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Benitec Ltd
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Benitec’s ddRNAi Hepatitis B Opportunity
Non-Confidential Presentation
Benitec Ltd
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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.
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Table of Contents
ddRNAi Technology Investment Thesis 4
Benitec Corporate Overview 5
Overview of the ddRNAi Technology 7
Chronic Hepatitis B Market Overview 9
The ddRNAi Chronic HBV Infection Target 12
Preclinical Chronic HBV Infection Data 13
Chronic HBV Infection Product Development Plan 18
Additional ddRNAi Program – Hepatitis C 19
Investment Opportunity Summary 20
Contact Information 21
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ddRNAi Technology for HBV -
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 infectious disease areas include programs in chronic hepatitis infection, including hepatitis B.
Currently available treatments for chronic HBV infection are based on the continued administration of antiviral therapeutics and are prone to viral drug resistance, creating significant need for a product with a novel mechanism of action.
Functional gene silencing constructs targeting the HBV DNA polymerase gene have been created and a delivery vehicle is being developed based on the AAV8 vector. Preclinical studies are moving towards in vivo testing.
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.
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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
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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.
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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
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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.
Unlike current treatments for chronic HBV infection, this
product is long-lasting and has the potential to be
curative whilst causing only minimal side effects and
eliminate the risk of inducing viral drug resistance.
The ddRNAi product is delivered through a AAV-based
vector construct, which target the liver where it
transfects the infected hepatocytes.
ddRNAi Technology For Chronic Hepatitis
B Virus Infection Treatment
Utilizing the ddRNAi platform, Benitec is developing their gene silencing technology for the treatment of
chronic hepatitis B virus infection.
Benitec Technology
ddRNAi DNA construct
+
injection of AAV vector
containing ddRNAi DNA
construct
A ddRNAi Construct for Treating
Chronic HBV Infection The ddRNAi Platform Technology
Chronic HBV
infected liver
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Chronic Hepatitis B Market Overview
Despite the existence of a vaccine against the HBV, the prevalence rate in the population remains high. HBV
infection ranks second only to tobacco as a known human carcinogen.
2,000 million people alive today have been infected with
HBV at some time in their lives and of these about 350
million remain chronically infected and become
carriers of the virus.
In the USA alone there are over 1.25 million people living
with the consequences of chronic active HBV, and over
60,000 new cases per year.
Persons with chronic HBV infection have a 12-300 times
higher risk of developing hepatocellular carcinoma
than non-carriers and globally HBV causes 60-80% of
the world’s primary liver cancers.
Every year about 25% of the over 4 million acute clinical
cases (i.e. 1 million people worldwide) die from chronic
active hepatitis, cirrhosis or HBV-induced liver
cancer.
Approximately 1 in 3 people get
infected with HBV during their lifetime
Chronic HBV Infection Incidence and Prevalence Geographic distribution of
chronic HBV infection
Source: http://world-children.org/hepb/silentkiller_eng2.htm
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Current Treatments for
Chronic HBV Infection
The treatment of chronic HBV infection is based on the use of nucleoside/nucleotide analogues and
formulations of interferon.
There is no specific treatment for acute HBV infection.
Nucleoside/nucleotide analogs aim at disrupting the viral
replication cycle trough interaction with the HBV
polymerase.
Chronic use lead to the development of viral
resistance due to mutations in the catalytic region.
Administered Interferon acts as an immunoregulator by
boosting the natural immune response to viral infections
Interferon treatment is not associated with drug
resistance, but a variety of side effects may occur and
the treatment is dependents on the extent of liver
inflammation and disease
The effects of all existing therapies are transient and
require continued treatment.
Current FDA approved Drugs Nucleoside/nucleotide analogs • Lamivudine (Epivir) • Adefovir (Hepsera) • Telbivudine (Tyzeka) • Entecavir (Baraclude) • Tenofovir (Viread)
Interferons • peginterferon alfa-2a (Pegasys) • peginterferon alfa-2b (PegIntron)
Source: Business Insights: The Hepatitis Market Outlook to 2016
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Unmet Needs And Market Opportunity
in Chronic HBV Infection
A significant need exists for a therapy capable of a long term treatment of chronic HBV infection without the
risk of viral drug resistance and minimal side effects.
Unmet Needs in Chronic HBV Infection
Despite the existence of a vaccine, a sizeable population of chronically infected patients exists
(350 million), and is expected to persist for several generations.
Viral resistance as a result of chronic lamivudine therapy typically develops after 6 months of
treatment.
The treatment-failure population represents 40% of the total HBV infected population and is
expected to grow by 10% each year.
Current treatments do not meet the needs of patients with limited or disrupted access to the
therapeutic standards.
In geographic regions with high infection prevalence, prevention of re-infection of treated patients
becomes an issue.
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The ddRNAi Chronic HBV Infection Target
Benitec has identified the HBV RNA-dependent DNA polymerase as a unique target to address the unmet
need in chronic HBV infection treatment.
HBV polymerase gene
The hepatitis B virus is encoded by a compact genome encoding four open
reading frames; core, polymerase, surface and X protein.
The pregenomic mRNA serves for translation of the core-protein, the surface
antigen and the polymerase-reverse transcriptase, and also represents the
template of reverse transcription. Therefore, it makes an excellent target for
a gene silencing approach.
The mechanism of RNA-directed DNA synthesis has been well characterised
and plays a unique and essential role in the viral replication cycle.
Additional gene targets can be incorporated into the DNA construct to
allow for more efficient inhibition of viral replication.
– Additional targets unique to the HBV genome can be identified.
Hepatitis B Virus Genome Map
Source: http://www.abbottmolecular.com/products/infectious-diseases/realtime-pcr/hepatitis-hbv-assay.html
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ddRNAi Chronic HBV Infection Product
Preclinical Studies - Outline
Preclinical studies have been conducted by Biomics in collaboration with Benitec to determine the efficacy of
HBV DNA polymerase targeted ddRNAi on viral replication in chronic HBV infection.
Study Design
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ddRNAi Chronic HBV Infection Product
Preclinical Studies — Results to date
These preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieve
inhibition of viral replication.
Step 1: Large Scale Sequencing
Step 2: Target Screening by siRNA Expression
Cassettes (SECs)
5000 clones were sequenced and 642 non-repeat siRNA
targets ranging 19-32bp were obtained, randomly distributed
along the target gene.
The most effective siRNA sequences were identified through
transfection of HepG2 2.2.15 cells with siRNA expression cassettes.
Functional siRNA sequences were identified in optimized
transfection conditions.
Transfection efficiency in optimal conditions is >70%
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ddRNAi Chronic HBV Infection Product
Preclinical Studies — Results to date
Step 3: Large Scale Screening using SECs
Step 4: Activity Validation With Chemically
Synthesized siRNA
100 siRNA sequences were identified produced that produced
>50% HBV mRNA knock down, 14 of which resulted in >70%
knock down.
The activity of selected sequences was validated through
quadruplicate independent transductions with chemically
synthesized siRNA. Five candidate siRNAs were selected as the
basis for gene construct design.
These preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieve
inhibition of viral replication.
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ddRNAi Chronic HBV Infection Product
Preclinical Studies — Results to date
Step 5: Construct Development And Expression
Optimization
shRNA constructs were developed based on the candidate
siRNAs and optimized for expression in hepatocytes.
Step 6: Delivery Vehicle Design – In Progress
shRNA constructs are packaged into delivery vehicles based
on the AAV 8 vector specifically targeting hepatocytes, to be
administered by i.v. injection
These preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieve
inhibition of viral replication.
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ddRNAi Chronic HBV Infection Product
Preclinical Studies — Future steps
In vivo Testing of Construct and Delivery Vehicle
Undertake Toxicology and Biodistribution Studies
These preclinical studies demonstrate the potential of HBV DNA polymerase-targeted ddRNAi to achieve
inhibition of viral replication.
HBV transgenic mice as animal model:
• Stable HBV particles in serum
• High expression of HBsAg、HBcAg etc. in serum and hepatocyte
• Luciferase assay （in-vivo bioluminescence imaging）
• siRNA toxicity:
monitor IF effects: detection of expression
of interferon response genes
• Gene toxicity: microarray analysis
• Peak expression time and dose optimization
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Development Plan and Timeline for
HBV ddRNAi Program
HBV ddRNAi Programs Clinical Development Timeline
Program 2011 2012 2013 2014 2015
Hepatitis B
Target Sequence Efficacy
Design vector-expressed constructs
Preclinical testing (in vitro and in vivo models)
In vivo Toxicology
Phase I Clinical Trial
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Additional ddRNAi Hepatitis 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
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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
Curative Aspect
Long Term Effect of Treatment and
Prevention of Re-infection
Unmet Medical Need Large, Unmet Need for Treatment of Chronic HBV Infection
Large Market Opportunity High Revenue Potential in Chronic Infected and
Treatment-failed Population
Potential for Accelerated Timeline Through Leverage of Experience Gained in
the Hepatitis C Program
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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]