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Benitec Closes Financing, Passes RAC Meeting as it Nears the Clinic

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Benitec Biopharma hit two key milestones recently in its effort to advance its expressed RNAi-based hepatitis C treatment TT-034 into the clinic, securing a commitment to sell A$7 million ($6.7 million) of its stock to new and existing shareholders and receiving a favorable review by the National Institutes of Health’s Recombinant DNA Advisory Committee.

With the added cash and the RAC’s decision not to suggest any significant changes to the design of the planned phase I/IIa trial of TT-034, Benitec remains on track to initiate the study before the end of the year — a goal that would mark the completion of the company’s long and complicated path to becoming a clinical-stage drug developer.

To raise the A$7 million, Benitec said last week that it will issue roughly 636.4 million new shares of its stock in two tranches. In the first, around 37.5 million shares will be issued under a 15 percent placement capacity, and in the second approximately 598.9 million shares will be issued subject to stockowner approval at a July meeting.

The company also said it may elect to sell an additional A$3 million in shares to cover over-allotments. The financing comes just months after Benitec closed an A$800,000 private placement (GSN 3/7/2013).

Additionally, this week Benitec researchers went before the RAC to detail the company’s plans for TT-034.

The RAC was established in 1974 to address concerns over the safety of using recombinant DNA techniques to manipulate genetic material. Because TT-034 comprises a multi-cassette vector designed to express shRNAs targeting three areas of the HCV genome, the company was required to present details about the drug’s development plan to the committee.

According to Benitec, the committee has yet to issue its final recommendations on the proposed clinical trial, but during the meeting indicated that there would be no requests for “any significant alternation to the [study’s] protocol.”

Given this outcome, Benitec said that it would move ahead with an investigational new drug application filing for TT-034 with the US Food and Drug Administration, with the expectation that it will be given approval to start the phase I/IIa trial before the end of 2013.

That trial will examine single, ascending doses of TT-034 in around 14 HCV patients who have failed the current standard of care, Benitec CEO Peter French told Gene Silencing News. Depending on patient responses, the company has the option to enroll a few additional patients.

The first cohort of patients will receive sub-therapeutic doses, with safety as the primary endpoint, he said. “We expect to start getting into therapeutic dosing in the second and third cohorts,” which could be treated as early as late this year or the beginning of next year.

Benitec is also laying the groundwork for a follow-on phase II trial that will test the lowest effective dose identified in the phase I/IIa study, he noted.

Meanwhile, buoyed by the latest cash infusion, Benitec is also preparing to enter the clinic with its expressed RNAi treatment for non-small cell lung cancer, Tribetarna.

The therapy is a cocktail of shRNAs against three regions of the beta III tubulin gene and is designed to overcome drug resistance in non-small cell lung cancer patients.

While the drug had previously trailed other candidates in Benitec’s pipeline, the company positioned it behind TT-034 earlier this year, in part because of promising preclinical data showing that Tribetarna boosted survival in an orthotopic mouse model of non-small cell lung cancer when used in combination with chemotherapy (GSN 4/11/2013).

With the proceeds from the latest private placement, Benitec said it will conducted preclinical toxicology, biodistribution, and dose-finding studies for the cancer drug, with a goal of launching a phase I/IIa trial in Europe within the next 18 months, French said.

“We would be looking at patients with lung disease who were resistant to chemotherapy and who have elevated levels of beta III tubulin,” French explained, adding that Tribetarna would be administered in conjunction with a chemotherapeutic like cisplatin.

Road to the Clinic

Early on, Benitec had been a key player in RNAi therapeutics, in part due to its ownership of one of the field’s earliest patents, and at one time predicted it would begin phase I testing of its HCV candidate in 2005 (GSN 5/21/2004).

However, the company ran into trouble under its original management, which initiated a number of lawsuits over alleged infringement of that intellectual property.

One of those companies, now-defunct Nucleonics, fought back in court, as well as in various patent offices worldwide, seeking reexaminations of Benitec’s IP. The cost of the litigation weighed heavily on Benitec, and the company was forced to shut down its US operations in 2006 to reorganize as a much smaller firm in its native Australia with a new executive team.

Meanwhile, the US Patent and Trademark Office deemed the claims in Benitec’s patent — No. 6,573,099, which covers the use of DNA that transcribes double-stranded RNA for target gene inhibition — invalid. While the USPTO’s decisions were never final, they hurt the company’s efforts to attract investors.

The same year it left the US, Benitec sold off the rights to its fledgling hepatitis C program to Tacere Therapeutics, a startup founded by former Benitec executives (GSN 10/12/2006).

By 2010, the tide began to turn for Benitec, with the USPTO upholding the claims in the ‘099 patent and ending the reexamination process. Meanwhile, Tacere had signed on Pfizer as a partner for the HCV program, and together the companies successfully brought a drug candidate — TT-034 — through preclinical development.

But when Pfizer decided to end its in-house development of oligonucleotide therapeutics in early 2011, it backed out of its alliance with Tacere, leaving TT-034 available for licensing. Having regained its financial footing, in late 2012 Benitec bought up Tacere and the HCV drug program for just $1.5 million in stock (GSN 11/11/2012).

Now, with clearance by the RAC and additional funding in its coffers, Benitec is poised to finally move its first drug candidate into human testing, with a second potentially a few months behind.

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