Below are details of our in-house programs that target life-threatening and chronic diseases and conditions, that are gene-associated.
Benitec is developing a ground-breaking ‘single dose cure’ for Hepatitis C.
Market
Hepatitis C virus (HCV) infects over 170 million people worldwide, and is the main cause of cirrhosis and hepatocellular carcinoma, often requiring liver transplant. There are 7 HCV genotypes, yet genotype 1 accounts for 75% of cases. The virus persists in the liver of 85% of those infected and, prior to July 2011, the Standard of Care (SoC) for genotype 1 was pegylated-interferon (PEG-interferon) and ribavirin administered over 48 weeks. The SoC had a cure rate of 50-55% yet was associated with significant side effects including hematological, flu-like symptoms, and cognitive impairment.
Since July 2011, cure rates of up to 75% have been achieved by combining Specifically Targeted Antiviral Therapy (STAT-C) with PEG-interferon and ribavirin, also administered over long periods. However, a significant percentage of patients has either withdrawn due to side effects or not responded.
Rationale
With its subsidiary, Tacere Therapeutics, Benitec has designed a ddRNAi –based multi-cassette vector called TT-034, which targets 3 parts of the HCV genome in a single intravenous dose. TT-034 has achieved over 90% transfection of liver cells and, by targeting 3 separate, well-conserved regions of HCV simultaneously, it prevents generation of drug-resistant mutants, a major problem in the treatment of Hepatitis C. The targeted regions of HCV are also conserved across all genotypes, so TT-034 has likely application to all HCV-caused conditions.
The figure above illustrates the composition of TT-034 with dotted arrows pointing to the regions of the Hepatitis C virus genome that are targeted by the drug.
Status
Benitec is moving TT-034 into the clinic in 2013 via these steps:
Benitec is developing a breakthrough, single treatment to overcome currently untreatable and intractable chronic pain.
Market
Pain is one of the most common symptoms of cancer, with chronic neuropathic pain suffered by 65% of all cancer patients and 80% of those in the terminal phases. As neuropathic and chronic pain is resistant to conventional opioid therapies, pain is both under-treated in cancer patients and increasing.
The development of novel treatments for this class of pain, characterized by central sensitization, is a significant unmet medical need, and one that Benitec’s ddRNAi shRNA technology is uniquely positioned to fulfill.
Rationale
Benitec is designing ddRNAi therapeutics to target a specific gene that encodes a spinal enzyme, PKC gamma, which has been implicated in the development of central sensitization-mediated neuropathic pain.
The aim of the program is to develop a single intrathecal injection of a ddRNAi construct that can achieve significant silencing of the spinal enzyme leading to pain relief equivalent to that of opioid infusion. The initial target clinical group is terminally ill cancer patients. Published research has demonstrated the feasibility of the ddRNAi approach targeting the PKC-gamma gene in vivo
Status
Specific sequences on the target gene that are effective at silencing the gene in vitro have been identified and a patent application has been filed. The pain program is at the pre-clinical stage and a clinical trial is targeted for 2012-13.
Benitec Biopharma is developing a treatment for chemotherapy drug-resistant non-small cell lung cancer.
Market
In terms of incidence and mortality, lung cancer is the highest-ranked cancer and non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancers. First line chemotherapy for NSCLC includes both tubulin-binding and DNA-damaging agents. However, many tumours become quickly resistant to these drugs, leading to high mortality and dismal prognoses for patients with advanced cases.
Rationale
Benitec is designing ddRNAi therapeutics to target and silence the gene for beta III-tubulin, which is known to be associated with clinical resistance of these drugs, and to be upregulated in many cancers including non-small cell lung cancer (Cancer Research, May 2010.)
The aim of the program is to deliver a highly effective ddRNAi construct to lung tumors, thereby silencing the beta III tubulin gene in those cancers and increasing the effectiveness of chemotherapeutic drugs to kill the cancer cells.
Status
Benitec Biopharma’s scientific collaborators at the CCIA at UNSW have produced in vitro data showing that our multicassette shRNA construct is highly effective at knocking down the target gene, and initial in vivo data showing safety and efficacy. Preliminary in vivo data demonstrates encouraging results in systemic delivery of the construct to an orthotopic lung cancer model, resulting in silencing of the target gene. Further comprehensive in vivo data is targeted for 2012, which, if successful should lead to commencement of a clinical trial.
Benitec is developing a curative therapy for chronic hepatitis B virus (HBV) infection.
Market
Today, more than 2,000 million people have been infected with HBV at some time in their lives and about 350 million of them remain chronically infected carriers. In the USA alone there are over 1.25 million people living with chronic active HBV with over 60,000 new cases per year. In most chronic infections, current therapies have limited impact on viral gene expression and replication.
The aim of the program is to silence a key HBV gene, which results in the virus being unable to proliferate, with minimal off-target effects on human genes, thereby enabling a revolutionary and potentially curative approach to HBV treatment.
Rationale
Although there is a prophylactic vaccine available, there is no treatment available for acute HBV infection. Treatment of chronic HBV is aimed at:
There are two main classes of treatment:
i. antiviral drugs aimed at suppressing or eliminating HBV by interfering with viral replication (this is the class of treatment into which an RNAi therapeutic would be included), and
ii. immune modulators aimed at helping the human immune system to mount a defence against the virus.
Complete elimination of the virus is rarely achieved.
EPIVIR-HBV (lamivudine) was introduced by GlaxoSmithKline in 1998 and was the first FDA-approved oral antiviral for the treatment of chronic hepatitis B in adults with evidence of hepatitis B viral replication and active liver inflammation. Lamivudine is a 2',3'-dideoxy cytosine analogue that has strong inhibitory effects on the hepatitis B virus polymerase and therefore on HBV replication in vitro and in vivo. Lamivudine suppresses HBV replication in carriers, but the effect is reversible if therapy is stopped.
A major limitation of chronic lamivudine therapy, however, is the development of viral resistance. Resistance to lamivudine typically develops after 6 months of treatment and is associated with mutations in the highly conserved catalytic region of the HBV polymerase gene.
The polymerase gene is the target of Benitec’s ddRNAi approach, with the development of a multicassette linking three shRNAs targeting different regions of the polymerase gene, thus providing a high barrier to viral resistance.
Status
In September 2009, Benitec initiated a program to develop a ddRNAi-based therapeutic for the treatment and long term elimination of chronic HBV infection. The studies are being carried out in collaboration with China-based Biomics Biotechnologies Co. Ltd.
Several effective RNAi sequences were identified in the first stage of the collaboration, and in February 2011 Benitec and Biomics agreed to extend the program aimed at designing, manufacturing and testing ddRNAi-based constructs in a preclinical model of HBV infection. Ultimately the therapeutic will be tested in a clinical trial of HBV-infected patients
Benitec is developing a treatment and potential cure for a genetic disorder - oculopharyngeal muscular dystrophy
Market
OPMD is a rare disease affecting 1 in 100,000 people in Europe yet it has worldwide distribution and is the most common muscular dystrophy in Quebec (1 in 1,000) due to a founder effect (loss of genetic variation due to isolation of a small population). It is an autosomal dominant inherited (needing only one gene from one parent) degenerative muscle disorder which is slow progressing, late onset and usually starts in the fifth or sixth decade of life. In all patients, the disease is mainly characterized by progressive eyelid drooping (ptosis) and swallowing difficulties (dysphagia). The pharyngeal and cricopharyngeal muscles are specific targets in OPMD.
Status
In January 2012 Benitec Biopharma commenced the development of a ddRNAi-based treatment/cure for OPMD with researchers at the Royal Holloway University London and the Paris-based Institut de Myologie. shRNA constructs have been designed and will be tested in vitro and in a preclinical in vivo model in 2012.
Benitec is developing a single dose treatment Age-related Macular Degeneration (AMD).
Market
AMD is an acquired degeneration of the retina that causes significant central visual impairment. AMD affects 10% of the population between 60 and 75 years of age, increasing to 25% of those over 75 years. AMD is the leading cause of irreversible vision loss in the US and afflicts an estimated 1.75 million people. There are 2 forms of AMD, wet and dry. The wet form accounts for 10% of all cases and is the more severe of the two.
At present wet AMD is largely treated by antibody therapies, such as Lucentis and Avastin, which bind to and inhibit the biological activity of human vascular endothelial growth factor A (VEGF-A). These treatments stabilize vision in 95% of patients, and marginally improve vision in 29% to 40%, yet have a half-life of just 9 days. As a result, injections are needed monthly, which is inconvenient and very expensive.
Rationale
With its subsidiary Tacere Therapeutics, Benitec is developing a treatment based on ddRNAi technology which delivers a DNA construct to target cells via AAV vectors and has the potential to confer years of benefit from a single administration of the drug.
Status
The endogenous mRNA which will be targeted by the therapeutic, has been well-validated and is ‘druggable’ (susceptible to this approach). The expressed RNAi approach (direct delivery of the DNA construct to the nucleus directing the cell to produces specific shRNA and hence siRNA to bind to the mRNA) avoids activation of Toll-Like Receptors (TLRs) which are linked to inflammation and immune response. The AMD program is in the discovery phase.
