Details of our in-house programs

Below are details of the programs Benitec runs in-house, which target life-threatening and chronic diseases and conditions which are high value and associated with identifiable genes.


We are developing BB-HB-331 for the treatment of HBV. We are currently conducting preclinical studies of BB-HB-331 and are targeting completion of the in vivo proof-of-concept preclinical studies in the second quarter of 2016. Results of recent in vivo and in vitro studies, from March 2016 and December 2015, respectively, have, we believe, demonstrated the potential utility of an approach that combines RNAi with gene therapy to treat HBV, and we intend to advance the HBV program towards the clinic.

About HBV

The human hepatitis B virus is a small DNA virus that, according to the WHO, infects up to 240 million people worldwide, resulting in up to 780,000 deaths per year. Infection with HBV occurs in phases ranging from a silent, acute phase that can be resolved by the immune system to a persistent chronic infection requiring life-long therapy. In the case of a chronic HBV infection, the presence of viral proteins, particularly the s-antigen, causes hepatic inflammation leading to liver dysfunction, acute hepatic failure, cirrhosis or hepatocellular carcinoma. 

According to GlobalData, a market research firm, the global hepatitis B therapeutics market was $3 billion in 2011, and is expected to grow to $4.4 billion by 2019. The current therapies used as standard of care for HBV consist of antivirals composed of nucleotide and nucleoside analogues, or NUCs, and, less commonly, interferon therapy. 

The most common anti-viral medications are taken as tablets each day for a year or longer and primarily act to inhibit viral replication. Most of these therapies can provide long-term viral load suppression but have low cure rates and have the additional risk of drug-resistant mutations. The long-term use of interferon, particularly in high doses, may also be associated with significant side effects, including nausea, vomiting, shortness of breath, dizziness and fatigue, adding to issues with patient compliance for the course of treatment. We believe that there is significant unmet medical need for HBV treatment due to the following factors: 

A problem inherent to all of the current HBV antiviral treatment approaches is their inability to achieve a curative outcome.

Our Solution

We are developing BB-HB-331 to address many of the limitations of therapeutics for HBV currently on the market and those in development. BB-HB-331 is expected to be a single administration ddRNAi-based monotherapy that is delivered using an AAV vector that targets the liver and expresses three shRNAs that target highly conserved regions on the HBV genome to inhibit both viral replication and viral protein, including s-antigen, production on a long-term basis.

We have designed BB-HB-331 to mimic our now discontinued product candidate for HCV, TT-034, as both HBV and HCV replicate in the liver. The same AAV vector is used in both therapeutic candidates, designed to achieve the same biodistribution and liver transduction properties. The AAV vector is expected to be delivered by a single administration monotherapy. The AAV vector will target the liver and express three shRNAs that target three separate conserved regions of the genome. The most significant change is the replacement of the three anti-HCV shRNAs of TT-034 with three anti-HBV shRNAs in BB-HB-331. Though we have discontinued our clinical trial for TT-034 for commercial reasons, we believe the early stage clinical results of TT-034 provide support for the safety of our platform technology.

Despite the discontinuation of the TT-034 Phase I/IIa trial and the need for further analysis of the final trial data once available, we believe useful information was obtained from the trial which should be beneficial for BB-HB-331’s clinical development, its IND-enabling studies, the design and regulatory approval pathway for its initial clinical trials, and potentially its starting clinical dose, in light of the similarities between TT-034 and BB-HB-331.

Initial in vitro data from preclinical results in December 2015 demonstrated the efficacy of BB-HB-331 to suppress multiple aspects of HBV in infected human liver cells. The in vitro data was supported by in vivo experiment results reported in March 2016, which demonstrated suppression of HBV in vivo in a mouse model following a single administration. Key findings from the in vivo study indicated that a single BB-HB-331 treatment:


We are developing two ddRNAi-based therapies, one for the treatment of wet AMD, which is designated BB-AMD-211, and the other potentially for both wet and dry AMD, which is designated BB-AMD-231. The aim of this program is to develop a therapeutic that provides long-term treatment of AMD from a single intravitreal injection. We believe this could replace the need for regular injections of therapeutics into the eye, which is the current standard of care.

About AMD

AMD is the deterioration of the eye's macula. The macula is a small area in the retina that is responsible for central vision. AMD is the leading cause of blindness and visual impairment in older adults, often involving blood vessel overgrowth and damage to the retina resulting in the loss of vision in the central visual field. The vascular endothelial growth factor, or VEGF-A, is responsible for stimulating the new blood vessel growth. The disease occurs in two forms, wet and dry. Dry AMD is the most common type of macular degeneration and affects 85% to 90% of the people with AMD. Dry AMD often develops into wet AMD. 

In the dry form, there is a breakdown of retinal pigment epithelial cells in the macula. These cells support the light-sensitive photoreceptor cells that are critical for vision. Generally, the damage caused by the dry form is not as severe or rapid as that of the wet form. However, over time, it can cause profound vision loss. There are currently no approved treatments for dry AMD. 

Wet AMD is the more advanced type of AMD. In wet AMD, which is also called exudative, or neovascular, AMD, the Bruch's membrane underlying the retina thickens, then breaks. The oxygen supply to the macula is disrupted and, as a result, new abnormal blood vessels grow through the subretinal membrane towards the macula, often raising the retina. The blood vessels are fragile, and often leak fluid that damages the macula. VEGF-A is responsible for stimulating the new blood vessel growth in wet AMD. Although it affects only 10% to 15% of those who have AMD, wet AMD accounts for 90% of the severe vision loss caused by macular degeneration. 

According to a study published in JAMA Ophthalmology, AMD is the leading cause of irreversible vision loss in the United States, affecting an estimated 1.75 million people. It is estimated that 196 million people will be affected by AMD worldwide by 2020 according to a study published in Lancet Global Health. 

There are a number of treatments currently available for wet AMD. According to GlobalData, the annual wet AMD treatment market across the United States, the United Kingdom, Germany, France, Spain, Italy and Japan will almost double from US$5.1 billion in 2013 to US$10.1 billion by 2023. 

According to GlobalData, the global AMD treatment market is dominated by anti-VEGF drugs, including Lucentis, Avastin and Eylea, which together accounted for 98% of sales for AMD in 2013. These treatments have similar risks and potential for adverse events, due primarily to their use of frequent intravitreal injection. Risks of intravitreal injections include increase in intra-ocular pressure, retinal detachment and endophthalmitis, or inflammation of the internal chambers of the eye. Patients and doctors dislike ocular injections and tend to prefer treatments that require these injections less frequently. The use of VEGF inhibitors can also cause blood clots.

Our Solution

There are several challenges in the development of AMD therapeutic market and we believe that our ddRNAi technology has the potential to address and overcome a number of these challenges, including: 

  • The relatively short half-life of current standard-of-care therapies results in the need for regular administration by intravitreal injection every 4 to 8 weeks. We believe our ddRNAi-based therapies have the potential for sustained inhibition of VEGF-A, possibly for months or years, from a single intravitreal injection. 
  • AMD therapeutic programs under development at a number of other gene therapy companies focus on administering the product to target cells by subretinal injection. We are co-developing with 4DMT AAV vectors to target the subretinal cells following intravitreal injection, which we believe is a more commercially viable and less invasive route of administration and is the route used in most current anti-VEGF therapies. 
  • There are no approved treatments for dry AMD. We have designed and tested a ddRNAi construct that we believe has potential to address this unmet market need. 

We are developing two ddRNAi-based product candidates, one for wet AMD, called BB-AMD-211, and one for both wet and dry AMD, called BB-AMD-231, that are designed to address many of the limitations for therapeutics for AMD currently on the market or under development. 

BB-AMD-211 is a ddRNAi construct expressing a single shRNA targeting the VEGF-A gene. VEGF-A is responsible for stimulating the new blood vessel growth in wet AMD. 

BB-AMD-231 is our second generation product candidate designed to express three shRNAs, which target three different genes, VEGF receptor 2, PDGF-beta and human complement factor B, which all play a role in the progression of AMD. VEGFR2 is the receptor known to bind VEGF-A, so silencing that receptor should prevent it from functioning to stimulate new blood vessel growth. PDGF-beta has a known role in recruiting cells that stabilize newly formed blood vessels for long term-persistence. Human complement factor B is a known component of ocular drusen. 

We have observed in in vitro studies that both BB-AMD-211 and BB-AMD-231 are effective at silencing the target genes. We expect to complete in vivo preclinical proof-of-concept studies in the fourth quarter of 2016. 


We are developing a ddRNAi therapeutic for the treatment of oculopharyngeal muscular dystrophy (OPMD), an autosomal-dominant inherited, slow-progressing, late-onset degenerative muscle disorder that usually starts in patients during their 40s or 50s.

About OPMD

OPMD is manifested by progressive swallowing difficulties, or dysphagia, and eyelid drooping, or ptosis, due to specific effects on the pharyngeal and cricopharyngeal muscle, which is located at the top of the esophagus. The disease is caused by a specific mutation in the poly(A)-binding protein nuclear 1, or PABPN1, gene. The main pathological characteristic of OPMD is the presence of dense intranuclear inclusions of mutated PABPN1 protein. 

OPMD is a rare disease and has been reported in at least 33 countries. Patients suffering with OPMD are well identified and are aggregated in particular regions, which we believe should simplify clinical development and commercialization of Pabparna, if it is approved. The largest OPMD cluster is in the French-Canadian population, with estimated prevalence of one in every one thousand people, and its highest prevalence is among Bukhara Jews living in Israel, where it affects one in six hundred people. In Europe, the estimated prevalence is one in one hundred thousand people. The relatively low abundance of patients afflicted by this disease allows this indication to be characterized as a rare disease, potentially supporting an orphan drug designation. 

The therapies for OPMD currently available and under development consist of a symptomatic surgical intervention called cricopharyngeal myotomy, an intravenous trehalose injection, Cabaletta, and cell transplantation. Each of these therapies has treatment limitations.

Our Solution

We are developing our ddRNAi therapeutic, a single administration ddRNAi-based gene therapy, to correct the gene defect which causes the disease and to address many of the limitations of therapeutic approaches currently available and those in development for OPMD. Our ddRNAi therapeutic is a monotherapy delivered using an AAV vector and is designed to silence the expression of the mutant PABPN1 gene in esophageal muscle cells of OPMD patients while simultaneously introducing a silencing-resistant normal form of the gene. We believe OPMD is well suited for this "silence and replace" approach since the genetic mutation is well characterized and the target tissue is relatively small. Once validated, we believe a similar approach could be applied to other inherited disorders. 

Results from in vivo studies in an animal model of OPMD support proof of concept of this approach in our ddRNAi therapeutic’s individual components. In conjunction with collaborators, we are working to optimize the in vivo delivery of our ddRNAi therapeutic and, assuming successful results, we plan to progress it through IND-enabling studies, and subsequent submission of an IND application. 


About HCV

Hepatitis C is a complex public health problem, characterized by a high prevalence of chronic infection by an RNA virus, an increasing burden of HCV-associated disease, low rates of testing and treatment, and the prospect of increasing incidence associated with injectable drug abuse. According to the WHO, over 170 million individuals worldwide have chronic hepatitis C. Chronic infection can result in cirrhosis and death in 20% of patients due to end-stage liver disease or hepatocellular carcinoma.

Our Solution

We have been developing a ddRNAi-based therapeutic, TT-034, for the treatment of the most common genotype of the human hepatitis C virus. We began a Phase I/IIa first-in-human clinical trial of TT-034 in January 2014. 

The primary endpoint for this study was safety, measured by incidence of serious adverse events and changes in clinical parameters. The secondary endpoints were efficacy-based, measured by shRNA expression in the liver, and sustained reduction in HCV viral load in the blood. As of March 2016, nine patients had been dosed in connection with the Phase I/IIa clinical trial and there have been no treatment-related serious adverse events observed in the study to date. Of the seven patients biopsied to date, a dose-dependent transduction of TT-034 in hepatic tissues and an increase in shRNA has been observed.

Although early stages of the clinical trial of TT-034 indicated that TT-034 caused no treatment-related serious adverse events among the nine patients dosed to date, and results from the seven biopsied patients also indicated a relationship between the amount of the compound administered and hepatic tissue transduction, in February 2016 we decided to discontinue the HCV program as a result of feedback from potential commercial partners.
Following the commencement of the clinical trial of TT-034, a number of new and effective therapeutics were approved for the treatment of HCV. In recent months before the date of this prospectus, competitors' products showed improvements in the efficacy, delivery and success rate of treatments for HCV while, at the same time, reducing the price and duration of their treatments.

As a result of the increasingly competitive landscape, in February 2016 we concluded that the TT-034 program no longer offered the commercial value necessary to attract a worthwhile commercial partnership deal and, as a result, did not warrant additional expenditure or focus of our resources beyond completion of the existing patients. We are committed to completing the collection of trial data and monitoring patients through the required long-term safety follow-up period. Final data will be reported in the fourth quarter of 2016 when the study is completed. We believe that completing this work will provide us with valuable data that supports our ddRNAi technology platform and other pipeline programs.