Chronic Hepatitis B Program


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Chronic Hepatitis B Program

  1. 1. Benitec’s ddRNAiHepatitis B OpportunityNon-Confidential PresentationBenitec Ltd
  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
  3. 3. Table of Contents ddRNAi Technology Investment Thesis 4 Benitec Corporate Overview 5 Overview of the ddRNAi Technology 7 Chronic Hepatitis B Market Overview 9 The ddRNAi Chronic HBV Infection Target 12 Preclinical Chronic HBV Infection Data 13 Chronic HBV Infection Product Development Plan 18 Additional ddRNAi Program – Hepatitis C 19 Investment Opportunity Summary 20 Contact Information 21 Benitec Ltd 3
  4. 4. ddRNAi Technology for HBV -Investment 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 infectious disease areas include programs in chronic hepatitis infection, including hepatitis B.  Currently available treatments for chronic HBV infection are based on the continued administration of antiviral therapeutics and are prone to viral drug resistance, creating significant need for a product with a novel mechanism of action.  Functional gene silencing constructs targeting the HBV DNA polymerase gene have been created and a delivery vehicle is being developed based on the AAV8 vector. Preclinical studies are moving towards in vivo testing.  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
  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
  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 research bodies. start‐ups Benitec Ltd 6
  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 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 7
  8. 8. ddRNAi Technology For Chronic HepatitisB Virus Infection TreatmentUtilizing the ddRNAi platform, Benitec is developing their gene silencing technology for the treatment ofchronic hepatitis B virus infection. A ddRNAi Construct for Treating The ddRNAi Platform Technology Chronic HBV Infection  Benitec’s novel ddRNAi technology allows for long-term gene silencing.  The technology can be targeted to silence a specific injection of AAV vector gene or multiple selected genes. containing ddRNAi DNA + construct  Unlike current treatments for chronic HBV infection, this product is long-lasting and has the potential to be curative whilst causing only minimal side effects and eliminate the risk of inducing viral drug resistance. Chronic HBV infected liver  The ddRNAi product is delivered through a AAV-based Benitec Technology vector construct, which target the liver where it ddRNAi DNA construct transfects the infected hepatocytes. Benitec Ltd 8
  9. 9. Chronic Hepatitis B Market OverviewDespite the existence of a vaccine against the HBV, the prevalence rate in the population remains high. HBVinfection ranks second only to tobacco as a known human carcinogen. Chronic HBV Infection Incidence and Prevalence Geographic distribution of chronic HBV infection  2,000 million people alive today have been infected with HBV at some time in their lives and of these about 350 million remain chronically infected and become carriers of the virus.  In the USA alone there are over 1.25 million people living with the consequences of chronic active HBV, and over 60,000 new cases per year.  Persons with chronic HBV infection have a 12-300 times higher risk of developing hepatocellular carcinoma than non-carriers and globally HBV causes 60-80% of the world’s primary liver cancers.  Every year about 25% of the over 4 million acute clinical Approximately 1 in 3 people get cases (i.e. 1 million people worldwide) die from chronic infected with HBV during their lifetime active hepatitis, cirrhosis or HBV-induced liver cancer. Source: Benitec Ltd 9
  10. 10. Current Treatments forChronic HBV InfectionThe treatment of chronic HBV infection is based on the use of nucleoside/nucleotide analogues andformulations of interferon.  There is no specific treatment for acute HBV infection. Current FDA approved Drugs  Nucleoside/nucleotide analogs aim at disrupting the viral replication cycle trough interaction with the HBV Nucleoside/nucleotide analogs polymerase. • Lamivudine (Epivir)  Chronic use lead to the development of viral • Adefovir (Hepsera) resistance due to mutations in the catalytic region. • Telbivudine (Tyzeka) • Entecavir (Baraclude)  Administered Interferon acts as an immunoregulator by • Tenofovir (Viread) boosting the natural immune response to viral infections  Interferon treatment is not associated with drug Interferons resistance, but a variety of side effects may occur and the treatment is dependents on the extent of liver • peginterferon alfa-2a (Pegasys) inflammation and disease • peginterferon alfa-2b (PegIntron)  The effects of all existing therapies are transient and require continued treatment. Source: Business Insights: The Hepatitis Market Outlook to 2016 Benitec Ltd 10
  11. 11. Unmet Needs And Market Opportunityin Chronic HBV InfectionA significant need exists for a therapy capable of a long term treatment of chronic HBV infection without therisk of viral drug resistance and minimal side effects. Unmet Needs in Chronic HBV Infection  Despite the existence of a vaccine, a sizeable population of chronically infected patients exists (350 million), and is expected to persist for several generations.  Viral resistance as a result of chronic lamivudine therapy typically develops after 6 months of treatment.  The treatment-failure population represents 40% of the total HBV infected population and is expected to grow by 10% each year.  Current treatments do not meet the needs of patients with limited or disrupted access to the therapeutic standards.  In geographic regions with high infection prevalence, prevention of re-infection of treated patients becomes an issue. Benitec Ltd 11
  12. 12. The ddRNAi Chronic HBV Infection TargetBenitec has identified the HBV RNA-dependent DNA polymerase as a unique target to address the unmetneed in chronic HBV infection treatment. HBV polymerase gene  The hepatitis B virus is encoded by a compact genome encoding four open Hepatitis B Virus Genome Map reading frames; core, polymerase, surface and X protein.  The pregenomic mRNA serves for translation of the core-protein, the surface antigen and the polymerase-reverse transcriptase, and also represents the template of reverse transcription. Therefore, it makes an excellent target for a gene silencing approach.  The mechanism of RNA-directed DNA synthesis has been well characterised and plays a unique and essential role in the viral replication cycle.  Additional gene targets can be incorporated into the DNA construct to allow for more efficient inhibition of viral replication. – Additional targets unique to the HBV genome can be identified. Source: Benitec Ltd 12
  13. 13. ddRNAi Chronic HBV Infection ProductPreclinical Studies - OutlinePreclinical studies have been conducted by Biomics in collaboration with Benitec to determine the efficacy ofHBV DNA polymerase targeted ddRNAi on viral replication in chronic HBV infection. Study Design Benitec Ltd 13
  14. 14. ddRNAi Chronic HBV Infection ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieveinhibition of viral replication. Step 1: Large Scale Sequencing 5000 clones were sequenced and 642 non-repeat siRNA targets ranging 19-32bp were obtained, randomly distributed along the target gene. Step 2: Target Screening by siRNA Expression Cassettes (SECs) The most effective siRNA sequences were identified through transfection of HepG2 2.2.15 cells with siRNA expression cassettes. Functional siRNA sequences were identified in optimized transfection conditions. Transfection efficiency in optimal conditions is >70% Benitec Ltd 14
  15. 15. ddRNAi Chronic HBV Infection ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieveinhibition of viral replication. Step 3: Large Scale Screening using SECs 100 siRNA sequences were identified produced that produced >50% HBV mRNA knock down, 14 of which resulted in >70% knock down. Step 4: Activity Validation With Chemically Synthesized siRNA The activity of selected sequences was validated through quadruplicate independent transductions with chemically synthesized siRNA. Five candidate siRNAs were selected as the basis for gene construct design. Benitec Ltd 15
  16. 16. ddRNAi Chronic HBV Infection ProductPreclinical Studies — Results to dateThese preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieveinhibition of viral replication. Step 5: Construct Development And Expression Optimization shRNA constructs were developed based on the candidate siRNAs and optimized for expression in hepatocytes. Step 6: Delivery Vehicle Design – In Progress shRNA constructs are packaged into delivery vehicles based on the AAV 8 vector specifically targeting hepatocytes, to be administered by i.v. injection Benitec Ltd 16
  17. 17. ddRNAi Chronic HBV Infection ProductPreclinical Studies — Future stepsThese preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieveinhibition of viral replication. In vivo Testing of Construct and Delivery Vehicle HBV transgenic mice as animal model: • Stable HBV particles in serum • High expression of HBsAg、HBcAg etc. in serum and hepatocyte • Luciferase assay (in-vivo bioluminescence imaging) Undertake Toxicology and Biodistribution Studies • siRNA toxicity: monitor IF effects: detection of expression of interferon response genes • Gene toxicity: microarray analysis • Peak expression time and dose optimization Benitec Ltd 17
  18. 18. Development Plan and Timeline forHBV ddRNAi Program HBV ddRNAi Programs Clinical Development Timeline Program 2011 2012 2013 2014 2015 Target Sequence Efficacy Design vector- expressed constructs Hepatitis B Preclinical testing (in vitro and in vivo models) In vivo Toxicology Phase I Clinical Trial Benitec Ltd 18
  19. 19. Additional ddRNAi Hepatitis 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 19
  20. 20. Investment Opportunity Summary ddRNAi Product Asset Summary Large Market Opportunity Favorable KOL Response High Revenue Potential in Chronic Infected and Likely for the Unique MOA Treatment-failed Population Potential for Accelerated Timeline Curative Aspect Through Leverage of Experience Gained in Long Term Effect of Treatment and the Hepatitis C Program Prevention of Re-infection Unmet Medical Need Extensive IP Estate Large, Unmet Need for Treatment of Chronic HBV Infection Patent Coverage Through 2027 Benitec Ltd 20
  21. 21. 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: Benitec Ltd 21
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