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Benitec Provides Update on HCV, Earlier-stage Pipeline Programs

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NEW YORK (GenomeWeb) – As it pushed forward with a Phase I/IIa trial of its expressed RNAi-based treatment for hepatitis C, Benitec Biopharma said that it has streamlined the rest of its pipeline to focus on three other programs — hepatitis B, non-small cell lung cancer (NSCLC), and age-related macular degeneration (AMD).

Meanwhile, the company has struck licensing deals for DNA production and delivery technologies that it intends to develop for use with these upcoming clinical candidates.

Since its 2012 acquisition of Tacere Therapeutics and its HCV drug TT-034, Benitec has been largely focused on moving that compound through human testing. Earlier this year, the company dosed the first patient in a 14-patient trial designed to establish TT-034's safety, beginning with sub-therapeutic doses.

While it had expected to dose the second patient shortly thereafter, the company hit a delay when two potential study participants failed to meet the trial's inclusion criteria. Specifically, they experienced fluctuations in viral load and/or liver enzymes that were beyond the acceptable limits of the study.

Earlier this month, Benitec announced that it had dosed a second patient and identified a third patient who will receive TT-034 pending the positive outcome of a six-week review of the second patient's response to treatment.

During Benitec's annual shareholder meeting in mid-November, CEO Peter French said that the company is working to accelerate the rate of patient enrollment in the study by expanding the number of clinical sites with the assistance of a patient recruitment vendor.

He also noted that the inclusion criteria for patients are especially stringent as the Phase I/IIa trial represents a first-in-man study of the expressed RNAi technology. "Once safety has been established, we will have the data needed to be allowed to relax most if not all of the criteria and to offer [TT-034] to the broader HCV community," he said.

Next in Benitec's drug-development roster is Tribetarna, which is designed to silence beta III tubulin to overcome chemotherapy resistance in NSCLC.

Although Benitec had aimed to have this drug in the clinic by the end of 2014 as part of a combination therapy with the chemotherapeutic cisplatin, French indicated that this timeline would not be met as the company works to accommodate a US Food and Drug Administration request for additional animal data.

Currently, work is underway to establish optimal dosing concentration and timing, as well as the effect of staggered treatment regimens on beta III tubulin knockdown, in an orthotopic model of lung cancer, French said.

He added that Benitec will also hold off on the filing of an investigational new drug application for Tribetarna while it and collaborators at the University of New South Wales develop a companion diagnostic for Tribetarna.

"It appears that around 50 percent of non-small cell lung cancer patients express beta III tubulin in their cancer cells," French explained. As such, the company has decided that "a critical success factor" for the drug is the ability to identify which patients overexpress the gene using tumor samples or, ideally, blood samples.

Development of Benitec's HBV drug, dubbed Hepbarna, began through a collaboration with China's Biomics Biotechnologies in 2009. However, Benitec said this month that while it is still working with its partner, their arrangement has been modified so that Benitec holds the full rights to the program.

The HBV candidate has also been modified to mimic the design of TT-034, with the only changes being the replacement of anti-HCV RNAi sequences with ones directed against HBV.

French said that Benitec has been testing a number of different candidate sequences in recent months in order to identify the best three for inclusion into Hepbarna. Once they are selected, the company will run the in vitro and in vivo testing necessary to move the drug into the clinic, he added.

During the shareholder meeting, French disclosed that Benitec has acquired an option to pick up the exclusive rights to a DNA manufacturing technology for use in the NSCLC and HBV programs.

Called Doggybone DNA (dbDNA), the technology was developed by Touchlight Genetics and comprises closed linear DNA that is capable of expressing therapeutic shRNAs like the DNA plasmids Benitec currently uses, but which does not require bacterial fermentation to produce. Additionally, dbDNA purification does not require the removal of potentially hazardous components associated with fermentation.

French said that Benitec is currently testing the expression performance of the dbDNA technology.

The company also inked a deal to test out a proprietary adeno-associated viral vector technology developed by 4D Therapeutics for its ability to deliver its RNAi constructs into the retina as part of its fledgling AMD program, French said.

He didn't provide specific details about this effort, but said that, if successful, it could open the door for Benitec to pursue additional ocular diseases.

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