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Benitec Poised to Move HCV Drug into Clinic as Ag-bio Firms Oppose European Patents

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Australian expressed RNAi firm Benitec Biopharma provided an update on its research and development activities late last month, reporting that it remains on track to move its lead drug candidate, the hepatitis C therapy TT-034, into the clinic as early as this month.

Meanwhile, the company's chemotherapy-resistant lung cancer treatment Tribetarna is on track to enter human trials in late 2014.

Benitec, which provided the pipeline information as part of its annual report for the fiscal year ended June 30, also disclosed that it is currently dealing with oppositions filed against three of its European patents by several parties including ag-bio giant Syngenta and chemical company BASF, which develops crop-protection products through an agricultural division.

TT-034 is designed to express shRNAs targeting three portions of the HCV genome. It was originally developed by Benitec, but financial problems exacerbated by the potential invalidation of its core US patent, No. 6,573,099, prompted it to license the agent to startup Tacere Therapeutics in 2006 (GSN 10/12/2006).

Tacere successfully advanced TT-034 through preclinical development, but in 2011 lost the support of partner Pfizer, which made the decision to end its in-house nucleic acid drugs efforts as part of a company-wide restructuring. As a result, TT-034 was again available for licensing.

All the while, Benitec had begun to turn itself around, finding the necessary financing to sustain its operations as the US Patent and Trademark Office upheld its intellectual property. Seeing an opportunity to regain its HCV program, in late 2012 the company bought Tacere for roughly $1.5 million in stock, or roughly 9.5 percent of its shares (GSN 10/11/2012).

With the majority of the preclinical groundwork for TT-034 already laid, Benitec has focused the lion's share of its resources on getting the drug into a planned phase I/II study. According to the company, it has hired a US contract research organization to handle regulatory submissions and the trial, and this summer received the go-ahead from the National Institutes of Health’s Recombinant DNA Advisory Committee.

The study will assess the safety and tolerability of single escalating intravenous doses of TT-034 in 14 chronic HCV patients who have failed the current standard of care. It will also examine the drug's effect on viral load, the presence of viral escape mutations, as well as vector DNA and shRNA levels in the liver and blood.

According to the NIH's online clinical trial database, the study is slated to start before the end of September and wrap up in mid-2015.

On deck in Benitec's pipeline is Tribetarna, which was recently shown to improve survival in an orthotopic mouse model of non-small cell lung cancer when used in combination with chemotherapy (GSN 4/11/2013).

Benitec said it is also planning a phase I/II trial for this compound, which could begin in the fourth quarter of next year, and is mulling the development of a companion diagnostic that can identify lung cancer patients at the highest risk of developing chemoresistance.

'Equally confident'

Although Benitec develops RNAi drugs, its core technology has applications in agriculture, and the IP surrounding it has come under fire by a handful of companies in the field.

Specifically, Benitec said that oppositions have been filed against European patents EP1068311, EP1555317, and EP1624060. All three are assigned to Australia's Commonwealth Scientific and Industrial Research Organization, and licensed to Benitec exclusively for developing human therapeutics.

The '311 patent, entitled "Method and Means for Obtaining Modified Phenotypes," relates to the use of double-stranded RNA to reduce the expression of a nucleic acid sequence of interest in eukaryotic cells, particularly as a means to establish viral resistance.

The '317 patent is entitled "Synthetic Genes and Genetic Constructs Comprising the Same," and the '060 is entitled "Control of Gene Expression." Both claim the use of recombinant DNA to "post-transcriptionally modify or modulate the expression of a target gene" via RNAi.

In 2012, oppositions were filed against the '060 patent by BASF; against the '317 patent by BASF and an anonymous party listed only as Strawman Limited; and against the '311 patent by BASF, Strawman, and Syngenta.

Notably, the Carnegie Institution of Washington and the University of Massachusetts joined the opposition to the '311 patent. The two institutes own US patent 6,506,559, also known as the Fire-Mello patent, which covers the introduction of dsRNA into a cell to inhibit expression of a target gene and is widely considered the most fundamental IP in the RNAi field.

Benitec CEO Peter French told Gene Silencing News that CSIRO earlier this year responded to the issues raised by BASF and the others, and that oral hearings on each of the oppositions are expected to begin next year.

"CSIRO’s expectation is that the patents will be maintained without significant diminution of the scope," French said in an email. He added that Benitec is "equally confident of such an outcome," citing its success defending its '099 patent in the US, as well as corresponding patents in Great Britain and Australia.

He also pointed to the patents' utility in the agricultural field, particularly the '311 patent, and noted that CSIRO has already licensed the IP to a number of unnamed ag-bio firms as it negotiates licenses with several other such companies.

Fiscal year financials

For the 12-month period ended June 30, Benitec posted a net loss of A$3.5 million (US$3.2 million), down from A$4.1 million for the same period a year earlier. The loss for fiscal 2013 includes the write-off of A$1.5 million in goodwill and A$518,749 in share-based expenses related to the Tacere acquisition.

Income for the year was A$1.5 million, compared with A$503,304 the year before, and included roughly A$800,000 in research grants. Expenses, meanwhile, jumped to A$4.5 million from A$3.5 million.

As of June 30, Benitec had cash and cash equivalents totaling A$1.6 million.

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