Benitec Biopharma Ltd

Type	Biotechnology
Traded as	ASX :  BLT
Industry	RNA interference
Founded	1997
Headquarters	Sydney, Australia
Key people	Dr Peter French (CEO), Peter Francis (Chairman), Greg West (chief financial officer and company secretary ), Michael Graham (Chief Scientist)
Products	Gene silencing , Gene expression , RNA interference (ddRNAi)
Revenue	$ 207,770 (2011) [ 1 ]
Profit	( $ 3,534,874) (2011) [ 1 ]
Total assets	$ 6,865,358 (2011) [ 1 ]
Total equity	$ 5,204,348 (2011) [ 1 ]
Employees	4 (2011) [ 1 ]
Website	www.benitec.com

Benitec Biopharma Ltd is an Australian biotechnology company founded in 1997. ^{[ 2 ]} It is engaged in the development of gene-silencing therapies for the treatment of chronic and life-threatening diseases, through implementation of its proprietary technology, DNA-directed RNA interference (ddRNAi). ^{[ 3 ]}

The Commonwealth Scientific and Industrial Research Organisation (CSIRO) has researched RNAi extensively, developing the small hairpin RNA concept employed in ddRNAi. Benitec Biopharma has an exclusive license from CSIRO to this ddRNAi technology in human therapeutic uses and research. ^{[ 4 ]}

History and location [ edit ]

• Sydney, Australia – Principal place of business ^{[ 1 ]}


• Melbourne , Australia – Registered company address ^{[ 1 ]}


• Operations are ongoing in UK, US and Asian markets ^{[ 1 ] [ 3 ]}

Originally named Benitec and based in Australia, the Company operated from the US for an interim period but closed US operations in June 2006. The main catalyst for this was an intellectual property dispute , which was resolved in Benitec Biopharma's favour in 2011. ^{[ 3 ]}

In 2011, three significant events occurred:

• In March, the US Patent and Trademark Office ( USPTO ) reinstated Benitec Biopharma's core-technology patent to provide Benitec Biopharma exclusive US rights to ddRNAi technology in humans ^{[ 5 ]}


• Benitec Biopharma moved operational headquarters from its registered company address in Melbourne to its Sydney office in 2011. ^{[ 6 ]}


• The name change to Benitec Biopharma was announced at the Annual General Meeting in 2011, aimed to better reflect the company's ongoing activities. ^{[ 7 ]}

Partnerships and collaborations [ edit ]

Besides in-house programs, Benitec Biopharma expands its activities through commercial partnerships and collaborations. Current partnerships include: ^{[ 3 ] [ 8 ]}

• For laboratory reagents: Promega , Chemicon ( Millipore Corporation ), Integrated DNA Technologies , Genscript, Ambion Inc ( Applied Biosystems ), Origene Technologies, Sigma Aldrich


• For transgenic animals : Artemis Pharmaceutical GmbH, GenOway


• For commercial research use: Merck & Co , Pfizer


• Licensing agreements: Calimmune, Carnegie Institution for Science , Children's Cancer Institute Australia for Medical Research (CCIA) ( University of New South Wales ), Biomics Biotechnologies, Tacere Therapeutics

Research and development [ edit ]

Benitec Biopharma markets itself as an RNAi-based therapeutics company researching therapies for the treatment of life-threatening diseases with significant unmet need, aiming to silence target genes for the long-term improvement of human health. ^{[ 1 ] [ 3 ]}

Benitec Biopharma has a number of clinical research initiatives both in-house and as part of collaborations:

Chronic neuropathic pain [ edit ]

Program for pain relief in terminal cancer [ edit ]

Benitec Biopharma has identified a target enzyme, protein kinase C gamma ( PKC-gamma ), which is found in elevated levels in the spinal cord of patients with intractable pain. By silencing this gene, elevated levels of PKC-gamma cannot develop and pain relief is achieved. A lentiviral vector will be used to deliver the ddRNAi construct to the target spinal cord cells with the potential of only one injection providing long-term pain relief. ^{[ 9 ] [ 10 ]}

Antiviral therapies [ edit ]

Hepatitis B Viral Infection program [ edit ]

Hepatitis B is a virus infecting almost one-third of the world's population with no cure for chronic infection. ^{[ 11 ]} Collaborators Benitec Biopharma and China-based Biomics Biotechnologies have selected three key DNA sequences on a hepatitis B viral replication gene that achieve more than 70% silencing through the application of ddRNAi. ^{[ 12 ]} A near 100% success rate has been observed in delivering this ddRNAi construct via an adeno-associated virus (AAV), AAV8, ^{[ 9 ]} known to be very effective at transducing hepatocytes or liver cells.

Hepatitis C Viral Infection program [ edit ]

Three short hairpin RNAs targeted to 22 nucleotide regions highly conserved in the hepatitis C virus’ genome have been identified with preclinical evidence of antiviral activity. The ddRNAi multicassette vector, known as PF-05095808 or TT-034, contains multipromoters for the three target RNA sequences which when expressed, prevent the hepatitis C virus from propagating. ^{[ 13 ]}

Tacere Therapeutics received an exclusive worldwide sub-license from Benitec Biopharma for the development of ddRNAi in hepatitis C viral infection in 2006. ^{[ 14 ]} In December 2007, global pharmaceutical company Pfizer entered into a licensing agreement with Tacere Therapeutics to develop and commercialise Tacere Therapeutics’ hepatitis C compounds in all territories excluding Asia, with the potential payments exceeding US$145 million. Tacere Therapeutics acquired Asian rights from Japanese company Oncolys BioPharma in June 2007. ^{[ 15 ] [ 16 ]} After demonstrating the successful expression of the selected three short hairpin RNAs in animals after only one intravenous injection, Pfizer exercised its option to fully partner future development and conduct regulatory toxicology studies. ^{[ 16 ] [ 17 ]}

HIV/AIDS program [ edit ]

ddRNAi technology is currently being used for development for HIV/AIDS therapy with a number of groups including:

• The Berkhout Group, Amsterdam, has carried out extensive research on the application of multicassette ddRNAi constructs. ^{[ 18 ]}


• The City of Hope, US, is investigating the single administration of a stem cell-delivered treatment containing a ddRNAi construct, enabling the body to build and maintain a new and HIV-resistance immune system. The first trial confirmed the safety of the approach and demonstrated the ongoing expression of ddRNAi beyond two years. ^{[ 19 ]} The City of Hope, US, plans to progress to a second human clinical trial.


• In March 2012, a non-exclusive licensing agreement was confirmed with CalImmune, US. ^{[ 20 ]}

Cancer therapies [ edit ]

Drug-resistant non-small-cell lung cancer program [ edit ]

Non-small-cell lung cancer has a dismal prognosis, with a high proportion of patients developing resistance to conventional drug therapy within a short period of time. ^{[ 21 ]} Professor Maria Kavallaris and her fellow researchers at the Children's Cancer Institute Australia (CCIA), University of New South Wales , have demonstrated that targeting a specific ?-tubulin, class III ?-tubulin , with ddRNAi sensitises cancer cells to anti-cancer agents that tumor cells can become resistant to. In silencing other ?-tubulin isotypes, there is further potential to mediate responses to other clinical therapies. ^{[ 22 ]}

Genetic disorders [ edit ]

Oculopharyngeal Muscular Distrophy program [ edit ]

Benitec Biopharma commenced development of a gene-silencing therapy for oculopharyngeal muscular dystrophy (OPMD) in January 2012 with Professor George Dickson at Royal Holloway, University of London , and Dr Capucine Trollet at the Institut de Myologie in Paris. ^{[ 1 ] [ 9 ]}
OPMD is a rare, inherited, late onset degenerative muscle disorder, leading to difficulty swallowing with potentially fatal consequences. The genetic mutation involved is found in one small gene and is initially expressed in localised areas around the throat and eyelids, making the condition ideally suited to gene-silencing therapy. ^{[ 9 ]} As OPMD progresses limb weakness is common. In severe cases the patient may lose the ability to walk or lift their arms.

Intellectual property [ edit ]

Benitec Biopharma holds an intellectual property portfolio securing its ddRNAi technology in humans and mammals, currently totalling 104 patents in 20 jurisdictions. ^{[ 3 ]}

History [ edit ]

On 5 June 2003, Benitec Biopharma was granted its core technology patents in the US and the UK. These patents, with priority dating to 1998, describe a method for silencing any gene in any human cell using ddRNAi. US Patent 6,573,099 is entitled "Genetic constructs for delaying or repressing the expression of a target gene" and UK Patent 2353282 is entitled "Control of gene expression". Both patents contain world-first claims that describe the effect of RNAi in human cells and the DNA constructs which trigger RNAi. In 2006, Benitec Biopharma and siRNA competitor Alnylam were considered the key holders of strong patent positions within RNAi. ^{[ 23 ]}

Disputes [ edit ]

The Graham family of patents covering the core ddRNAi technology has overcome disputes across the globe. ^{[ 8 ]}

In October 2005, CSIRO and Benitec Biopharma were successfully re-awarded two jointly-held patents covering ddRNAi technology in plants, animals and humans following an Australian Patent Office re-examination requested by Pennsylvanian gene therapy Company Nucleonics. A rival patent application by Swiss-based company Syngenta was also withdrawn. ^{[ 8 ]}

Nucleonics also challenged the patents in US territory and lodged a "third party observation" to the European Patent Office. Nucleonics had licensed its RNAi intellectual property from the Carnegie Institution of Washington. ^{[ 8 ]}

In October 2010, the US Patent and Trademark Office ( USPTO ) overturned all objections raised in the US re-examination of the key Graham family patents. ^{[ 24 ]} The re-examination certificate was issued in March 2011, reinstating the patent to provide Benitec Biopharma exclusive US rights to ddRNAi technology in humans. ^{[ 25 ]}

The only territory awaiting re-issuing of the disputed patents is in Europe, where all outstanding objections have been overcome to date. ^{[ 25 ]}

Patent portfolio [ edit ]

• Graham family patents:
  
  
  
  • US 8067383, Granted November 2011
  
  
  • US 8048670, Granted November 2011
  
  
  • US 8053419, Granted November 2011
  
  
  • US Patent Application 11/218,999, Notice of Allowance January 2012
  
  
  • Europe 1555317, Issued January 2012
  
  
  • Europe 1624060, Issued January 2012.
  
  
  
  

• Waterhouse family patents:
  
  
  
  • Europe 1068311, Accepted April 2011, currently under opposition at the EPO (part of the standard process for patent granting in Europe).
  
  
  
  

• Benitec owned patents:
  
  
  
  • Europe 1725660 (Multi-promoter multi cassette), Granted July 2011
  
  
  • US 8076471 (Single-promoter, multi-cassette), Granted December 2011
  
  
  • US 8008468 (Minigene Expression cassette), Granted August 2011.
  
  
  
  

International presence [ edit ]

Benitec’s CEO, Dr Peter French, attended and presented at a range of conferences locally and internationally:

• Bioshares Queenstown, July 2011


• fifth Pain Summit, San Francisco, US, September 2011


• Australian Showcase: Amsterdam, the Netherlands, October 2011


• BioPartnering Europe, London, UK, October 2011


• Ausbiotech National Conference, Adelaide, Australia, October 2011


• Innovation Driving Next Generation Healthcare, Melbourne, Australia, May 2012

References [ edit ]

Further reading [ edit ]

• Chen C-C et al . Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus. Gene Therapy; 2012; 19: 25–33. doi: 10.1038/gt.2011.60. PMID 21562593


• Eekels JJ and Berkhout B. Toward a durable treatment of HIV-1 infection using RNA interference. Prog Mol Biol Transl Sci 2011;102:141:163 PMID 21846571


• Huang M et al . Double knockdown of prolyl hydroxylase and Factor-Inhibiting Hypoxia-Inducible Factor with nonviral minicircle gene therapy enhances stem cell mobilisation and angiogenesis after myocardial infarction. Circulation 124 [suppl 1]: S46–S54. PMID 21911818


• Lavender H et al . In vitro characterisation of the activity of PF-05095808 a novel biological agent for Hepatitis C Virus therapy. Antimicrobial Agents Chemotherapy 2011; 56(3): 1364–1375. doi:10.1128/AAC.05357-11. PMID 22203606


• Li R et al . Gene silencing of IL-12 in dendritic cells inhibits autoimmune arthritis. Journal of Translational Medicine 2012; 10: 19. doi:10.1186/1479-5876-10-19. PMID 22289162


• Senzer N et al . Phase I Trial of “bi-shRNAifurin/GMCSF DNA/ Autologous Tumor Cell” Vaccine (FANG) in Advanced Cancer. Molecular Therapy 20 December 2011. doi: 10.1038/mt.2011.269. PMID 22186789


• Zou W et al . Identification of differentially expressed proteins in the spinal cord of neuropathic pain models with PKC? silence by proteomic analysis. Brain Research 2012; 1440: 34–46. PMID 22284620

External links [ edit ]

• Official Benitec Biopharma website


• Official CalImmune website


• Official Tacere Therapeutics website