Benitec Biopharma Inc. · NASDAQ:BNTC

Benitec Biopharma — Technical Presentation (October 2013)

19 slides from Benitec Biopharma's technical presentation, October 2013

  1. Slide 1: Phase I/II Open-Label Dose Escalation Study of TT-034 in Chronic Hepatitis C

    A PHASE I/II, OPEN-LABEL DOSE ESCALATION STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SINGLE DOSES OF TT-034 IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) INFECTION David Suhy, PhD Sr. VP Research & Development

  2. Slide 2: TT-034: Many Attributes of an Ideal Therapy for HCV

    TT-034: Many Attributes of an “Ideal” Therapy for HCV TT-034 is an RNAi therapeutic that is intended as a one-shot-monotherapy • Recombinant AAV genome delivered via an AAV8 vector (high liver tropism) • Continuously produces replenishing pool of shRNAs for over 180 days • shRNA target three separat

  3. Slide 3: Overview of Expression Cassette from TT-034

    Overview of Expression Cassette from TT-034 TT-034 ITR A shRNA-22 B shRNA-19 C shRNA-6 ITR 5’ UTR 3’ UTR Structural Proteins Non-Structural Proteins p7 NS4A C E1 E2 NS2 NS3 NS4B NS5A NS5B • 3 independently transcribed RNAi elements target 3 separate, well-conserved regions of the HCV genome; helps p

  4. Slide 4: MOA of TT-034 Against the HCV Infectious Cycle

    MOA of TT-034 Against the HCV Infectious Cycle ITR A shRNA-22 B shRNA-19 C shRNA-6 ITR Exportin 5 TT-034 shRNA Dicer DNA HCV (+) RNA Viral proteins capsid replication complex RISC HCV (-) RNA HCV (+) RNA packaging Viral RNA No capsid No replication complex No packaging HCV Tacere Therapeutics, Inc O

  5. Slide 5: Strand bias of each shRNA for HCV target sequence

    Strand bias of each shRNA for HCV target sequence shRNA-6 shRNA-19 shRNA-22 HCV target Psv40 Ff-Luciferase Poly A sequences Tacere Therapeutics, Inc October2013 | 5

  6. Slide 6: TT-034 Activity Against Genotype 1a and 1b HCV Replicon Models

    TT-034 Activity Against Genotype 1a and 1b HCV Replicon Models and an Infectious Tissue Culture System HCV replicon HCVcc (representative data) (representative data) 100 100 80 80 % signal inhibition % signal inhibition 60 Rep 1b 60 40 Rep1a 40 20 20 JFH JFH-808 0 0 -20 -20 100.00 10,000.00 1,000,00

  7. Slide 7: Performance of individual TT-034 shRNA against prevalent clinical isolates

    Performance of individual TT-034 shRNA against sequences of most prevalent clinical isolates in public HCV databases 100 Percent inhibition 80 — — — — — — — — — — — — — — — — — — 60 shRNA6 40 20 0 100 — + + + + ++ +++ + ++ + ++ + + +++ — ++ ++ — 80 Percent inhibition 60 All isolates have >10% shRNA1

  8. Slide 8: Use of an AAV delivery system

    Use of an AAV delivery system Wildtype AAV8 REP/CAP removed and replaced with expression cassette TT-033 ITR A shRNA-22 B shRNA-19 C shRNA-6 ITR Recombinant AAV8 • Non-integrating, non-pathogenic viral delivery system • Has been used in hundreds of patients in clinical trials • Sustained expression

  9. Slide 9: AAV8 confers complete hepatocyte transduction

    AAV8 confers complete hepatocyte transduction: shRNA expression within cyno liver sections via ISH shRNA 6 shRNA 19 shRNA 22 treated Saline 1.25x1012 vg/kg TT-033 Tacere Therapeutics, Inc October2013 | 9

  10. Slide 10: Biodistribution of vector in cynomolgus monkey tissues

    Biodistribution of vector in cynomolgus monkey tissues Copies of vector per cell Tacere Therapeutics, Inc October2013 | 10

  11. Slide 11: TT-034: Optimized for Safety and Efficacy

    TT-034: Optimized for Safety and Efficacy TT-033 ITR A shRNA-22 B shRNA-19 C shRNA-6 ITR weakened promoters TT-034 ITR A shRNA-22 B shRNA-19 C shRNA-6 ITR • First generation TT-033 toxicity associated with very high shRNA levels • Modifications to the U6 promoters to reduce expression of shRNA • AAV

  12. Slide 12: Liver shRNA-19 levels from TT-033 & TT-034 treated mice

    Liver shRNA-19 levels from TT-033 & TT-034 treated mice TT-033 TT-034 TT-034 Test Article TT-033 1.25x1011 1.25x1012 1.25x1013 1.25x1011 1.25x1012 1.25x1013 2.5x1011 2.5x1011 1 1x1012 1 1x1012 Dose (vg/kg) 1 2 3 4 5 6 7 8 9 10 Animal Number 1 2 3 4 5 6 7 8 9 10 100000 10000 Copies of shRNA-19 / cell

  13. Slide 13: Clinically Relevant Doses Produce Efficacious shRNA Levels Without Liver Toxicity

    TT-034: Clinically Relevant Doses Produce Predictive Efficacious shRNA Levels in the Absence of Liver Toxicity shRNA-6 shRNA-22 shRNA-19 18 66 9 782 1223 196 8350 6090 1463 Avg. from dose cohort shRNA expression Minimal liver toxicity shRNA/cell in NHPs eliminates virus in NHPs (50 days) Tacere Ther

  14. Slide 14: Summary of TT-034 GLP Safety Data

    Summary of TT-034 GLP Safety Data Sustained and preferential transduction of hepatocytes with concomitant shRNA expression. • 180 Day GLP studies in 520 mice and 80 NHPs at 3 dose levels Day 60 Day 180 Minimal and transient adverse events • No test-article dependent findings in clinical observations

  15. Slide 15: Outline of Clinical Protocol

    Outline of Clinical Protocol A PHASE I/II, OPEN-LABEL DOSE ESCALATION STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SINGLE DOSES OF TT-034 IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) INFECTION Tacere Therapeutics, Inc October2013 | 15

  16. Slide 16: Key Personnel

    Key Personnel Duke University – Clinical Site • Keyur Patel, MD, Principal Investigator • Barry Mangum, PharmD, Clinical Pharmacology University of California at San Diego – Clinical Site • David Wyles, MD, Investigator • Robert Schooley, MD, Consultant Tacere Therapeutics - Sponsor • David Suhy, Ph

  17. Slide 17: Phase I/II Study Design

    Phase I/II Study Design • Open label, single-dose, dose escalation safety study in 14 HCV genotype 1 patients • 5 dose cohorts • DSMB review after first patient in each cohort and between cohorts • Extensive safety monitoring during 24 weeks observation • Liver biopsy at day 21 (expected peak shRNA

  18. Slide 18: Dose Escalation Scheme

    Dose Escalation Scheme Cohort Dose Dose Total No Dosing scheme Observation period per (vg/kg) escalation subjects for subjects subject and between cohorts step (log 10) before dose escalation 1 4.00 × 1010 Starting dose 2 Sequential (1+1) 6 week 2 1.25 × 1011 0.5 3 Sequential and 6 week parallel (1+

  19. Slide 19: Acknowledgements

    Acknowledgements: Tacere Therapeutics: Pfizer: Tin Mao Romu Corbau Shih Chu Kao Larry Whiteley Peter Roelvink Bernard Souberbielle Sasha Kolykhalov Kevin Brady Linda Couto Hubert Denise Helen Lavender Benitec: Keith Anderson Mick Graham Jeff Southerton Per Lindell Duke: Children’s Hospital of Philad

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