts which are RISC-independent agents. double stranded RNA into short pieces (siRNA)  Antisense oligonucleotides were initially used primarily as an in vitro research tool but have been developed as a means of modifying RNA levels in human therapeutic applications. The antisense strand is  RNAi was subsequently found to offer up to 1000 x more loaded into the RNA-induced efficient silencing than antisense agents. silencing complex (RISC) and links the complex to the mRNA strand by base pairing  Modern RNAi therapeutic approaches utilize short, chemically synthesized RNA duplexes that mimic natural products.  The RNAi mechanism allows protein function to be modulated by controlling the translation of mRNA. The RISC complex cuts the Modulating Gene RNA Small Molecules mRNA strand and the mRNA Agent: Therapy Therapy mAbs is subsequently degraded Target: DNA RNA Protein Source: The Nobel Prize in Physiology or Medicine 2006. Nobelprize.org. Accessed October 2011.Sources: Datamonitor. RNA Therapy. October 2008; Business Insights. The Future of RNAi Therapeutics. August 2008. Benitec Ltd 9 www.benitec.com
  10. 10. Benitec’s NovelRNA Interference TechnologyBenitec’s ddRNAi technology platform utilizes a self-inactivating lentiviral vector to express shRNA moleculeswhich silence a targeted gene of interest. ddRNAi Mechanism of Action ddRNAi Mechanism of ActionBenitec technology  The ddRNAi-based product consists of a third-generation ddRNAi DNA construct vesicular stomatitis virus G (VSV-G) pseudotyped self- inactivating lentiviral vector containing a novel gene construct.  The construct expresses a short hairpin RNA (shRNA) molecule intended to silence the selected gene of interest.  The expressed shRNA integrates into the host’s native RNAi process where it is separated into single strands and binds to the target mRNA. – This results in cleavage of the target RNA and silencing of the gene of interest. Sources: Zou W et al., Intrathecal Lentiviral-Mediated RNA Interference Targeting PKCγ Attenuates Chronic Constriction Injury–Induced Neuropathic Pain in Rats. Human Gene Therapy. 22:465–475 (April 2011) Benitec Ltd 10 www.benitec.com
  11. 11. Differences between ddRNAiand Conventional siRNAWhile siRNA has demonstrated considerable limitations for clinical use, ddRNAi has the potential toovercome many of the delivery obstacles previously faced by siRNA. Differences Between ddRNAi and siRNAProperty ddRNAi siRNA Description  Double stranded RNA for siRNA must be manufactured, while in ddRNAi, theOrigin shRNA is continuously expressed by the host cell.  ddRNAi-generated shRNA is up to 250x more potent than siRNA and thus requiresPotency less material to silence a gene.  Off-target effects are common and problematic with siRNA. ddRNAi results inOff-Target Effects minimal off-target effects due to its expression being restricted to the transfected cell type.  ddRNAi is capable of utilising a range of established delivery options includingDelivery viral, non-viral and stem cell vectors, while siRNA must be modified for systemic or targeted delivery.  Unlike siRNA, which is capable of only short-term silencing, ddRNAi has a variableDuration of Action duration of action including the potential for long-term silencing.  Multiple targets can be targeted with a single DNA construct using ddRNAi, whileTargeting Options only a single target can be targeted with each siRNA.  Production of the shRNA DNA construct and delivery system is low cost, whileCost siRNA requires expensive custom synthesis Positive Negative Neutral Attribute AttributeSource: Datamonitor. Gene Therapy. December 2009. Benitec Ltd 11 www.benitec.com
  12. 12. Proof of Concept Study for ddRNAi in AIDS Lymphoma Patients (Phase I) The advantages of the ddRNAi technology were demonstrated in a pilot study (phase I clinical trial) to assess the safety and feasibility of using a lentiviral RNA vector encoding multiple targets in stem cells of AIDS lymphoma patients. Study Design Apheresis Stem-cell enrichment Healthy HIV positive or chemo-responsive AIDS lymphoma Lentiviral-mediated CD34+ PBPC transduction of CD34 GCSF Pool and infuse Patient follow-upGCSF – Granulocyte colony-stimulating factorPBPC – Peripheral blood progenitor cell Results of the AIDS Lymphoma Study  ddRNAi therapy is safe and feasible.  The therapy is long-lasting (at least two years) from a single treatment.  Patients are able to rebuild a new and resistant immune system following treatment. Benitec Ltd 12 www.benitec.com
  13. 13. Current ddRNAi Programs:Cancer Pain ProductUtilizing the ddRNAi platform, Benitec has developed their gene silencing technology for the treatment of painin terminal cancer patients. Cancer Pain Rationale:  PKCγ has been shown to play a major role in the Collaborator: transmission of neuropathic pain and in overcoming tolerance to morphine.  The restricted spinal cord location of the PKCγ- containing interneurons allows a selective inhibitor to Status: inhibit nerve injury-induced neuropathic pain.  Benitec has planned a phase I/II study of the ddRNAi-  KOLs see strong potential for the ddRNAi cancer pain based product in terminal cancer patients with intractable product to be used in terminal patients suffering from all pain and a quick timeline to approval is expected. types of cancer. Market Size:  There are approximately 11.7 million people in the US Preclinical in vivo studies have been conducted with cancer. Approximately 65% of all cancer successfully showing the efficacy of PKCγ-targeted patients experience pain. ddRNAi on pain inhibition.  The cancer pain ddRNAi product may be used in up to 65% of cancer patients receiving invasive pain therapy. Benitec Ltd 13 www.benitec.com
  14. 14. Current ddRNAi Programs:Hepatitis BThe ddRNAi technology is also being developed for HBV under collaboration with Biomics. Hepatitis B Virus Rationale: Collaborator:  Successful ddRNAi delivery to the liver has been demonstrated.  The targeted enzyme is key to HBV replication. Status:  The strategy provides treatment of the existing infection and long-lasting protection from re-infection.  Benitec is working with Biomics to evaluate RNAi candidates for hepatitis B silencing for preclinical testing and a China-based clinical trial. Market Size:  There are about 400 million people worldwide with chronic HBV infection. Of 5000 potential sequences, 14 RNA sequences have been identified by Biomics that provide ≥70%  Carriers of HBV are up to 300 times more likely to knockdown of HBV gene mRNA. develop liver cancer than non-carriers, and HBV causes 60-80% of the world’s primary liver cancers. Benitec Ltd 14 www.benitec.com
  15. 15. Current ddRNAi Programs:Hepatitis CBenitec has sub-licensed its technology platform to Tacere to develop a ddRNAi-based therapeutic targetingthe Hepatitis C viral genome. Hepatitis C Virus Rationale: Collaborator:  Successful ddRNAi delivery to the liver has been demonstrated.  The strategy provides treatment of the existing infection and long-lasting protection from re-infection. Status:  Multi-target construct (three sequences) to prevent viral  Pfizer have closed the Sandwich facility, escape in a single drug “cocktail” uncertain status of program Market Size:  Over 170 million people worldwide, are chronically infected with HCV, with 3-4 million new infections occurring each year. Tacere have demonstrated both efficacy and safety with their AAV8-delivered ddRNAi-based therapeutic  Licensed to Tacere Therapeutics Inc. - USD$143M deal in non-human primates with Pfizer Inc. Benitec has an equity stake in Tacere. Benitec Ltd 15 www.benitec.com
  16. 16. Development Plan and Timeline forCurrent ddRNAi Programs Current ddRNAi Programs Clinical Development TimelineProgram 2011 2012 2013 2014 2015 Target Sequence Efficacy Design vector-Hepatitis B expressed constructs Preclinical testing (in vitro and in vivo models) Proof of concept in pre-clinical model of pain Additional clinical studies to be planned in both HepatitisB and Cancer PainCancer Pain Toxicology studies IND Preparation Phase I/II Trial (cancer patients and Submission with intractable pain) Benitec Ltd 16 www.benitec.com
  17. 17. Current ddRNAi Programs:Drug Resistant NSCLCBenitec is collaborating with University of New South Wales researchers to develop a ddRNAi-basedtherapeutic targeting a gene associated with chemotherapy resistance. Non-small Cell Lung Cancer (NSCLC) Rationale: Collaborator:  βIII-tubulin has been shown to be associated with drug resistance in non-small cell lung cancer (NSCLC).  Silencing βIII-tubulin using ddRNAi increases the killing of NSCLC cells by chemotherapy agents. Status:  Researchers are using Benitec’s technology to develop a ddRNAi-based therapy to overcome chemotherapy Market Size: resistance in NSCLC cells.  Lung cancer is the leading form of cancer worldwide in terms of incidence and mortality.  NSCLC account for >80% of all lung cancers and has a In vitro results show highly effective silencing of high mortality rate due to rapid development of βIII-tubulin and effective targeting of NSCLC cells resistance to chemotherapy drugs. with the ddRNAi construct. Benitec Ltd 17 www.benitec.com
  18. 18. Development Plan and Timeline forNSCLC ddRNAi Program NSCLC ddRNAi Programs Clinical Development Timeline Program 2011 2012 2013 2014 Animal model (lung) In vivo NSCLC Toxicology IND Preparation Phase I Clinical and Submission Trial Benitec Ltd 18 www.benitec.com
  19. 19. Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets withcoverage through 2027 with additional exclusivity anticipated for biologic upon launch. Graham& family& patents! "revocable)license)from)CSIRO!for$ human$ the$ field)! Patent& Number Description! Jurisdiction! Geneticconstructsfordelayingorrepressingtheexpressionofa target& gene Sense strand Widely! granted!in! Hair pin countries! Complementary strand including! Australia,! South!Africa,! A family of patents that covers Benitec’s gene silencing platform technology in New!Zealand,! expressed RNA interference. UK,!Canada,! India,!Japan,! Generally the patents cover a double stranded DNA construct which comprises: Europe,!USA! • one or more sequences directed to one or more targets ! • sequences of around 20 to 30 nucleotides in length • sequences substantially identical or identical to the target gene sequence Expiry!from! June!2018! • target is either exogenous or endogenous genes • in mammalian cells, preferably human Benitec Ltd 19 www.benitec.com
  20. 20. Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets withcoverage through 2027 with additional exclusivity anticipated for biologic upon launch. Waterhouse!familypatents! xclusive)worldwide!licensefromCSIROforthehumanfield)! Patent& Number Description! Jurisdiction! Methods(And(Means(For(Obtaining(Modified(Phenotypes Sense strand Hair pin China! Complementary strand 200910206175.7# CN# ! # This patent covers a cell that contains either a double stranded DNA construct for expressing a hairpin RNA, or a hairpin RNA itself. The hairpin comprises: Expiry!from! • Sense and anti-sense sequences of at least 20 nucleotides in length June!2018! • sense sequence is sequence of target • antisense sequence is 100% identical to complement of sense sequence The patent covers an RNA molecule that comprises · a sense sequence and an anti-sense sequence of at least ten consecutive 1068311# EP# nucleotides Europe! · 75% to 100% sequence identity to a target sequence · in a hairpin RNA structure Benitec Ltd 20 www.benitec.com
  21. 21. Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets withcoverage through 2027 with additional exclusivity anticipated for biologic upon launch. Benitec!Owned& Patents! Patent& Number! Description! Jurisdiction! Expression* cassettes* delivery* ddRNAi* for* of* agents* targeting(hepatitis(C( US7,727,970;! JP4763681;!!!!!!!!!!!!!!!!!!! Virus# EP05727680.0;!!!!!!!!!!!!!! patent families covering the use of ddRNAi expressing multiple shRNAs from either single Two USA,!Europe,!Australia,! AU2005222084;! or multiple promoters, targeting sequences on the hepatitis C viral genome Japan,!New!Zealand! NZ550284! AU2006210443;! US11/883645;! ! Expiry:!2025L2027! US7,803,611;! NZ560936! Liver(cell(specific(RNAi(expression(constructs( US8,008,468;! Patents that cover the use of a ddRNAi expression construct which has liver specific promoter US11/731198! US! and enhancer components to complement Benitec’s hepatitis programs A"long"double>stranded(nucleic(acid# construct# AU2004243347;! Australia,!New!Zealand,! Patents that cover the use of a long double stranded DNA construct expressing multiple double NZ543815;! Singapore,!South!Africa! stranded RNA silencing molecules, each 17 to 30 nucleotides in length. ZA2005/09813;!!!! SG200507474L 5! Expiry:!2024! Geneticsilencing( A genetic construct, that reduces the translation of a target endogenous gene, comprising a GB!2377221;! sequence of nucleotides substantially identical to a sequence of the target gene and a Great!Britain,!Singapore,! SG91678;! nucleotide sequence complementary or substantially complementary to the target gene ZA2002/07428! South!Africa! sequence wherein the nucleotide sequences identical and complementary to said target endogenous nucleotide sequence are separated by a spacer sequence.! Benitec Ltd 21 www.benitec.com
  22. 22. Benitec Intellectual PropertyPortfolioBenitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets withcoverage through 2027 with additional exclusivity anticipated for biologic upon launch. Benitec Ltd 22 www.benitec.com
  23. 23. Investment Opportunity Summary ddRNAi Product Asset Summary Large Market Opportunities Favorable KOL Responses Non-Small Cell Lung Cancer, Pain, Hepatitis and a plethora of other opportunities Novel Approach Favorable preclinical data Novel class of therapeutics for treatment and cure From Extensive in vitro and in vivo Studies Unmet Medical Need Extensive IP Estate ddRNAi can treat undrugable targets Patent Coverage Through 2027 Benitec Ltd 23 www.benitec.com
  24. 24. Contact InformationTo respond to this introduction to the ddRNAi opportunity, please contact: Dr. Peter French, Ph.D., M.B.A. CEO Benitec Ltd. Phone: +61 (0)412 457 595 E-mail: pfrench@benitec.com Benitec Ltd 24 www.benitec.com
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