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Benitec Starts Market Research, Hires CRO as It Moves Neuropathic Pain Rx Toward Human Testing


By Doug Macron

Benitec has taken additional steps to fast track its preclinical neuropathic pain treatment by commissioning a report on the market potential for such a drug and hiring a contract research organization to prepare the compound for phase I testing under US Food and Drug Administration protocols, the company said this week.

The Australian firm also released details on a variety of targets it is exploring through the pain program, including protein kinase C gamma, which was described earlier this year in a paper by a group of independent Chinese investigators.

Benitec had been struggling in recent years under the weight of costs associated with a protracted patent-infringement lawsuit with defunct expressed-RNAi firm Nucleonics and the invalidation of its core US patent, No. 6,573,099. As a result, the company shuttered its US operations in 2006 and eliminated much of its staff.

However, about a year ago the company announced that it had successfully petitioned the US Patent and Trademark Office to reverse its previous rejections of the claims within the '099 patent (GSN 9/30/2010). With the uncertainty surrounding its intellectual property removed, Benitec eight months later successfully raised $8.5 million in much-needed cash through a renounceable rights issuance (GSN 5/19/2011).

With that money in hand, the company has set its sights on its three pipeline programs, which includes lung cancer, hepatitis B, and cancer- and chronic disease-associated pain. Late last year, Benitec CEO Peter French told Gene Silencing News that the company was working with the University of Queensland to test various RNAi constructs in pain models to "determine which specific target sequences have the strongest effect on reducing neuropathic pain from a single injection" (GSN 11/11/2010).

He added that regulatory hurdles related to evaluating the long-term effects of a drug were lower among terminally ill patients versus those with non-life-threatening conditions. Therefore, Benitec began considering advancing the pain program ahead of its other drug-development initiatives to demonstrate “the efficacy and advantage” of the firm's expressed RNAi technology.

This week, Benitec disclosed its plans to do so.

It said it hired management consulting firm Campbell Alliance Group to evaluate the commercial potential of an expressed RNAi treatment for neuropathic pain and found that pain specialists rated the “overall attractiveness of the potential Benitec product highly” due to its minimal toxicity profile and because it could avoid the side effects of opioids and other existing treatments.

Campbell also estimated that potential annual revenues for the drug could be as high as $600 million among terminal cancer patients in the palliative care setting according to Benitec.

“These findings … [reinforce] our focus on the pain program and provide the impetus for Benitec to mobilize additional resources to the program … [as we] seek to fast track its development,” French said in a statement this week.

As part of that strategy, Benitec has hired CRO Ground Zero Pharmaceuticals to help it move the pain program into clinical testing under FDA-approved protocols. Benitec said it has also brought on TetraQ, a preclinical drug-development organization based at the University of Queensland, to generate the data needed to begin human trials.

“Although the pain program is at an early preclinical stage, we are aware of the significant unmet clinical need for [the] product,” French added. “This is an opportunity for Benitec to demonstrate the power and potential of [its] gene-silencing technology in both clinical and commercial settings over the next 12 months.”

Benitec's pain program is centered around the use of a lentiviral vector that expresses shRNAs against a gene involved in “the transmission of pain stimuli to achieve long-lasting pain relief,” the company said.

According to a Benitec poster slated for presentation at the Florida Pain Initiative's annual Pain Summit this week, a variety of genes have been successfully targeted using RNAi in animal pain models. These include ATP receptor P2X3; NMDA receptor NR2B; NMDA receptor NR1; MMP-2 and MMP-9; potassium channel 4.1; capsaicin receptor TRPV1; EP receptor EP4; and protein kinase C gamma, on which Benitec has been focusing its efforts.

Mostly found in the brain and spinal cord, protein kinase C gamma is believed to be a messenger in intracellular signal transduction, and research has shown that its inhibition blocks neuropathic pain while preserving acute pain, the company said in the poster.

“From a clinical perspective, the very restricted spinal cord location of the protein kinase C gamma-containing interneurons is advantageous,” it said. “Development of specific inhibitors of protein kinase C gamma could provide solutions to alleviate neuropathic pain states without the profound side effects that are inevitable with non-selective inhibitors” such as narcotic analgesics.

Earlier this year, Benitec highlighted the work of researchers from Central South University in China, who were not affiliated with the company, showing that lentiviral-delivered shRNAs against protein kinase C gamma could alleviate chronic neuropathic pain in an animal model.

According to that paper, which appeared in the April issue of Human Gene Therapy, rat models of chronic constriction injury-induced neuropathic pain received intrathecial injections of the shRNA-expressing vectors.

“This method decreased the expression of PKCg mRNA and protein, and additionally attenuated chronic constriction injury-induced mechanical allodynia and thermal hyperalgesia for more than six weeks,” the investigators wrote.

In light of these and other data, Benitec said in its poster that it is “designing and testing” a range of expressed RNAi constructs against protein kinase C gamma and other potential targets localized in the spinal cord as pain therapeutics, initially for terminal cancer patients.

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