Benitec’s ddRNAi Non SmallCell Lung Cancer Opportunity   Non-Confidential Presentation   Benitec Ltd                     1...
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           ...
ddRNAi TechnologyInvestment Thesis   !  DNA-directed RNA interference (ddRNAi) is a"novel technology platform capable of a...
Benitec Corporate Overview                          Based in Sydney, Australia, Benitec is a biopharmaceutical company dev...
Benitec Senior Leadership TeamBenitec’s management team has demonstrated experience and expertise in developing and licens...
Benitec’s NovelRNA Interference TechnologyBenitec’s ddRNAi technology platform utilizes a self-inactivating lentiviral vec...
ddRNAi Technology for Non-Small CellLung Cancer TreatmentUtilizing the ddRNAi platform, Benitec is developing their gene s...
Non-Small Cell Lung CancerMarket OverviewLung carcinoma is the leading cause of cancer-related death worldwide and has bee...
Current Treatments for                                                           Diagnosis, treatment, and managementNon-S...
Unmet Needs And Market Opportunityin Non-Small Cell Lung CancerA significant need exists for a therapy capable of restorin...
The NSCLC Drug Resistance TargetThe upregulation of βIII-tubulin gene expression is associated with clinical drug resistan...
ddRNAi NSCLC ProductPreclinical Studies - OutlinePreclinical studies have been conducted by the UNSW in collaboration with...
ddRNAi NSCLC ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of βIII-tubul...
ddRNAi NSCLC ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of βIII-tubul...
ddRNAi NSCLC ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of βIII-tubul...
three shRNAs targeting different regions on the beta III tubulin gene were produced and                                   ...
Development Plan and Timeline forNSCLC ddRNAi Program                      NSCLC&ddRNAi&Programs&Clinical&Development&Time...
Investment Opportunity Summary                                                      &                                     ...
Contact InformationTo respond to this introduction to the ddRNAi opportunity, please contact:                             ...
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Non Small Cell Lung Cancer Program

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An overview of the Benitec Non Small Cell Lung Cancer program.

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Non Small Cell Lung Cancer Program

  1. 1. Benitec’s ddRNAi Non SmallCell Lung Cancer Opportunity Non-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 Overview of the ddRNAi Technology 7 Non-Small Cell Lung Cancer Market Overview 9 The ddRNAi NSCLC drug resistance Target 12 Preclinical Chronic HBV Infection Data 13 Non-Small Cell Lung Cancer Product Development Plan 18 Investment Opportunity Summary 19 Contact Information 20 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. !  Currently available treatments for non-small cell lung cancer are based on the repeated administration of chemotherapeutic drugs and are challenged by the emergence of drug resistant tumor cells, creating significant need for a product to overcome this hurdle. !  Functional gene silencing constructs targeting the βIII-tubulin gene in NSCLC cells have been created and a delivery vehicle has been developed based on jetPEITM. Preclinical in vivo studies proving the safety and efficacy of the product have been concluded. !  Benitec’s technology platform is applied in a number of other therapeutic areas, both in-house and through partnerships, including programs concerning Hepatitis C, Drug Resistant Lung Cancer and Cancer Associated Pain. 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 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 start research bodies. ups Benitec Ltd 6 www.benitec.com
  7. 7. 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&Ac1on& Benitec&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"Len;viral=Mediated"RNA"Interference"Targe;ng"PKCγ"AFenuates"Chronic"Constric;on"Injury–Induced"Neuropathic"Pain"in"Rats.""Human"Gene" Therapy.""22:465–475"(April"2011)" Benitec Ltd 7 www.benitec.com
  8. 8. ddRNAi Technology for Non-Small CellLung Cancer TreatmentUtilizing the ddRNAi platform, Benitec is developing their gene silencing technology for the treatment ofnon-small cell lung cancer (NSCLC). A ddRNAi Construct for Treating The ddRNAi Platform Technology Non-Small Cell Lung Cancer !  Benitec’s novel ddRNAi technology allows for long-term gene silencing. Non-Small Cell Lung Cancer tissue !  The technology can be targeted to silence a specific injection of jetPEITM - gene or multiple selected genes. ddRNAi DNA vector +" construct !  ddRNAi technology allows to target cancer cell lines that have developed resistance to chemotherapeutic drugs, thus restoring treatment efficacy and lowering dose requirement. !  The ddRNAi product is delivered through the Benitec Technology transfection agent jetPEITM, a cationic DNA binding ddRNAi DNA construct polymer which prefers to target lung tissue. Benitec Ltd 8 www.benitec.com
  9. 9. Non-Small Cell Lung CancerMarket OverviewLung carcinoma is the leading cause of cancer-related death worldwide and has been identified as a majorhealth issue confronting both developed and developing countries. Non-Small Cell Lung Cancer Incidence and Prevalence Worldwide incidence of Lung Cancer !  NSCLC is the most common form of lung cancer and accounts for over 80% of lung cancer cases. !  The primary risk factor for NSCLC is smoking, which is responsible for more than 85% of deaths related to lung cancer. !  In the seven major markets, there are over 500.000 individuals affected with NSCLC, making it the third largest cancer market in terms of numbers of patients diagnosed. !  There is a clear upward trend for lung cancer in developing countries including China, India and much of Asia. !  The NSLCL drug market was estimated around $4 billion New"cases"per"100.000"people"per"annum" in the seven major markets in 2009. Source:"hFp://globocan.iarc.fr/" Benitec Ltd 9 www.benitec.com
  10. 10. Current Treatments for Diagnosis, treatment, and managementNon-Small Cell Lung Cancer Usually symptoms of lung cancer do not appear until the disease is in its advanced stages. But some lung cancers are diagnosed early, and are often found as a result of tests for other medical conditions, mainly through chest X-rays. Clinical manifestations of lung cancer are dependent on the location of the tumor andThe standard of care in patients with advanced non-small cell lung cancer is based on platinum-based the extent of metastasis. The most common symptoms of local-regional cancer include coughing, dyspnea,doublet chemotherapy regimens. hemoptysis, wheezing, chest pain, and pneumonia. Figure 1 illustrates the treatment of lung cancer !  The treatment of lung cancer depends on several factors, according to the growth stage. Treatment of Lung Cancer by Stage such as discovery stage and form of the cancer, and the age and general medical state of the patient. Figure 1: Treatment of lung cancer by stage Five-year !  Typical treatment involves some combination of surgery, Stage Primary treatment Adjuvant therapy survival rate (%) chemotherapy and radiation therapy. Non-small-cell lung cancer (NSCLC) !  Chemotherapy regimens are based on the therapy combining (platinum based) DNA damaging agents and I Resection Chemotherapy 60 to 70 tubulin binding agents, inhibiting cellular replication Chemotherapy and inducing apoptosis. IIA Resection with or without 40 to 50 radiation therapy Chemotherapy Resection with or without !  Chemotherapy is associated with a wide range of side IIIA (resectable) preoperative chemotherapy with or without 15 to 30 radiation therapy effects with varying degree of severity, and the efficacy IIIA (unresectable) or IIIB Chemotherapy with concurrent or remains limited due to high incidence of dose limiting (involvement of contralateral subsequent radiotherapay None 10 to 20 lymph nodes) toxicity and emergence of drug resistance cell lines. Chemotherapy or resection of 10 to 15 (two IIIB (pleural effusion) or IV primary brain metastasis and None year survival) primary T1 tumor !  Despite advances in treatment, the prognosis of NSCLC remains poor with only 15% of patients surviving 5 Small-cell lung cancer (SCLC) years from the time of diagnose. Chemotherapy with concurrent Limited disease None 15 to 25 radiotherapy Extensive disease Source:"Business"Insights:"The"Cancer"Market"Outlook"to"2016" Chemotherapy None <5 Benitec Ltd 10 www.benitec.com Source: Spira and Ettinger, 2004 BUSINESS INSIGHTS
  11. 11. Unmet Needs And Market Opportunityin Non-Small Cell Lung CancerA significant need exists for a therapy capable of restoring and/or improving the effect of therapeutic drugs inresistant cell lines and minimizing side effects associated with chemotherapy treatment. Unmet Needs in Non-Small Cell Lung Cancer Treatment !  A sizeable patient population exists, which is projected to grow modestly in the seven major markets and to increase rapidly in China and other growing markets. !  With around 65% of patients dying within one year of diagnosis, non-small cell lung cancer is the leading cause of cancer-related deaths worldwide. !  The rapid emergence of drug resistance cancer cell lines provides a major challenge in the treatment of non small cell lung cancer. !  The efficiency of existing chemotherapeutic agents is restricted by dose limiting systemic toxicity. A significant opportunity therefore exists for treatments that enhance the effect of therapeutic drugs in a targeted way or are capable of reducing side effects. Benitec Ltd 11 www.benitec.com
  12. 12. The NSCLC Drug Resistance TargetThe upregulation of βIII-tubulin gene expression is associated with clinical drug resistance and aggressivedisease in non-small cell lung cancer. βIII-tubulin gene Progressionfree$survival$$ !  βIII-tubulin is a structural component of microtubules, which are multifunctional cytoskeletal proteins involved in many essential cellular roles. low$βIIItubulin$ !  βIII-tubulin is the target of chemotherapeutic tubulin binding agent, a drug class which lies at the basis of cancer treatment high$βIIItubulin$ standards. !  An increased expression of βIII-tubulin results in drug resistance and is further associated with poorly differentiated tumour Overall$survival$$ tissue, high-grade malignancy and metastatic potential, playing a broad role in NSCLC development. low$βIIItubulin$ !  Inhibition of βIII-tubulin expression has been shown to restore sensitivity to drug-induced apoptosis in tumour cells. high$βIIItubulin$ Source:"Seve$et$al.$Mol$Cancer$Ther$2005$ Benitec Ltd 12 www.benitec.com
  13. 13. ddRNAi NSCLC ProductPreclinical Studies - OutlinePreclinical studies have been conducted by the UNSW in collaboration with Benitec to determine the efficacyof βIII-tubulin targeted ddRNAi in negating drug resistance in NSCLC cells. Study Design Benitec Ltd 13 www.benitec.com
  14. 14. ddRNAi NSCLC ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity todrug induced apoptosis in resistant tumour cells. Step 1: Design of siRNA encoding multi-cassette A multipromotor multi-cassette was designed coding for three shRNAs targeting different regions in the βIII-tubulin gene and optimized for expression in lung cells. Step 2: Generation of βIII-tubulin Expressing Cells A stable βIII-tubulin shRNA expressing tumour cell line was created though transfection with jetPEITM, a cationic DNA binding polymer. Source:"hFp://www.funakoshi.co.jp/node/10658" Benitec Ltd 14 www.benitec.com
  15. 15. ddRNAi NSCLC ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity todrug induced apoptosis in resistant tumour cells. Step 3: Demonstration of Efficacy in vitro In vitro expression tests COMMERCIAL-IN-CONFIDENCE The efficacy of the expression of the ddRNAi construct in the %"Knockdown"of"βIII"tubulin"mRNA" !"#$%&(%)$"%*"!+++",-.-/0$"1234" transfected cell line was confirmed through a series of in vitro a b :## #4 # +# #; # , 89 8: 8: /23 tests: - protein expression (100% silencing) 100" A>># 7, 80" @># 44#$%&##!!2565+./# 60" ;># - gene expression (95-100% silencing) 40" ?># !"#$%&#()%*## +,&-./0#1,/23,+# 20" "># - drug sensitivity assessment (Cisplatin and Taxane) !<<<#2565+./#83,2=./# CISPLATIN 0" ># Taxol !III knockdownRS"mix" - clonegenic9:#C.D# *?;>#B assay 8:4#pS6" 8:;# !III knockdown - clonogenic data H460") pS5" luc" +51# 100 100 H460 - apoptosis assays 80 pS5 80 TRP2control vector % survival % survival 60 In vitro drug sensitivity assessment 60 pS5 target !III tubulin Step 4: Assessment of Off-target and 40 40 Taxol Immunomodulatory Effects in vivo 20 c CISPLATIN βIII knockdown - clonogenic data 20 d βIII knockdown - clonegenic assay 0 0 -1.0 -0.5 0.0 -1.0 -0.5 0.0 0.5 1.0 100 100 In vivo studies were undertaken to determine the effects of log [ µM CISPLATIN ] H460 log[nM Taxol] Fig 3.1. Data from Benitec’s NSCLCpS5 80 program. A multipromoter multicassette construct was designed in which ddRNAi treatment on systemic toxicity and the potential of 80 three shRNAs targeting different regions on the beta III tubulin gene were produced and transduced into human TRP2control vector NSCLC cells in vitro using JetPEI. The very high degree of protein and mRNA silencing was associated with a % survival % survival undesired immunogenicity: 60 60 significant increase in the sensitivity of the cancer cells to chemotherapy agents. pS5 target βIII tubulin 40 40 4. Assessment of off-target and immunomodulatory effects in vivo a. Assessment of JetPEI (+/- constructs) on toxicity and immunogenicity - assessment of JetPEI (+/- constructs) 20 b. Assessment of effects on neurons 20 on toxicity and immunogenicity 0 5. -1.0 Assessment -0.5 efficacy of 0.0 tubulin knock down in vivo (3 months) 1.0 of β-III 0 -1.0 -0.5 0.0 0.5 a. Assessment of] tumour targeting of jetPEI-DNA construct complexes in vivo. log [ µM CISPLATIN log[nM Taxol] b. Efficacy of JetPEI-shRNA constructs to silence βIII-tubulin in orthotopic lung - assessment of effects on neurons tumours (Fig 3.2). c. Assessment of increased drug sensitivity of βIII-tubulin knock down in vivo. 6. Preclinical toxicology studies 7. Preparation of an IND 8. A Phase I/II clinical study on safety and efficacy. Benitec Ltd 15 www.benitec.com Fig 3.2. Nude mice bearing human
  16. 16. ddRNAi NSCLC ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity todrug induced apoptosis in resistant tumour cells. βIII-tubulin Inhibition reduces the incidence and progression of NSCLC tumours Step 5: Assessment of Efficacy in vivo 1000 Tumor Volume mm3 800 800 The therapeutic efficacy of the ddRNAi construct was 600 600 confirmed through a series of in vivo preclinical tests: 400 400 - Assessment of tumour targeting of jetPEI-DNA 200 200 construct complexes in vivo. 00 1 1 2 2 33 4 4 5 5 6 6 7 7 Time (weeks) Post-Inoculation - Efficacy of JetPEI-shRNA constructs to silence βIII-tubulin in orthotopic lung tumors. Inhibition of βIII-tubulin increases sensitivity to cisplatin in - Assessment of increased drug sensitivity of βIII- Control NSCLC xenografts vs βIII 4 s h RNA s h RNA tubulin knock down in vivo. 100 Control shRNA vehicle Cont shRNA (PBS) Control shRNA cisplatin Cont shRNA (CDDP) Control shRNA βIII shRNA 80 Percent survival βIII shRNA 4 vehicle βIII shRNA 4 (PBS) 60 βIII shRNA 4 cisplatin βIII shRNA 4 (CDDP) 40 20 0 0 10 20 30 40 50 3 Time Days to Reach 1000mm Benitec Ltd 16 www.benitec.com
  17. 17. three shRNAs targeting different regions on the beta III tubulin gene were produced and NSCLC cells in vitro using JetPEI. The very high degree of protein and mRNA silencing significant increase in the sensitivity of the cancer cells to chemotherapy agents.ddRNAi NSCLC Product 4. Assessment of off-target and immunomodulatory effects in vivo a. Assessment of JetPEI (+/- constructs) on toxicity and immunoPreclinical Studies — Future steps b. Assessment of effects on neurons 5. Assessment of efficacy of β-III tubulin knock down in vivo (3 mon a. Assessment of tumour targeting of jetPEI-DNA construct comp b. Efficacy of JetPEI-shRNA constructs to silence βIII-tubulin tumours (Fig 3.2). c. Assessment of increased drug sensitivity of βIII-tubulin knock 6. Preclinical toxicology studiesThese preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity to 7. Preparation of an INDdrug induced apoptosis in resistant tumour cells. 8. A Phase I/II clinical study on safety and efficacy. Fig 3.2. Nude mice bearin NSCLC tumours following Toxicology and Biodistribution Studies – In Progress inoculation with varying nu luciferase-expressing tumo Tumours were visualised b Xenogen imaging instrume Further preclinical studies are undertaken to determine the the toxicological effects and biodistribution characteristics of in vivo treatment. !"!#$%&(()! *"!#$%&(()! +"!#$%&(()! Preparation For IND Discussion Document: Benitec-Mesoblast Collaboration 07072011 Undertake"the"necessary"steps"to"file"an"Inves;ga;ve"New"Drug"applica;on." Phase I/II Clinical Study On Safety and Efficacy Prepare"to"move"towards"phases"of"clinical"tes;ng." Source:"hFp://www.insightpharmareports.com/" 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&Prepara1on& Phase"I"Clinical" and&Submission& Trial" Benitec Ltd 18 www.benitec.com
  19. 19. Investment Opportunity Summary & ddRNAi&Product&Asset&Summary& Large&Market&Opportunity" High$Revenue$PotenLal$in$Treatment$Of$$ Favorable&KOL&Response" Likely$for$the$Unique$MOA$ NonISmall$Cell$Lung$Cancer$ Novel&Approach" Favorable&preclinical&data& To$Overcome$Clinical$Drug$Resistance$$ From$Extensive$in$vitro$and$in$vivo$Studies$ Unmet&Medical&Need" Large,$Unmet$Need$for$Treatment$of$ Extensive&IP&Estate" Patent$Coverage$Through$2027$ NonISmall$Cell$Lung$Cancer$ Benitec Ltd 19 www.benitec.com
  20. 20. 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 20 www.benitec.com

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