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An overview of the Benitec Non Small Cell Lung Cancer program.
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Benitec Ltd www.benitec.com
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Benitec’s ddRNAi Non Small Cell Lung Cancer Opportunity
Non-Confidential Presentation
Benitec Ltd www.benitec.com
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This presentation contains forward looking statements that involve risks and uncertainties. Although we 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 results could differ materially from those anticipated. Reasons may include risks associated with drug development and manufacture, risks inherent in the regulatory processes, delays in clinical trials, risks associated with patent protection, future capital needs or other general risks or factors.
Benitec Ltd www.benitec.com
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 www.benitec.com
4
ddRNAi Technology 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 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 www.benitec.com
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 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 transformational, proprietary ddRNAi platform technology for human therapeutics and research.
Benitec has a strong management team with deep scientific and clinical resources and extensive experience with the commercialization of biological intellectual property.
Benitec is currently utilising ddRNAi technology internally across multiple therapeutic areas where there is a significant unmet need to develop ddRNAi-based therapeutic products for a range of conditions including lung cancer, neuropathic pain, and infectious disease (hepatitis B and hepatitis C).
Business Overview
Business Strategy
Management Team
Product Strategy
Benitec has a robust patent portfolio protecting their platform technology across the major pharmaceutical markets with patent coverage extending through 2027. Intellectual Property
Benitec Ltd www.benitec.com
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Benitec Senior Leadership Team
CEO Peter French, PhD
Cell and molecular biologist with an MBA in Technology Management. Founder of stem cell
storage company Cryosite Ltd, launched six new probiotic-based products with Probiomics.
CFO, Company Secretary Greg West
Chartered Accountant, Director and audit committee chairman of ITC Ltd, IDP
Education Pty Ltd, Education Australia Ltd, and Sydney International Film School Pty Ltd.
Board of Directors
Peter Francis LLB Grad Dip (Intellectual Property) Non-
executive Chairman Partner at Francis Abourizk Lightowlers (FAL), a legal specialist in the areas of
intellectual property and licensing and provides legal advice to a
large number of corporations and research bodies.
Mel Bridges BAppSc FAICD Non-executive Director
More than 30 years experience in the global biotechnology and healthcare industry. During this
period, he founded and managed successful
diagnostics, biotechnology and medical device businesses.
John Chiplin PhD Non-executive Director
His most recent accomplishment was the corporate reengineering of Arana Therapeutics, a world
leading Antibody developer, which resulted in the acquisition of the company by Cephalon for a significant premium to market.
Iain Ross BSc ChD Non-executive Director
Over 30 years experience in the international life sciences sector. Following a career with Sandoz, Fisons, Hoffman La Roche, and Celltech he has undertaken and
had input to a number of company turnarounds and start�
ups
Benitec’s management team has demonstrated experience and expertise in developing and licensing novel therapeutic technology.
Benitec Ltd www.benitec.com
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Benitec’s Novel RNA Interference Technology
ddRNAi&Mechanism&of&Ac1on&Benitec&technology&ddRNAi"DNA"construct"
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’s ddRNAi technology platform utilizes a self-inactivating lentiviral vector to express shRNA molecules which silence a targeted gene of interest.
! The ddRNAi-based product consists of a third-generation 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.
ddRNAi Mechanism of Action
Benitec Ltd www.benitec.com
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! Benitec’s novel ddRNAi technology allows for long-term gene silencing.
! The technology can be targeted to silence a specific gene or multiple selected genes.
! 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 transfection agent jetPEITM, a cationic DNA binding polymer which prefers to target lung tissue.
ddRNAi Technology for Non-Small Cell Lung Cancer Treatment
Utilizing the ddRNAi platform, Benitec is developing their gene silencing technology for the treatment of non-small cell lung cancer (NSCLC).
Benitec Technology ddRNAi DNA construct
+"injection of jetPEITM - ddRNAi DNA vector construct
A ddRNAi Construct for Treating Non-Small Cell Lung Cancer The ddRNAi Platform Technology
Non-Small Cell Lung Cancer tissue
Benitec Ltd www.benitec.com
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Non-Small Cell Lung Cancer Market Overview
Lung carcinoma is the leading cause of cancer-related death worldwide and has been identified as a major health issue confronting both developed and developing countries.
! 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 in the seven major markets in 2009.
Non-Small Cell Lung Cancer Incidence and Prevalence Worldwide incidence of Lung Cancer
Source:"hFp://globocan.iarc.fr/"
New"cases"per"100.000"people"per"annum"
Benitec Ltd www.benitec.com
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Current Treatments for Non-Small Cell Lung Cancer
The standard of care in patients with advanced non-small cell lung cancer is based on platinum-based doublet chemotherapy regimens.
! The treatment of lung cancer depends on several factors, such as discovery stage and form of the cancer, and the age and general medical state of the patient.
! Typical treatment involves some combination of surgery, chemotherapy and radiation therapy.
! Chemotherapy regimens are based on the therapy combining (platinum based) DNA damaging agents and tubulin binding agents, inhibiting cellular replication and inducing apoptosis.
! Chemotherapy is associated with a wide range of side effects with varying degree of severity, and the efficacy remains limited due to high incidence of dose limiting toxicity and emergence of drug resistance cell lines.
! Despite advances in treatment, the prognosis of NSCLC remains poor with only 15% of patients surviving 5 years from the time of diagnose.
Source:"Business"Insights:"The"Cancer"Market"Outlook"to"2016"
23
Diagnosis, treatment, and management
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 and
the extent of metastasis. The most common symptoms of local-regional cancer include coughing, dyspnea,
hemoptysis, wheezing, chest pain, and pneumonia. Figure 1 illustrates the treatment of lung cancer
according to the growth stage.
Figure 1: Treatment of lung cancer by stage
Stage Primary treatment Adjuvant therapyFive-year survival rate (%)
I Resection Chemotherapy 60 to 70
IIA ResectionChemotherapy with or without radiation therapy
40 to 50
IIIA (resectable) Resection with or without preoperative chemotherapy
Chemotherapy with or without radiation therapy
15 to 30
IIIA (unresectable) or IIIB (involvement of contralateral lymph nodes)
Chemotherapy with concurrent or subsequent radiotherapay
None 10 to 20
IIIB (pleural effusion) or IVChemotherapy or resection of primary brain metastasis and primary T1 tumor
None 10 to 15 (two year survival)
Limited disease Chemotherapy with concurrent radiotherapy
None 15 to 25
Extensive disease Chemotherapy None < 5
Non-small-cell lung cancer (NSCLC)
Small-cell lung cancer (SCLC)
Source: Spira and Ettinger, 2004 BUSINESS INSIGHTS
Treatment of Lung Cancer by Stage
Benitec Ltd www.benitec.com
11
Unmet Needs And Market Opportunity in Non-Small Cell Lung Cancer
A significant need exists for a therapy capable of restoring and/or improving the effect of therapeutic drugs in resistant 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 www.benitec.com
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The NSCLC Drug Resistance Target
The upregulation of βIII-tubulin gene expression is associated with clinical drug resistance and aggressive disease in non-small cell lung cancer.
βIII-tubulin gene
! βIII-tubulin is a structural component of microtubules, which are multifunctional cytoskeletal proteins involved in many essential cellular roles.
! βIII-tubulin is the target of chemotherapeutic tubulin binding agent, a drug class which lies at the basis of cancer treatment standards.
! An increased expression of βIII-tubulin results in drug resistance and is further associated with poorly differentiated tumour tissue, high-grade malignancy and metastatic potential, playing a broad role in NSCLC development.
! Inhibition of βIII-tubulin expression has been shown to restore sensitivity to drug-induced apoptosis in tumour cells.
Source:"Seve$et$al.$Mol$Cancer$Ther$2005$
low$βIII'tubulin$
low$βIII'tubulin$
high$βIII'tubulin$
high$βIII'tubulin$
Overall$survival$$
Progression'free$survival$$
Benitec Ltd www.benitec.com
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ddRNAi NSCLC Product Preclinical Studies - Outline
Preclinical studies have been conducted by the UNSW in collaboration with Benitec to determine the efficacy of βIII-tubulin targeted ddRNAi in negating drug resistance in NSCLC cells.
Study Design
Benitec Ltd www.benitec.com
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ddRNAi NSCLC Product Preclinical Studies — Results to date
These preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity to drug induced apoptosis in resistant tumour cells.
Step 1: Design of siRNA encoding multi-cassette
Step 2: Generation of βIII-tubulin Expressing Cells
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.
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 www.benitec.com
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ddRNAi NSCLC Product Preclinical Studies — Results to date
Step 3: Demonstration of Efficacy in vitro
Step 4: Assessment of Off-target and Immunomodulatory Effects in vivo
The efficacy of the expression of the ddRNAi construct in the transfected cell line was confirmed through a series of in vitro tests: - protein expression (100% silencing)
- gene expression (95-100% silencing)
- drug sensitivity assessment (Cisplatin and Taxane)
- apoptosis assays
In vivo studies were undertaken to determine the effects of ddRNAi treatment on systemic toxicity and the potential of undesired immunogenicity:
- assessment of JetPEI (+/- constructs) on toxicity and immunogenicity
- assessment of effects on neurons
These preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity to drug induced apoptosis in resistant tumour cells.
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20
40
60
80
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pS5
CISPLATINβIII knockdown - clonogenic data
log [ µM CISPLATIN ]
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Taxol βIII knockdown - clonegenic assay
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20
40
60
80
100
log[nM Taxol]
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TRP2control vector
pS5 target βIII tubulin
COMMERCIAL-IN-CONFIDENCE
Discussion Document: Benitec-Mesoblast Collaboration 07072011 20
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CISPLATIN!III knockdown - clonogenic data
log [ µM CISPLATIN ]
% s
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Taxol !III knockdown - clonegenic assay
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20
40
60
80
100
log[nM Taxol]
% s
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pS5 target !III tubulin
Fig 3.1. Data from Benitec’s NSCLC program. A multipromoter multicassette construct was designed in which three shRNAs targeting different regions on the beta III tubulin gene were produced and transduced into human NSCLC cells in vitro using JetPEI. The very high degree of protein and mRNA silencing was associated with a significant increase in the sensitivity of the cancer cells to chemotherapy agents.
4. Assessment of off-target and immunomodulatory effects in vivo a. Assessment of JetPEI (+/- constructs) on toxicity and immunogenicity b. Assessment of effects on neurons
5. Assessment of efficacy of β-III tubulin knock down in vivo (3 months) a. Assessment of tumour targeting of jetPEI-DNA construct complexes in vivo. b. Efficacy of JetPEI-shRNA constructs to silence βIII-tubulin in orthotopic lung
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.
!"!#$%&'(()! *"!#$%&'(()! +"!#$%&'(()!
Fig 3.2. Nude mice bearing human NSCLC tumours following inoculation with varying numbers of luciferase-expressing tumour cells. Tumours were visualised by a Xenogen imaging instrument
a b
c d
0"
20"
40"
60"
80"
100"
H460")luc"
RS"mix" pS5" pS6"
%"Knockdown"of"βIII"tubulin"mRNA"
In vitro expression tests
In vitro drug sensitivity assessment
Benitec Ltd www.benitec.com
16
0
200
400
600
800
1000
1 2 3 4 5 6 70
200
400
600
800
1 2 3 4 5 6 7
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Time (weeks) Post-Inoculation
Inhibition of βIII-tubulin increases sensitivity to cisplatin in NSCLC xenografts
ddRNAi NSCLC Product Preclinical Studies — Results to date
Step 5: Assessment of Efficacy in vivo
The therapeutic efficacy of the ddRNAi construct was confirmed through a series of in vivo preclinical tests:
- Assessment of tumour targeting of jetPEI-DNA construct complexes in vivo.
- Efficacy of JetPEI-shRNA constructs to silence βIII-tubulin in orthotopic lung tumors.
- Assessment of increased drug sensitivity of βIII- tubulin knock down in vivo.
These preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity to drug induced apoptosis in resistant tumour cells.
Control shRNA vs βIII shRNA 4
0 10 20 30 40 500
20
40
60
80
100Control shRNA (PBS)
Control shRNA (CDDP)
βIII shRNA 4 (PBS)
βIII shRNA 4 (CDDP)
Time Days to Reach 1000mm3
Pe
rce
nt
su
rviv
al
Cont shRNA vehicle Cont shRNA cisplatin βIII shRNA 4 vehicle βIII shRNA 4 cisplatin
βIII-tubulin Inhibition reduces the incidence and progression of NSCLC tumours
Control shRNA βIII shRNA
Benitec Ltd www.benitec.com
17
ddRNAi NSCLC Product Preclinical Studies — Future steps
Toxicology and Biodistribution Studies – In Progress
Preparation For IND
These preclinical studies demonstrate the potential of βIII-tubulin targeted ddRNAi to restore sensitivity to drug induced apoptosis in resistant tumour cells.
Further preclinical studies are undertaken to determine the the toxicological effects and biodistribution characteristics of in vivo treatment.
COMMERCIAL-IN-CONFIDENCE
Discussion Document: Benitec-Mesoblast Collaboration 07072011 20
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20
40
60
80
100H460
pS5
CISPLATIN!III knockdown - clonogenic data
log [ µM CISPLATIN ]
% s
urvi
val
Taxol !III knockdown - clonegenic assay
-1.0 -0.5 0.0 0.5 1.00
20
40
60
80
100
log[nM Taxol]
% s
urv
ival
TRP2control vector
pS5 target !III tubulin
Fig 3.1. Data from Benitec’s NSCLC program. A multipromoter multicassette construct was designed in which three shRNAs targeting different regions on the beta III tubulin gene were produced and transduced into human NSCLC cells in vitro using JetPEI. The very high degree of protein and mRNA silencing was associated with a significant increase in the sensitivity of the cancer cells to chemotherapy agents.
4. Assessment of off-target and immunomodulatory effects in vivo a. Assessment of JetPEI (+/- constructs) on toxicity and immunogenicity b. Assessment of effects on neurons
5. Assessment of efficacy of β-III tubulin knock down in vivo (3 months) a. Assessment of tumour targeting of jetPEI-DNA construct complexes in vivo. b. Efficacy of JetPEI-shRNA constructs to silence βIII-tubulin in orthotopic lung
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.
!"!#$%&'(()! *"!#$%&'(()! +"!#$%&'(()!
Fig 3.2. Nude mice bearing human NSCLC tumours following inoculation with varying numbers of luciferase-expressing tumour cells. Tumours were visualised by a Xenogen imaging instrument
a b
c d
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 www.benitec.com
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Development Plan and Timeline for NSCLC ddRNAi Program
NSCLC&ddRNAi&Programs&Clinical&Development&Timeline&
Program& 2011& 2012& 2013& 2014&
NSCLC&
Animal"model"(lung)"
In"vivo"Toxicology""
Phase"I"Clinical"Trial"
IND&Prepara1on&
and&Submission&
Benitec Ltd www.benitec.com
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Investment Opportunity Summary
&
ddRNAi&Product&Asset&Summary&
Extensive&IP&Estate"Patent$Coverage$Through$2027$
Favorable&KOL&Response"Likely$for$the$Unique$MOA$
Favorable&preclinical&data&
From$Extensive$in$vitro$and$in$vivo$Studies$
Unmet&Medical&Need"Large,$Unmet$Need$for$Treatment$of$
NonISmall$Cell$Lung$Cancer$
Large&Market&Opportunity"High$Revenue$PotenLal$in$Treatment$Of$$
NonISmall$Cell$Lung$Cancer$
Novel&Approach"To$Overcome$Clinical$Drug$Resistance$$
Benitec Ltd www.benitec.com
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Contact Information
To 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:"[email protected]"
&