Benitec Biopharma Inc. · NASDAQ:BNTC
Benitec Biopharma — Benitec — Investor Presentation (October 2005)
49 slides from Benitec Biopharma's investor presentation, Oct 21, 2005
Slide 1: Corporate and Clinical Overview
Benitec Ltd. Corporate and Clinical Overview Non-Confidential Presentation October 21, 2005 © 2005 Benitec, Ltd.
Slide 2: Corporate Overview
Corporate Overview • Listed on Australian Stock Exchange (ASX:BLT) • Corporate headquarters in Mountain View, CA • Strong Intellectual Property Portfolio in RNAi – Out-licensed to multiple entities in many fields – Available for licensing in multiple fields • Two advanced pre-clinical programs – AID
Slide 3: Intellectual Property
Intellectual Property RNAi in living mouse model of human disease (McCaffrey and Kay, Nature) Plant Sequence-specific RNAi in vivo Cyclodextrin Delivery co-suppression RNA interference (Fire HBV and HCV (Kay) HCV (Calando) (Jorgensen) and Mello) Exclusive/Co-Exclusive Exclusive 1990 1991 1997 1998 1
Slide 4: Current Licensees
Current Licensees © 2005 Benitec Ltd October 21, 2005 | 4
Slide 5: Capital Structure
Capital Structure • Shares outstanding 152.1M • Share price at 21 Oct 2005 (USD) $0.11 • Market capitalization $16.7M • Options/warrants outstanding 54.3M • Fully diluted shares 206.4M © 2005 Benitec Ltd October 21, 2005 | 5
Slide 6: Product Pipeline
Product Pipeline Development Pre-Clinical Clinical HIV/AIDS Lymphoma Q1 ‘06 Program Hepatitis C Virus Q4 ‘06 HIV/AIDS (T-cell) © 2005 Benitec Ltd October 21, 2005 | 6
Slide 7: Mechanism of RNA interference (RNAi)
Mechanism of RNA interference (RNAi) dsRNA Dicer Natural mechanism Rapidly deployed Highly specific siRNA or Catalytic Activated RNAi RISC Target Binding AAAAA Target Destruction AAAAA © 2005 Benitec Ltd October 21, 2005 | 7
Slide 8: RNAi Therapeutics
RNAi Therapeutics DNA RNA Protein Function Small RNAi Molecules Antibodies • Target: RNA • Target: Protein • Target: Protein • Challenge: Delivery • Challenge: Specificity • Challenge: Penetration • Advantage: Destroys • Advantage: Gold standard • Advantage: Market disease causing agent of treatment
Slide 9: The Hepatitis C Program
The Hepatitis C Program © 2005 Benitec Ltd October 21, 2005 | 9
Slide 10: HCV Program
HCV Program • Molecular Target: Hepatitis C Virus genome • Data published in Nature and Nature Biotech • IND filing: Q4 2006 • RNAi Therapeutics – Multi-targeting to prevent viral escape – “Cocktail” in one drug Structural Proteins Non-Structural Proteins 5’ UTR 3’ UTR © 2005 Benitec Ltd October 21,
Slide 11: HCV Therapeutics Market
HCV Therapeutics Market Present Market Data: • Total 2004 sales ~$3.8B • Side effects are very serious: include depression, anemia, and chronic flu-like symptoms • Only ~25-40% of all HCV patients are eligible for Interferon-A (PEG-Intron A) treatment • Less than 50% success for genotype 1a/1b, domi
Slide 12: HCV Infectious Cycle
HCV Infectious Cycle 5’ UTR 3’ UTR Structural Proteins Non-Structural Proteins p7 NS4A C E1 E2 NS2 NS3 NS4B NS5A NS5B protease polymerase BI protease inhibitor BLN 2061 Vertex protease inhibitor VX950 Merck polymerase Rigel polymerase R803, R809 Idenix polymerase NM 283 Viropharma/Wyeth polymerase H
Slide 13: Drug Resistance in HCV
Drug Resistance in HCV Small molecule inhibitors Vertex protease inhibitor VX950 Rigel polymerase inhibitor R803 • Drug-resistant mutants recovered after a single passage in the HCV replicon model RNAi Ontario Cancer Institute studies • Selection of HCV escape mutants after treatment with siRNA in t
Slide 14: RNAi Drug Development Strategy
RNAi Drug Development Strategy Develop broad specificity therapeutics • Select RNAi targets to cover most of patient population (RNAi advantage over small molecule): Prevent generation of escape mutants • Combination of two or three targets together in a single therapeutic (ddRNAi advantage): A shRN
Slide 15: Benitec's Multi-targeting Clinical Candidate
Hepatitis C Virus Viral RNA genome 5’ UTR 3’ UTR Structural Proteins Non-Structural Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B HCV Benitec’s Multi-targeting Clinical Candidate (A) Viral RNA Replication Polymerase Inhibitor Drugs (B) Viral Protein Virus Particle Viral Amplification Production He
Slide 16: Activity of siRNA vs. HCV-luciferase Fusion Constructs
Percent Inhibition from a nonspecific control sequence -20 0 20 40 60 80 100 siRNA-1 © 2005 Benitec Ltd siRNA-2 siRNA-3 siRNA-4 siRNA-5 siRNA-6 siRNA-7 siRNA-8 siRNA-9 siRNA-10 siRNA-11 siRNA-12 siRNA-13 siRNA-14 siRNA-15 siRNA-16 siRNA-17 siRNA-18 siRNA-19 siRNA-20 siRNA-21 siRNA-22 siRNA-23 siRNA-
Slide 17: Assessment of siRNA Toxicity using WST-1
Assessment of siRNA Toxicity using WST-1 100 Activity Percent Inhibition of replicon N=4 4 nM 40 nM 16 nM 600 pM 250 pM 100 pM 80 60 40 20 0 -20 1.6 Toxicity Relative Proliferation (OD) 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Non-specific siRNA-1 siRNA-3 siRNA-6 siRNA-8 siRNA-16 siRNA-19 siRNA-22 © 2005 Benitec
Slide 18: Strategies for Simultaneous Expression of Multiple shRNA
Strategies for Simultaneous Expression of Multiple shRNA loop seq. 1 loop seq. 2 loop seq. 3 A shRNA-1 B shRNA-2 C shRNA-3 Term. A Term. B Term. C loop seq. 1 loop seq. 2 loop seq. 3 A shRNA-1 shRNA-2 shRNA-3 Term. A loop seq. 1 shRNA-1 shRNA-2 shRNA-3 A shRNA-1 shRNA-2 shRNA-3 Term. A Mature, shRNA
Slide 19: In vivo testing of the pre-clinical candidate
In vivo testing of the pre-clinical candidate Normal mouse model system • Hydrodynamic tail vein injection of luciferase fusion reporter constructs to validate shRNA constructs Alberta mouse model system • Xenograft model: human hepatocytes transplanted in uPA-SCID mice • Currently evaluating AAV-sh
Slide 20: Validation of HCV shRNAs in normal mice
Validation of HCV shRNAs in normal mice liver lysates: total protein FF Luc activity R Luc activity Injection: RNA analysis Reporter plasmid (FF Luc/HCV target) Test plasmid (shRNA) Transfection control plasmid (R Luc, hAAT) FF Luc mRNA shRNA © 2005 Benitec Ltd October 21, 2005 | 20
Slide 21: In vivo analysis of triple promoter shRNA construct
Percent Inhibition 100 20 40 60 80 0 0 20 40 60 80 100 © 2005 Benitec Ltd shRNA-6 shRNA-19 shRNA-22 Single promoter shRNA-6 shRNA-6 LUC Reporter Unrelated shRNA shRNA-6 shRNA-19 shRNA-22 Single promoter shRNA-19 Unrelated shRNA shRNA-19 LUC Reporter shRNA-6 shRNA-19 shRNA-22 Single promoter shRNA-22
Slide 22: Compilation of in vitro and in vivo analyses
Compilation of in vitro and in vivo analyses 100 80 Percent Inhibition 60 40 20 0 shRNA-6 shRNA-8 shRNA-9 shRNA-19 shRNA-22 shRNA-23 In vivo Fusion constructs © 2005 Benitec Ltd Replicon October 21, 2005 | 22
Slide 23: RNAi Delivery
RNAi Delivery DNA-directed RNAi (ddRNAi) • AAV vectors • Lentiviral vectors • Plasmid vectors (mini-circles) Synthetic small-interfering RNAi (siRNA) • Recently announced deal with Calando Pharmaceuticals for non-viral delivery © 2005 Benitec Ltd October 21, 2005 | 23
Slide 24: Delivery of RNAi Using Adeno-Associated Virus
Delivery of RNAi Using Adeno-Associated Virus AAV is a non-pathogenic Parvovirus • Small (20-25 nm), non-enveloped virus • Single stranded DNA genome • Not associated with human disease Replication defective • Requires helper viral genes for replication Broad host range • Infects wide range of cell
Slide 25: AAV Vectors
AAV Vectors AAV ITR REP CAP ITR AAV vector ITR Promoter Therapeutic Sequence(s) ITR • Direct in vivo administration • Efficient gene delivery • Sustained, high levels of gene expression • Many serotypes (AAV1-10) with different tropisms © 2005 Benitec Ltd October 21, 2005 | 25
Slide 26: Levels of transduction of mouse liver cells with AAV2 and AAV8
Levels of transduction of mouse liver cells with AAV2 and AAV8 AAV2-EF1α-nlslacZ AAV8-EF1α-nlslacZ 9% 97% H Nakai H, MA Kay J.Virol 79:214; 2005 © 2005 Benitec Ltd October 21, 2005 | 26
Slide 27: Long-term Inhibition of HBsAg in Blood of HBV Transgenic Mice
Long-term Inhibition of HBsAg in Blood of HBV Transgenic Mice 140 PBS AAV- HBV shRNA 120 Percent of starting levels of HBsAg 100 80 60 40 20 0 -20 20 40 60 80 100 120 Days following treatment with rAAV D Grimm and MA Kay, Unpublished Results © 2005 Benitec Ltd October 21, 2005 | 27
Slide 28: Delivery of RNAi with Nanoparticles
Delivery of RNAi with Nanoparticles Benitec has exclusive, worldwide rights to Calando Pharmaceuticals Cyclodextrin nanoparticles for HCV/RNAi Cyclodextrin Nanoparticles • Non-toxic • Non-immunogenic • Amenable to repeat dosing • 50nm particles • Efficient delivery to cytoplasm • High packing effici
Slide 29: Cyclodextrin-mediated Silencing in Tumor Cells
Cyclodextrin-mediated Silencing in Tumor Cells Targeted Cyclodextrin formulation Injection Regimen: Twice Weekly for 4 Weeks – 2.5 mg/kg Source: Calando Pharmaceuticals Inc. © 2005 Benitec Ltd October 21, 2005 | 29
Slide 30: Cyclodextrin-mediated Delivery to Ewing's Sarcoma
Cyclodextrin-mediated Delivery to Ewing’s Sarcoma * MRI confirms bioluminescence imaging Source: Calando Pharmaceuticals Inc. © 2005 Benitec Ltd October 21, 2005 | 30
Slide 31: In vivo Testing of Pre-clinical Candidate
In vivo Testing of Pre-clinical Candidate Normal mouse model system • Hydrodynamic tail vein injection of luciferase fusion reporter constructs to validate shRNA constructs Alberta mouse model system • Xenograft model: human hepatocytes transplanted in uPA-SCID mice • Currently evaluating AAV-shRNA
Slide 32: GBV-B Marmoset Model
GBV-B Marmoset Model • GBV-B/HCV chimerae: (Rijinbrand et al Hepatology May 2005) GBV-B genome HCV GBV-B • The closest related virus to HCV; hepatotropic; causes hepatitis • Efficiently replicates in tamarins and marmosets • Molecular clones are established © 2005 Benitec Ltd October 21, 2005 | 32
Slide 33: Safety testing of clinical candidate
Safety testing of clinical candidate Toxicology study in marmosets • Hematology • Clinical chemistry • Histopathology GLP Toxicology study in rodents • Hematology • Clinical chemistry • Histopathology GLP Biodistribution study in rodents • Q-PCR and QRT-PCR analysis of tissues © 2005 Benitec Ltd Oct
Slide 34: HCV Program- Path to Clinic
HCV Program- Path to Clinic • HCV ideal target for RNA interference – Access to non-druggable targets – Cytoplasmic RNA virus with no DNA phase – Highly mutable virus requires multi-targeting provided by ddRNAi • Ongoing Research – In vivo safety & efficacy testing of clinical candidates – Toxicolog
Slide 35: HCV Timeline
HCV Timeline ID Task Name 4Q04 1Q05 2Q05 3Q05 4Q05 1Q06 2Q06 3Q06 4Q06 1Q07 2Q07 1 Choose triple clinical candidate(s) 5/30 2 AAV production:research grade 3 Non-viral formulation production:research grade 4 RNA Assay Development 5 In vivo analysis of AAVshRNAs in mice 6 In vivo analysis of Non-vira
Slide 36: The HIV/AIDS Lymphoma Program
The HIV/AIDS Lymphoma Program © 2005 Benitec Ltd October 21, 2005 | 36
Slide 37: AIDS Lymphoma Program
AIDS Lymphoma Program • Molecular Targets: – HIV genome – cell-surface receptor – replication machinery • Data published in Nature Reviews, PNAS, and Molecular Therapy • Clinical Development Partner: City of Hope – Principal Investigator: John Rossi, Ph.D. – Clinical Investigator: John Zaia, M.D. –
Slide 38: HIV/AIDS Therapeutics Market
HIV/AIDS Therapeutics Market • HIV/AIDS Global health crisis (in 2004) – 42 million infected worldwide – More than 4 million deaths – More than 5 million acquired HIV • Highly Active Anti-Retroviral Therapy (HAART) is not ideal – Acute and chronic side effects – HIV replication not completely suppre
Slide 39: Background
Background • AIDS Lymphoma patients transduced with a retrovirus expressing a ribozyme demonstrated that transplantation of autologous, genetically modified stem cells is safe • AIDS Lymphoma patients who have undergone successful chemotherapy have a life expectancy of six to nine months, in the abs
Slide 40: Benitec/COH Clinical Trial for AIDS Lymphoma Patients
Benitec/COH Clinical Trial for AIDS Lymphoma Patients Goal: Introduction of a combination of multi-targeted RNA based HIV inhibitors into hematopoietic stem cell using gene therapy. This approach will protect the entire population of HIV infectible hematopoietic cells including CD4+ T-cells, monocyt
Slide 41: Rationale for a Combinatorial RNA-based Therapy
Rationale for a Combinatorial RNA-based Therapy • Most efficacious HAART therapeutic regimens for HIV use a cocktail of three or more anti-retroviral agents targeting at least two different viral proteins • shRNA is very potent, but can be overcome by viral resistance and high viral challenge • Targ
Slide 42: Composition of HIV Drug
Composition of HIV Drug RNA 1 Chimeric ribozyme against HIV cellular receptor RNA 2 RNA decoy to inhibit replication of HIV RNA 3 RNAi molecule against HIV genome 1+2+3 2+3 1+3 Controls - RNA 1 - RNA 2 Expression of RNA cocktail in vitro - Loading Control - RNA 3 Rossi et al., submitted © 2005
Slide 43: Highly Promising HIV Drug Candidate
Highly Promising HIV Drug Candidate 8,000,000- 7,000,000- *HIV load (p24 antigen in pg/ml) Day 7 Day 28 500,000- 70,000- 8,000- Control 1+3 2+3 1+2+3 Composition of RNA Cocktail * Y-axis not to scale Rossi et al., submitted © 2005 Benitec Ltd October 21, 2005 | 43
Slide 44: Summary of Safety Data
Summary of Safety Data • Differentiation in vitro: transduced CD34+ cells differentiate into macrophages and resist HIV challenge • Differentiation in SCID-hu Mouse model: transduced CD34+ differentiate into T cells in vivo and resist HIV challenge in vitro • Non-human primate studies: fetal rhesus
Slide 45: AIDS/lymphoma Clinical Trial Design
AIDS/lymphoma Clinical Trial Design Stem-cell Apheresis enrichment Healthy HIV positive or chemo-responsive AIDS lymphoma Lentiviral-mediated patient transduction of CD34+ PBPC CD34+ stem cells GCSF Pool and infuse into patient after 5-day chemotherapy Patient follow-up for marking Hannon & Rossi, N
Slide 46: HIV Program- Path to Clinic
HIV Program- Path to Clinic Stem Cell Therapy For AIDS Lymphoma • HIV/AIDS lymphoma therapeutic currently in cGMP manufacture at City of Hope • RAC submission reviewed at the NIH on 21 September 2005 • Pre-IND meeting held on 17 October 17 2005 • In Phase I trials by Q1 2006 • Single site Phase I tr
Slide 47: HIV Timeline
HIV Timeline ID Task Name 4Q04 1Q05 2Q05 3Q05 4Q05 1Q06 2Q06 3Q06 1 Preclinical Studies 2 Lentiviral Assay Development 3 Lentiviral Process Development 4 GMP Manufacture Lentivirus 5 Release Testing Lentivirus 6 CD34 Assay Development 7 CD34 Process Development 8 IND Filing 3/10 9 Initiate Clinical
Slide 48: Intellectual Property Dispute Resolution
Intellectual Property Dispute Resolution Promega • Contract dispute was settled, with Promega reverting to a non- exclusive licensee without right to sublicense • Case was dismissed with prejudice, all legal issues resolved Re-examination Proceedings in Australia • Both issued patents in Australia w
Slide 49: Sigma-Aldrich
Sigma-Aldrich • On 21 October 2005 Benitec entered into strategic licensing and equity agreements with Sigma-Aldrich – Sigma was granted an exclusive license to the research reagent field in exchange for $2.0M and on-going royalties – Sigma acquired a $2.5M equity stake in Benitec • Benitec establis