benitec company overview
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Benitec Ltd
www.benitec.com
1
Benitec’s Gene Silencing Platform Technology – An overview
Non-Confidential Presentation
Benitec Ltd
www.benitec.com
2
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
RNA Interference Background 9
Introduction to the ddRNAi Technology 10
Current ddRNAi Programs 13
Benitec Intellectual Property Portfolio 19
Investment Opportunity Summary 23
Contact Information 24
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 and relief of cancer-associated neuropathic pain.
Benitec’s infectious disease areas include programs in chronic hepatitis infection, including hepatitis B and C.
Functional gene silencing constructs for all of the programs have been created. Preclinical in vivo studies proving the safety and efficacy of the products are in progress.
Benitec’s technology platform is applicable to a large number of other therapeutic areas In which up-regulation of a gene is associated with a disease or disorder, including genetic diseases.
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
6
Benitec Corporate Strategy
to Build Value
ddRNAi Technology
Human Therapeutics Research Tools
Partner Individual Therapeutics
Develop the ddRNAi therapeutic product
pipeline in-house through pre-clinical
and early stage clinical studies, and
potentially partner products for late-
stage development and
commercialization
Partner Therapeutic Platform
Partner the technology platform for a
wide range of therapeutics in the near
term for development and
commercialization
Partner Technology For Research
License the ddRNAi platform
technology as a research tool to
research institutions, pharmaceutical
and biotech companies
Benitec has a value-building strategy based on to partnering its proprietary ddRNAi technology with
pharmaceutical and biotechnology companies both as research tools and as potential therapeutics.
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
8
Indication Discovery Pre- clinical Human Clinical
Collaborator/ Licensee
Collaboration Status
Cancer-associated pain
University of Queensland (Australia)
Benitec has contracted with TetraQ to generate data to be able to conduct a clinical trial on terminally ill cancer patients suffering from pain.
Drug resistant lung cancer
University of New South Wales (Australia)
Researchers are collaborating with Benitec to develop a ddRNAi-based therapy to overcome chemotherapy resistance in non-small cell lung cancer.
Hepatitis B Biomics (China) Benitec is working with Biomics to develop ddRNAi candidates for hepatitis B silencing for preclinical testing and a China-based clinical trial.
Hepatitis C Tacere (Pfizer)
(US)
Benitec’s preclinical hepatitis C program was outlicenced to Tacere in 2006, and then outlicensed by Tacere to Pfizer in 2008. In 2010, Pfizer exercised an option to further develop and commercialize Tacere’s Hepatitis C compounds as a result of favorable primate and mouse efficacy and toxicity studies. The companies observed no maximum tolerated dose, no safety signals, viral inhibition and >90% penetration of human hepatocytes.
Licensed program
Benitec has a pipeline of ddRNAi-based therapeutics targeted for indications where their technology provides
a significant competitive advantage.
Benitec funded programs Partnered program
ddRNAi Product
Development Timeline
Benitec Ltd
www.benitec.com
9
RNAi Mechanism
RNA Interference
Technology Background
RNAi is a technology which silences targeted genes through a natural mechanism, the discovery of which
earned Andrew Fire and Craig Mello the Nobel Prize in Physiology and Medicine in 2006.
Sources: Datamonitor. RNA Therapy. October 2008; Business Insights. The Future of RNAi Therapeutics. August 2008.
Source: The Nobel Prize in Physiology or Medicine 2006. Nobelprize.org. Accessed October 2011.
Technology Background
RNA therapies can be divided into RNAi therapies, which are
mediated by the RISC enzyme, and antisense therapies,
which are RISC-independent agents.
Antisense oligonucleotides were initially used primarily as an
in vitro research tool but have been developed as a means of
modifying RNA levels in human therapeutic applications.
RNAi was subsequently found to offer up to 1000 x more
efficient silencing than antisense agents.
Modern RNAi therapeutic approaches utilize short, chemically
synthesized RNA duplexes that mimic natural products.
The RNAi mechanism allows protein function to be modulated
by controlling the translation of mRNA.
Gene
Therapy
RNA
Therapy
Small Molecules
mAbs
DNA RNA Protein
Modulating
Agent:
Target:
The Dicer endonuclease cuts
double stranded RNA into
short pieces (siRNA)
The antisense strand is
loaded into the RNA-induced
silencing complex (RISC) and
links the complex to the
mRNA strand by base pairing
The RISC complex cuts the
mRNA strand and the mRNA
is subsequently degraded
Benitec Ltd
www.benitec.com
10
Benitec’s Novel
RNA Interference Technology
ddRNAi Mechanism of Action Benitec technology
ddRNAi DNA construct
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’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
11
Differences between ddRNAi
and Conventional siRNA
While siRNA has demonstrated considerable limitations for clinical use, ddRNAi has the potential to
overcome many of the delivery obstacles previously faced by siRNA.
Source: Datamonitor. Gene Therapy. December 2009.
Differences Between ddRNAi and siRNA
Property ddRNAi siRNA Description
Origin Double stranded RNA for siRNA must be manufactured, while in ddRNAi, the
shRNA is continuously expressed by the host cell.
Potency ddRNAi-generated shRNA is up to 250x more potent than siRNA and thus requires
less material to silence a gene.
Off-Target Effects
Off-target effects are common and problematic with siRNA. ddRNAi results in minimal off-target effects due to its expression being restricted to the transfected cell type.
Delivery
ddRNAi is capable of utilising a range of established delivery options including viral, non-viral and stem cell vectors, while siRNA must be modified for systemic or targeted delivery.
Duration of Action Unlike siRNA, which is capable of only short-term silencing, ddRNAi has a variable
duration of action including the potential for long-term silencing.
Targeting Options Multiple targets can be targeted with a single DNA construct using ddRNAi, while
only a single target can be targeted with each siRNA.
Cost Production of the shRNA DNA construct and delivery system is low cost, while
siRNA requires expensive custom synthesis Positive Attribute
Neutral Negative Attribute
Benitec Ltd
www.benitec.com
12
Proof of Concept Study for ddRNAi
in AIDS Lymphoma Patients (Phase I)
The advantages of the ddRNAi technology were demonstrated in a pilot study (phase I clinical trial) to assess
the safety and feasibility of using a lentiviral RNA vector encoding multiple targets in stem cells of AIDS
lymphoma patients.
Results of the AIDS Lymphoma Study
ddRNAi therapy is safe and feasible.
The therapy is long-lasting (at least two years) from a single treatment.
Patients are able to rebuild a new and resistant immune system following treatment.
Lentiviral-mediated
transduction of CD34
Pool and infuse
Patient follow-up
Healthy HIV positive
or chemo-responsive
AIDS lymphoma
GCSF
Stem-cell enrichment Apheresis
CD34+ PBPC
Study Design
GCSF – Granulocyte colony-stimulating factor
PBPC – Peripheral blood progenitor cell
Benitec Ltd
www.benitec.com
13
Preclinical in vivo studies have been conducted
successfully showing the efficacy of PKCγ-targeted
ddRNAi on pain inhibition.
Current ddRNAi Programs:
Cancer Pain Product
Utilizing the ddRNAi platform, Benitec has developed their gene silencing technology for the treatment of pain
in terminal cancer patients.
Rationale:
PKCγ has been shown to play a major role in the
transmission of neuropathic pain and in overcoming
tolerance to morphine.
The restricted spinal cord location of the PKCγ-
containing interneurons allows a selective inhibitor to
inhibit nerve injury-induced neuropathic pain.
KOLs see strong potential for the ddRNAi cancer pain
product to be used in terminal patients suffering from all
types of cancer.
Market Size:
There are approximately 11.7 million people in the US
with cancer. Approximately 65% of all cancer
patients experience pain.
The cancer pain ddRNAi product may be used in up to
65% of cancer patients receiving invasive pain therapy.
Cancer Pain
Collaborator:
Status:
Benitec has planned a phase I/II study of the ddRNAi-
based product in terminal cancer patients with intractable
pain and a quick timeline to approval is expected.
Benitec Ltd
www.benitec.com
14
Of 5000 potential sequences, 14 RNA sequences
have been identified by Biomics that provide ≥70%
knockdown of HBV gene mRNA.
Current ddRNAi Programs:
Hepatitis B
The ddRNAi technology is also being developed for HBV under collaboration with Biomics.
Rationale:
Successful ddRNAi delivery to the liver has been
demonstrated.
The targeted enzyme is key to HBV replication.
The strategy provides treatment of the existing infection
and long-lasting protection from re-infection.
Market Size:
There are about 400 million people worldwide with
chronic HBV infection.
Carriers of HBV are up to 300 times more likely to
develop liver cancer than non-carriers, and HBV causes
60-80% of the world’s primary liver cancers.
Hepatitis B Virus
Collaborator:
Status:
Benitec is working with Biomics to evaluate RNAi
candidates for hepatitis B silencing for preclinical testing
and a China-based clinical trial.
Benitec Ltd
www.benitec.com
15
Current ddRNAi Programs:
Hepatitis C
Benitec has sub-licensed its technology platform to Tacere to develop a ddRNAi-based therapeutic targeting
the Hepatitis C viral genome.
Hepatitis C Virus
Rationale:
Successful ddRNAi delivery to the liver has been
demonstrated.
The strategy provides treatment of the existing infection
and long-lasting protection from re-infection.
Multi-target construct (three sequences) to prevent viral
escape in a single drug “cocktail”
Market Size:
Over 170 million people worldwide, are chronically
infected with HCV, with 3-4 million new infections
occurring each year.
Licensed to Tacere Therapeutics Inc. - USD$143M deal
with Pfizer Inc. Benitec has an equity stake in Tacere.
Collaborator:
Status:
Pfizer have closed the Sandwich facility,
uncertain status of program
Tacere have demonstrated both efficacy and safety
with their AAV8-delivered ddRNAi-based therapeutic
in non-human primates
Benitec Ltd
www.benitec.com
16
Development Plan and Timeline for
Current ddRNAi Programs
Current ddRNAi Programs Clinical Development Timeline
Program 2011 2012 2013 2014 2015
Hepatitis B
Cancer Pain
Additional clinical studies to be planned in both HepatitisB and Cancer Pain
Proof of concept in pre-clinical model of pain
Toxicology studies
IND Preparation and Submission
Phase I/II Trial (cancer patients with intractable pain)
Target Sequence Efficacy
Design vector-expressed constructs
Preclinical testing (in vitro and in vivo models)
Benitec Ltd
www.benitec.com
17
Current ddRNAi Programs:
Drug Resistant NSCLC
Benitec is collaborating with University of New South Wales researchers to develop a ddRNAi-based
therapeutic targeting a gene associated with chemotherapy resistance.
Non-small Cell Lung Cancer (NSCLC)
Rationale:
βIII-tubulin has been shown to be associated with drug
resistance in non-small cell lung cancer (NSCLC).
Silencing βIII-tubulin using ddRNAi increases the killing
of NSCLC cells by chemotherapy agents.
Market Size:
Lung cancer is the leading form of cancer worldwide in
terms of incidence and mortality.
NSCLC account for >80% of all lung cancers and has a
high mortality rate due to rapid development of
resistance to chemotherapy drugs.
Collaborator:
Status:
Researchers are using Benitec’s technology to develop a
ddRNAi-based therapy to overcome chemotherapy
resistance in NSCLC cells.
In vitro results show highly effective silencing of
βIII-tubulin and effective targeting of NSCLC cells
with the ddRNAi construct.
Benitec Ltd
www.benitec.com
18
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 Preparation and Submission
Benitec Ltd
www.benitec.com
19
Benitec Intellectual Property
Portfolio
Benitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets with
coverage through 2027 with additional exclusivity anticipated for biologic upon launch.
Graham&family&patents'!
"revocable)license)from)CSIRO!for$the$human$field)!
Patent&Number Description! !Jurisdiction
Genetic'constructs'for'delaying'or'repressing'the'expression'of'a'target&gene
Sense strand
Hair pin
Complementary strand
A family of patents that covers Benitec’s gene silencing platform technology in
expressed RNA interference.
Generally the patents cover a double stranded DNA construct which comprises:
• one or more sequences directed to one or more targets
• sequences of around 20 to 30 nucleotides in length
• sequences substantially identical or identical to the target gene sequence
• target is either exogenous or endogenous genes
• in mammalian cells, preferably human
Widely!granted!in!countries!including!Australia,!
South!Africa,!New!Zealand,!UK,!Canada,!India,!Japan,!Europe,!USA!
!
Expiry!from!June!2018!
Benitec Ltd
www.benitec.com
20
Benitec Intellectual Property
Portfolio
Benitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets with
coverage through 2027 with additional exclusivity anticipated for biologic upon launch.
Waterhouse!family'patents'!
xclusive)worldwide!license'from'CSIRO'for'the'human'field)!
Patent&Number Description! Jurisdiction!
CN#200910206175.7#
#
Methods(And(Means(For(Obtaining(Modified(Phenotypes
Sense strand
Hair pin
Complementary strand
This patent covers a cell that contains either a double stranded DNA construct for
expressing a hairpin RNA, or a hairpin RNA itself. The hairpin comprises:
• Sense and anti-sense sequences of at least 20 nucleotides in length
• sense sequence is sequence of target
• antisense sequence is 100% identical to complement of sense sequence
China!
!
Expiry!from!June!2018!
EP#1068311#
The patent covers an RNA molecule that comprises
· a sense sequence and an anti-sense sequence of at least ten consecutive
nucleotides
· 75% to 100% sequence identity to a target sequence
· in a hairpin RNA structure
Europe!
Benitec Ltd
www.benitec.com
21
Benitec Intellectual Property
Portfolio
Benitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets with
coverage through 2027 with additional exclusivity anticipated for biologic upon launch.
Benitec!Owned&Patents!
Patent&Number! Description! Jurisdiction!
US7,727,970;!JP4763681;!!!!!!!!!!!!!!!!!!!
EP05727680.0;!!!!!!!!!!!!!!AU2005222084;!NZ550284!
AU2006210443;!US11/883645;!US7,803,611;!NZ560936!
Expression*cassettes*for*delivery*of*ddRNAi*agents*targeting(hepatitis(C(Virus#
Two patent families covering the use of ddRNAi expressing multiple shRNAs from either single or multiple promoters, targeting sequences on the hepatitis C viral genome
!
USA,!Europe,!Australia,!Japan,!New!Zealand!
Expiry:!2025L2027!
US8,008,468;!US11/731198!
Liver(cell(specific(RNAi(expression(constructs(
Patents that cover the use of a ddRNAi expression construct which has liver specific promoter
and enhancer components to complement Benitec’s hepatitis programs US!
AU2004243347;!NZ543815;!
ZA2005/09813;!!!!SG200507474L5!
A"long"double>stranded(nucleic(acid#construct#
Patents that cover the use of a long double stranded DNA construct expressing multiple double
stranded RNA silencing molecules, each 17 to 30 nucleotides in length.
Australia,!New!Zealand,!Singapore,!South!Africa!
Expiry:!2024!
GB!2377221;!SG91678;!
ZA2002/07428!
Genetic'silencing(
A genetic construct, that reduces the translation of a target endogenous gene, comprising a
sequence of nucleotides substantially identical to a sequence of the target gene and a nucleotide sequence complementary or substantially complementary to the target gene
sequence wherein the nucleotide sequences identical and complementary to said target endogenous nucleotide sequence are separated by a spacer sequence.!
Great!Britain,!Singapore,!South!Africa!
Benitec Ltd
www.benitec.com
22
Benitec Intellectual Property
Portfolio
Benitec has an extensive patent estate for the ddRNAi product that spans key pharmaceutical markets with
coverage through 2027 with additional exclusivity anticipated for biologic upon launch.
Benitec Ltd
www.benitec.com
23
Investment Opportunity Summary
ddRNAi Product Asset Summary
Extensive IP Estate Patent Coverage Through 2027
Favorable KOL Responses
Favorable preclinical data
From Extensive in vitro and in vivo Studies
Unmet Medical Need ddRNAi can treat undrugable targets
Large Market Opportunities Non-Small Cell Lung Cancer, Pain, Hepatitis
and a plethora of other opportunities
Novel Approach Novel class of therapeutics for treatment and cure
Benitec Ltd
www.benitec.com
24
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: pfrench@benitec.com
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