corporate presentation at cappello us investor conference

Corporate Presentation
January 2013
Copyright © Benitec Biopharma Ltd,
www.benitec.com
1"
Forward looking statement
This"presenta-on"contains"forward"looking"statements"that"involve"risks"
and"uncertain-es.""
Although"we"believe"that"the"expecta-ons"reflected"in"the"forward"
looking"statements"are"reasonable"at"this"-me,"Benitec"Biopharma""can"
give"no"assurance"that"these"expecta-ons"will"prove"to"be"correct.""
Actual"results"could"differ"materially"from"those"an-cipated."Reasons"
may"include"risks"associated"with"drug"development"and"manufacture,"
risks"inherent"in"the"regulatory"processes,"delays"in"clinical"trials,"risks"
associated"with"patent"protec-on,"future"capital"needs"or"other"general"
risks"or"factors."
"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
2"
Benitec Biopharma:
Company Profile
! Unique"patent"protected"long"las-ng"gene"silencing"technology""
! DNA"Directed"RNA"interference"(ddRNAi)"with"poten-al"to"provide"“one"
shot"cures”"
“Unlike(current(an.retroviral(therapies,((shRNA):based(gene(therapy(may(be(
poten.ally(cura.ve,(reversing(the(virus’s(damage((to)(the(immune(system,(with(
a(single(or(few(administra.ons.”(*"
! Pipeline"in"infec-ous"disease,"cancer,"pain,"ocular"and"orphan"diseases""
"  Applica-ons"selected"to"maximize"the"unique"advantages"of"ddRNAi"""
! Lead"product"against"Hepa--s"C"virus"(HCV)"will"enter"clinic"in"2013"
"
*"Ringpis"et"al,"PLoS"ONE"7(12):"e53492."doi:10.1371/journal.pone.0053492"
!
Copyright © Benitec Biopharma Ltd,
www.benitec.com
3"
Benitec Biopharma:
Financial Profile
! Australian"biotechnology"company"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
Key!Financials!at"30"June"2012"
ASX:BLT!
Price"per"share!
Market"capitalisa-on!
Issued"equity:"ordinary"shares!
Op-ons"on"issue"!
Cash"balance"!
Monthly"burn"rate!
AUD"0.017"!
AUD"16.7"million!
970,628,529!
428,985,202!
AUD"3.1"million"!
AUD"263,000!
4"
Benitec Biopharma:
ddRNAi Technology
! ddRNAi!technology!u;lizes!the!power!and!
specificity!of!RNAi!while!avoiding!many!of!
the!problems!with!siRNA!
1.  DNA"construct"is"delivered"to"the"nucleus"by"
a"clinically"proven"vector;"avoids"interac-on"
with"toll`like"receptors"and"subsequent"
interferon"response"typical"with"siRNA"
delivery"
2.  DNA"constructs"con-nuously"produce"short"
hairpin"RNAs"(shRNAs)"in"nucleus"which"are"
processed"by"the"cell"into"siRNAs."
3.  The"endogenously"processed"siRNA"is"
incorporated"into"the"RISC"complex"and"
“silences”"the"target"gene."
1"
EnzymaIc"cleavage"of"
hairpin"loop"by"DICER"
siRNA"
enzyme"
complex"
(RISC)"
3"
2"
Target"mRNA"cleaved"
"
!  Long!term!expression!of!shRNA!provides!
a!poten;al!“single!shot!cure”!
Copyright © Benitec Biopharma Ltd,
www.benitec.com
Benitec!technology!
ddRNAi!DNA!
construct!
Protein"
"
shRNA!
Con;nually!
expressed!
Gene"
5"
Benitec Biopharma:
Pipeline
Indica;on!
Partners/Collaborators!
HIV/AIDS"
Calimmune"
OutVlicensed""
Hepa--s"C"
""
Acquired"from"
Tacere/Pfizer"
Discovery"
Pre`clinical"
Clinical"
University"of"New"South"
Non"Small"Cell"Lung"Cancer"*" Wales"
Cancer"associated"pain"
Stanford"University"
Hepa--s"B"
Biomics"Biotechnologies"
OPMD**"
Royal"Holloway,"University"of"
London"
AMD***"
""
Re-ni-s"Pigmentosa"
"Genable"
OutVlicensed""
Hun-ngton’s"Disease"
"uniQure"
OutVlicensed!!
Acquired"from""
Tacere"
*And"other"tubulin"chemotherapeuIc"resistant"cancers"
**Oculopharyngeal"muscular"dystrophy"
***AgeVRelated"Macular"DegeneraIon"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
6"
Lead program (TT-034):
Novel Hepatitis C Therapeutic
! A"“molecular"monotherapy”"intended"to"treat"and"cure"HCV"
infec-on"with"a"single"injec-on"
! Developed"in"collabora-on"with"Pfizer"
"  Developed"on"a"large"pharma"scale"to"very"high"standards"
"  Ended"with"the"closure"of"the"Sandwich"UK"facility"due"to"restructure"following"
Wyeth"acquisi-on"(not"for"lack"of"confidence"in"program)"
! Reversion"of"program"from"Pfizer"gives"Benitec"worldwide"rights"
"  Pfizer"has"been"very"suppor-ve"and"coopera-ve"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
7"
Lead program (TT-034):
Novel Hepatitis C Therapeutic
TTS034!
HCV!Genome!
! TT`034"comprises"three"shRNAs"targe-ng"three"separate,"highly"conserved"
regions"in"the"virus"genome"
! Robust:"expression"of"mul-ple"shRNAs"from"a"single"construct"avoids"
genera-on"of"escape"mutants""
! Targeted"against"genotype"1"(largest"group"&"highest"rate"of"non`responders)"
! Can"be"customized"for"other"genotypes"and"resistant"strains"(personalized(
therapeu.c)"
! Broad"therapeu-c"window"
Copyright © Benitec Biopharma Ltd,
"
www.benitec.com
8"
TT-034 - Broad Therapeutic Window
!  Clinically"relevant"doses"of"TT`034"produce"sustained"levels"of"shRNA"
without"toxicity""
Quan;;es!of!shRNA/cell!!required!
for!HCV!Replicon!Inhibi;on!
Assessment!of!liver!toxicity!
in!cynomolgus!monkeys!
1400!
!
1200!
!
1000!
!
800!
!
600!
!
400!
!
200!
shRNA/cell!in!cynomolgus!
monkey!livers!at!day!50!
shRNAS6! shRNAS22! shRNAS19!
18!
66!
9!
782!
1223!
196!
8350!
6090!
1463!
Avg.!from!dose!cohort!
Copyright © Benitec Biopharma Ltd,
www.benitec.com
9"
TT-034 - Delivery Into Near 100% Cells
With a Single Injection
!  Qualita-ve"ISH"analysis"of"shRNA"expression"in"liver"-ssue"demonstrates"
nearly"complete"transduc-on"of"cynomolgus"monkey"hepatocytes"
SALINE!
12!
1.25X10!!!vg/kg!
shRNAS6!
shRNAS19!
shRNAS22!
Copyright © Benitec Biopharma Ltd,
www.benitec.com
10"
TT-034 – High Liver Tissue Specificity
TTS034!Tissue!distribu;on;!!>90%!localized!to!liver!
Copies of vector per cell
Copyright © Benitec Biopharma Ltd,
www.benitec.com
11"
TT-034 is Ready For Clinic
! Benitec"plans"to"conduct"a"phase"I/IIa"study"in"HCV"pa-ents"in"2013"
"  All"required"safety"and"toxicology"studies"have"been"conducted"with"an"excellent"
safety"profile"
"  Pre`IND"mee-ngs"with"FDA"were"held"in"June"2007"and"January"2010"
"  GMP"clinical"product"has"been"manufactured"
"  CRO"appointed"December"2012"
"  IND"planned"Q1"2013"
"
! Success"with"HCV"will"be"a"posi-ve"predictor"for"HBV"therapeu-c"
! Unique"mechanism"of"ac-on"and"dosing"regimen"could"be"a"“game"
changer”"for"treatment"of"HCV"and"HBV"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
12"
TT-034 is a “Disruptive Technology” in
a market that will remain very large
! Even"with"promising"data"showing"high"cure"rates"for"new"drugs,"
HCV"will"remain"a"“Problem"Not"Solved”."According"to"many"KOLs:"
"  Significant"numbers"of"pa-ents"will"be"non`responders"
"  Treatment"-mes"and"side"effects"of"new"drugs"leave"much"room"for"
improvement"
"  HCV"is"likely"to"con-nue"to"develop"resistant"variants"to"new"treatment"op-ons"
"  Currently"all"transplanta-on"pa-ents"become"reinfected"with"HCV.""The"new"
treatments"are"not"well"tolerated"by"transplanta-on"pa-ents."
! A"“single"shot"cure”"will"supersede"small"molecule"cocktails"
"  A"single"shot"monotherapy"cure"will"be"preferred"over"3"to"6"month"daily"oral"
regimens"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
13"
TT-034 Significant Commercial
Opportunity in Western Markets
40"million"HCV"infected"
outside"US"&"EU""
HCV"Genotype"1"Prevalence"
((million(HCV(subjects(in(US,(JP(&(EU12)(
"12""
"10""
75"%"of"HCV"cases"
are"GT1."About"
10"million"in"US"&"
EU"
"8""
In"addiIon"there"is"
a"huge"emerging"
market"outside"US"
&"EU"
Emerging"drugs"are"
predicted"to"cure"
about"80%"of"paIents"
This"leaves"a"significant"
market"(>4M"paIents)"
for"the"next"generaIon"
therapies"
"6""
"4""
"2""
"`""
Copyright © Benitec Biopharma Ltd,
www.benitec.com
In"pracIce"a"large"
number"of"untreated"
or"nonVresponding"
paIents"will"remain"
Sources:"Datamonitor"2007"to"2011,"Chak"et"al"2011,"Sievert"et"al"2011,"Esteban"et"al"2008."
EU"12"is"Germany,"France,"Italy,"UK,"Spain,"Netherlands,"Belgium,"Sweden,"Denmark,"Norway,"Finland,"Austria."
Cure"rate"="number"of"paIents"that"achieve"a"cure"as"%"of"paIents"dosed.""J.W."Pawlotsky"(2011)"J."Hepatology""53:1742V50."
14"
HBV:
Companion Program to HCV
! The"HBV"therapeu-c"is"a"copy"of"HCV""
"  3"shRNAs"against"highly"conserved"regions"on"HBV"genome"
"  Same"delivery"vector"as"HCV"
"  Iden-cal"regulatory"path"
"  HCV"toxicology"studies"applicable"to"HBV"
! Significant"indica-on"but"limited"anen-on"–"absence"of"new"
therapies"
! Therapeu-cs"and"vaccines"exist"for"HBV"…"but"
"  Very"large"pool"of"infected"pa-ents"remain"
"  Current"therapies"not"very"effec-ve"
"  Pa-ent"compliance"is"low"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
15"
HBV:
Another Large Commercial Opportunity
Worldwide"HBV"is"3"Imes"
more"prevalent"than"HCV"
In"the"top"western"markets"HCV"is""
2"Imes"more"prevalent"than"HBV"
Chronic"HBV"and"HCV"prevalence"worldwide"
HBV"and"HCV"prevalence"in"top"7"markets*"
14"
12"
300"
Top"7"markets"
China"
200"
ROW"
Prevalence""(million)"
Prevalence"of"chronically"infected"
subjects"worldwide"(million)"
400"
10"
8"
6"
4"
2"
100"
0"
HBV"
HCV"
0"
HBV"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
HCV"
*US,"EU5"(UK,"France,"Germany,"Italy,"Spain),"Japan"
Sources:"Datamonitor"2004,"2007"to"2011."WHO,"CDC,"IMS,"analyst"reports"" 16"
Chemotherapy-Resistant
Cancer Therapeutic
! Therapeu-c"designed"to"inhibit""βIII"tubulin"expression"
! Tubulin"is"a"key"component"of"the"cellular"cytoskeleton"and"the"
target"of"Tubulin"Binding"Agents"(TBAs)"like"taxol"
! Many"cancers"become"resistant"to"TBAs"and"other"chemotherapy""
arer"ini-al"treatment"
! Resistance"is"strongly"correlated"with"over`expression""of"βIII"
tubulin"and"decreased"survival"
! Benitec’s"therapeu-c"silences"βIII"tubulin"and"restores"sensi-vity"of"
cancers"to"TBAs"and"DNA"damaging"agents"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
17"
Chemotherapy-Resistant
Cancer Therapeutic
! Ini-al"indica-on"is"Non`Small"Cell"Lung"Cancer;"the"overwhelming"
cause"of"lung"cancer`related"deaths"
"  3"shRNAs"used"in"construct"to"ensure"robust"inhibi-on"
! Delivery"using"Jet`PEI;"clinically"validated,"targets"lung"-ssue"
! Solid"proof"of"principle"in(vivo(
! Progressing"into"IND`enabling"studies"
Use!in!combina;on!with:!
" 
" 
" 
" 
Taxanes""
Vinca"alkaloids"
Epothilones"
Pla-nums"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
To!treat!mul;ple!βIII!expressing!cancers:!
"  Lung"(NSCLC"&"
SCLC)"
"  Ovarian"
"  Prostate"
"  Pancrea-c"
"  Breast"(metasta-c)"
"  Melanoma"(subset)"
"  Gliobastoma"
(subset)"
18"
Silencing βIII tubulin restores
sensitivity to chemotherapy
Triple"shRNA"knocks"down"βIII"tubulin"in"H460"
NSCLC"cells"
%!knockdown!of!βIII!tubulin!RNA!(qRTSPCR)!!
Control"
Single"
shRNA"
Triple"shRNA"
construct"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
Silencing"βIII"tubulin"restores"NSCLC"cell"
lines"sensiIvity"to"cisplaIn"
Triple shRNA
silences βIII tubulin in vivo
Experiment M2-Three: Combined data
The"JetPEI/βIII"tubulin"triple"shRNA"silences"
Relative Gene Expression
βIII"tubulin"in!vivo!in"orthotopic"lung"tumors"
BIII Expression (mean)
150
Trp Ctrl
BIII
Control"
100
βIII"tubulin"
triple"shRNA"
50
0
Trp Ctrl
BIII
Treatments
Copyright © Benitec Biopharma Ltd,
www.benitec.com
71.6%
Trp ctrl n=6
20"
ddRNAi as a Pain Therapeutic
“Chronic"pain"affects"a"large"propor-on"of"the"worldwide"
popula-on.""
The"socio`economic"stakes"are"huge.""
Clinical"management"of"chronic"pain"relies"mainly"on"opioids"and"
NSAIDs."However,"these"pharmacological"treatments"remain"
inefficient"for"pa-ents"coping"with"chronic"pain"condi-ons,"such"as"
neuropathic"or"cancer`related"pain.""
Gene-c"approaches"are"seen"as"an"innova-ve"solu-on."
RNA"interference"technology"represents"a"straightorward"and"
efficient"technology"for"gene-c"therapy"for"pain.”"*"
*Reference:"Serrat"P"et"al."RNA"Technologies"and"Their"ApplicaIons"2010,"pp"161V190."
Copyright © Benitec Biopharma Ltd,
www.benitec.com
21"
Benitec’s Pain Therapeutic
! Molecular"target"is"Protein"Kinase"C"γ"(PKCγ)"in"spinal"neurons"
! PKCγ"is"involved"in"transmission"of"both"neuropathic"and"
nocicep-ve"pain"
! Silencing"of"PKCγ"using"shRNA"has"been"demonstrated"to"abrogate"
neuropathic"pain"long"term"AND"overcome"morphine"tolerance"in(
vivo"*(
!
! Intended"to"provide"long"term"
pain"relief"(months)"with"a"
single"injec-on"of"a"DNA"
construct"expressing"a"single"
shRNA"against"a"conserved"
region"of"PKCγ"
"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
*References:""
Song"et"al,"J"Gene"Med"2010;12:"873–880;""
Zou"et"al"Human"Gene"Therapy"2011;"22:465–475."""
22"
Intractable Pain in Cancer Patients
! Ini-al"indica-on"is"intractable"pain"
in"late"stage"cancer"pa-ents"
Brain"
"  Significant"unmet"need"
"  No"opioid`like"side"effects"(opiate"haze,"
cons-pa-on,"nausea,"tolerance)"
"  Easier"regulatory"pathway""
Intrathecal"injecIon"
of"ddRNAi"construct"
Spinal"Cord"
! Delivered"by"intrathecal"injec-on"
into"the"spinal"canal"
"  Local"injec-on"facilitates"targeted"
delivery"to"spinal"neurons"
"  Minimises"off`target"effects"from"
systemic"injec-on"
! Collabora-on"with"Stanford"
University"for"POC"studies"in"2013"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
23"
Oculopharyngeal Muscular Dystrophy
(OPMD)
! Gene-c"orphan"disease"with"6,000"cases"in"western"countries"
! Severe"swallowing"difficul-es,"oren"leading"to"choking"and"death"
! No"effec-ve"treatment"
! Cause:"a"muta-on"in"the"Poly(A)"Binding"Protein"Nuclear"1"gene"
(PABPN1)"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
24"
pAAV-H1-shRNA-G-spc512-eGFP 5’ITR
H1 sh-G spc512
Oculopharyngeal Muscular Dystrophy
pAAV-Tri-shRNA(short)
pAAV-Tri-shRNA(long)
(OPMD)
pAAV-U61-shRNA-Luc-spc512-eGFP
! Benitec"therapeu-c"will"silence"
abnormal"gene"and"provide"a"
replacement"gene"
"  ddRNAi"silences"abnormal"gene"
"  Engineered"replacement"gene"not"
silenced"
! Localized"delivery"by"injec-on"into"
the"affected"muscle"
! Collabora-on"with"leading"
academic"groups"provides"access"to"
large"numbers"of"OPMD"pa-ents"
"  Royal"Holloway"`"University"of"London,"
UK"
"  Ins-tut"de"Myologie,"France."
Copyright © Benitec Biopharma Ltd,
www.benitec.com
eGFP
5’ITR
U61 sh-A U69 sh-F H1 sh-G
5’ITR
U61 sh-A U69 sh-F H1 sh-G
5’ITR
U61 Sh-Luc spc512
eGFP
3’ITR
pA
3’ITR
3’ITR
Stuffer
pA
3’ITR
Figure 8: AAV vectors expressing various single, tricistronic or control shRNAs.
! The!constructs!effec;vely!silence!PABPN1!
Densitometer"scan"of"Western"Blot"analysis"
120
Image-J Densitometry Scan (% of control lane 1)
100
80
60
40
20
0
1Controls2
3
shRNA
4Tri-ShRNA
5 (short)6
7 Tri-shRNA
8 long 9
Figure 9: Western blot for PABPN1 in 293T cells following transfection with AAV plasmids expressing single
(BOPMD1), and short (BOPMD2) and long (BOPMD3) tricistronic shRNAs.
5
25"
Wet Age-related Macular Degeneration
(wet AMD)
! Leading"cause"of"vision"loss"in"elderly"
! Over"2"million"pa-ents"in"US"
"  $2"Bn"market"
! Current"treatments"stabilize"disease"but"require"
monthly"injec-ons"into"the"eye"
"  All"approved"drugs"target"Vascular"Endothelial"
Growth"Factor"A"(VEGF`A)"
! Benitec’s"therapeu-c"is"designed"to"provide"
years"of"silencing"of"VEGF`A"from"a"single"
intravitreal"injec-on""(same"route"of"
administra-on"as"current"standard"of"care)"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
26"
Wet Age-related Macular Degeneration
(wet AMD)
! shMiR"–"Next"Genera-on"Technology"
"  ddRNAi"in"miRNA"backbone;"shMiR"–"Next"genera-on"Benitec"technology"
"  Cell`specific"promoters"for"controlled"expression"
"  Modified"vehicle"engineered"for"eye"–""permits"delivery"of"shMiR"through"all"cell"
layers"of"re-na"from"an"intravitreal"injec-on"
! Good"efficacy"data"available"
! Follow"on"product:"Mul-`targeted"shMiR"intended"to"reverse"AMD"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
27"
Multi-pronged strategy for
revenue generation
Plahorm!and!knowShow!
!  Strong!patent!posi;on!and!unique!development!knowShow!in!ddRNAi!therapeu;cs!
"  A"con-nually"evolving"technology"platorm"applicable"to"numerous"diseases""
!  Discovery!collabora;ons!
"  Most"pharma’s"use"shRNA"vectors"for"target"
valida-on,"then"design"a"small"molecule"drug""
"  Benitec’s"know`how"provides"the"ability"to"
translate"the"shRNA"directly"into"a"drug"
!  Many!other!opportuni;es!in!miRNA!,!research!
tools,!etc.!
!  Internal!product!pipeline!
"  Selected"for"technology"fit,"target"valida-on"
status,"medical"need,"market"size,"etc."
!  Strategy!is!to!develop!with!partners!
"  Pre`clinical"(AMD,"Tubulin,"Pain,"OPMD)"
"  Arer"phase"I/II"(HCV,"HBV)"
"  Typically"will"retain"co`promote"op-on"
!  Near!and!long!term!revenue!
"  Upfronts","milestones"and"license"fees"
"  Royal-es"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
28"
Strong Management and Board
Management"
! CEO:!Peter!French,!PhD,!MBA,!MSc!
"  Fermiscan,"Cryosite,"Probiomics."Past"
President"Australia"Society"for"Cell"Biology""
! CSO:!Michael!Graham,!PhD!
"  Inventor"of"ddRNAi"technology"
"  CSIRO,"University"of"Queensland"
! CBO:!Carl!Stubbings,!BSc!
"  Panbio,"Quest"Diagnos-cs,"Focus"
Diagnos-cs"
! SVP!R&D:!David!Suhy,!PhD!
"  Tacere,"Avocel,"Antara"Biosciences,"PPD"
Discovery"
! CFO:!Greg!West,!CA!
Board"
Chairman:!!
! Peter!Francis,!LLB,!Grad!Dip.!
"  Partner"at"Francis"Abourizk"Lightowlers""
Directors:!!
! Mel!Bridges,!BAppSc,!FAICD!
"  Tissue"Therapies,"Alchemia,"Pacific"
Diagnos-cs,"PanBio"
! John!Chiplin,!PhD!
"  Arana,"ITI"Life"Science"Fund,""
! Ian!Ross,!BSC,!CH.D.!
"  Sandoz,"Fisons,"Roche,"Celltech,"Silence"
Therapeu-cs"
"  Price"Waterhouse,"Bankers"Trust,"
Deutsche"Bank,"NZI"
Copyright © Benitec Biopharma Ltd,
www.benitec.com
29"
Summary and upcoming events
Summary"
! Product`focused"biotech"
company"
! Unique"proprietary"long"term"
gene"silencing"platorm"–"new"
therapeu-c"modality"
! Lead"program"in"HCV"can"become"
a"game"changer"and"market"
leader"
! Strong"pipeline"that"leverages"
technology""
Copyright © Benitec Biopharma Ltd,
www.benitec.com
Upcoming"milestones"
! First`in`man"phase"I/IIa"trial"in"
Hepa--s"C"in"2013"
! Out`Iicensing"agreements"for"
other"disease"areas"
! Significant"milestones"reached"
by"current"licensees"
"  Calimmune"ddRNAi"HIV/AIDS"therapeu-c"
expected"to"enter"clinic"in"2013"
! Animal"model"data"for"pipeline"
therapeu-cs"
! Commercial"agreements"with"
pharmaceu-cal"partners"
30"