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Benitec Aims for Three Clinical Programs, Industry Partnership in 2013


By Doug Macron

Benitec Biopharma last week broke out new details about its in-house pipeline, stating that it aims to have three drugs in clinical studies next year and possibly a fourth by 2014.

The update comes as Benitec, which is also eyeing a big pharma partnership for next year, works to refocus on drug development following years of uncertainty driven by litigation, financial woes, and threats to its core intellectual property.

Benitec was one of the first players in the RNAi drugs space, holding an early US patent — No.6,573,099 — covering its expressed RNAi technology. However, troubles began in 2004 when the company, expanding into the US from its native Australia, launched a patent-infringement war against three companies, including now-defunct Nucleonics (GSN 4/2/2004).

Nucleonics fought the case for years, both in the courts and the US Patent and Trademark Office, where it requested a reexamination of the '099 patent. Although Benitec successfully had the case dismissed, it buckled under the weight of its legal costs in 2006, shuttering its US operations and reorganizing back in Australia as a much smaller firm (GSN 7/13/2006).

The USPTO also deemed the '099 patent invalid in light of prior art, and although this determination was not final, it cast doubt on Benitec's survival and upended its efforts to attract new investment.

But in 2010, the company's fortunes began to change when it raised $6 million by signing a convertible note with an investment group and, more importantly, the USPTO backtracked on the '099 ruling and reinstated the patent in full (GSN 11/11/2010). Less than a year later, Benitec was able to raise $8.5 million through a renounceable rights issuance (GSN 5/19/2011).

With cash and IP in hand, Benitec has now gotten back to the business of drug development, and last week offered new details about this effort.

Leading the pack is a candidate called Nervarna for the treatment of cancer-associated pain. The drug is designed to inhibit protein kinase C gamma, which plays a role in various cellular signaling pathways.

According to Benitec, data suggests that inhibiting PKC gamma can alleviate neuropathic pain, while data from an independent Chinese group has shown that shRNAs against the target can reverse morphine tolerance in rats.

Benitec CEO Peter French said that the company has identified two PKC gamma sequences that are conserved across key species, including humans, giving it a slight edge when it comes to developing Nervarna.

“The advantage of that is we can test the same construct in the rat and the dog and the human ... because of the sequence conservation, which saves us time in terms of the [toxicology] and pharmacology testing program,” he told Gene Silencing News.

Although French had hoped to begin phase I testing this year, he said that a clinical trial will not likely begin until early 2013 due to setbacks with manufacturing partner Oxford Biomedica.

The drug, which is delivered intrathecally, uses a proprietary Oxford lentivirus to express shRNAs against the two PKC gamma targets. But French said that there have been difficulties scaling up manufacturing of the lentivirus, slightly delaying the start of the clinical study.

“I'd still like to get it done this year, but the reality is … it will probably be early next year,” he said.

He added that Benitec expects to run the study in either the US or the UK, or perhaps both, in part because it will be the company's foray into human trials.

With the US and Europe the largest pharmaceutical markets in the world, clearing regulatory hurdles in those territories are key. By running its first clinical program in one of these markets, Benitec will be able to familiarize itself with their regulations so it can ensure compliance if it decides to run future clinical studies in other countries, he explained.

Previously, Benitec had said that it was considering running the pain program in collaboration with the Chinese team that reported on PKC gamma and morphine tolerance (GSN 11/3/2011). This week, however, French said that this partnership would not happen.

“We've contacted that group and we've investigated the possibility of a collaboration, but … there are some cultural and language difficulties working with that group in China,” he said. “We maintain a good communication with them, but at this stage a collaboration isn't going to work for us.”

He added that Benitec does not believe it needs any IP from the Chinese investigators since a patent they hold relates to a rat-specific PKC gamma sequence. “Our technology … is all we need to be able to do this,” French said.

Through Benitec's deal with Oxford Biomedica and its own patent applications, “we've got all the IP access we need.”

Next up in Benitec's pipeline is Tribetarna, a cocktail of shRNAs against three regions of the beta III tubulin gene that is being developed to overcome drug resistance in non-small cell lung cancer patients.

According to the company, increased expression of beta III tubulin has been associated with chemotherapy resistance, and preliminary data in orthotopic mouse models suggests that the drug can knock down its target specifically in the lung using Polyplus Transfection's JetPEI polyethylenimine polymer technology.

French said that Benitec hopes to begin phase I testing of Tribetarna in 2013, most likely in Australia.

“We have a good relationship with the University of New South Wales,” and the company has already received interest from clinicians at an associated teaching hospital about running the study, he noted.

Benitec's third drug candidate is the hepatitis B treatment Hepbarna. Less mature than the other two compounds, the drug's exact shRNA payload is still being worked out, as is its delivery technology.

The company anticipates settling on the design of an expressed RNAi construct by next month, and then to begin in vitro testing over the summer. French said that Benitec anticipates using an adeno-associated viral delivery approach; “we're just assessing which one is the best.”

Phase I testing of Hepbarna is expected to begin in mid-to-late 2013, likely in China given the high incidence of the disease in that country.

The newest addition to Benitec's pipeline is Pabparna, which is being developed to treat a rare form of muscular dystrophy called oculopharyngeal muscular dystrophy. The disease is characterized by weakness in the muscles of the eyelids and throat, resulting in difficulty swallowing and keeping the eyes open, according to the Muscular Dystrophy Association. As the disease progresses, weakness in facial and limb muscles often occurs. There is no treatment.

Benitec is still working out the target sequences for the drug, as well as the delivery approach, but it expects to be ready for phase I testing in 2014 or 2015.

French said that Benitec hopes the program will have a relatively rapid development time line as OPMD is an orphan disease, which means regulators are likely to offer Pabparna a shorter path toward approval, and because the condition affects only specific areas of the body.

“It's a lot more localized, we can control the delivery, and we can probably get quite a quick readout,” he said.

French added that Benitec hopes the OPMD program will also act as a proof of concept for the company's technology as a way to address currently untreatable genetic disorders.

As its drug-development plans move ahead, Benitec is also preparing to seek out a big pharma partnership, which it hopes to land within the next 12 months, but not before it enters the clinic.

“We've started discussing our programs with big pharma, making some of the key decision makers … aware of our programs,” French said. However, “our view is that we wouldn't seek to do a partnership before we're in the clinic because I think we would be devaluing our programs.”

Further, given the troubles gene therapy has had in the past, he believes that pharmaceutical companies would be more likely to embrace an expressed RNAi approach once safety has been demonstrated in man.

“With big pharmas having been educated about what we're doing, and with some interesting data, that will be the time to realize some significant value for our shareholders through a co-development or partnership or licensing” arrangement, French said.

Have topics you'd like to see covered in Gene Silencing News? Contact the editor
at dmacron [at] genomeweb [.] com.

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