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As RNAi Rx Space Heats Up, Norwegian Shop Pins Hopes on Cancer Candidate; Clinical Trials in 08?


With several RNAi-based drugs in the clinic, including one already in phase II trials, the number of companies working in the field continues to grow. One of the newest is Norway-based siRNAsense, which is focusing on cancer and says it could be ready for human trials of its own -possibly as early as 2008.

According to Mohammed Amarzguioui, research director for siRNAsense, the company was founded in December 2004 as "an umbrella organization for the commercialization of RNAi research … coming from the various universities from Norway," including the Centre for Molecular Biology and Neuroscience, Rikshospitalet University Hospital, and the University of Oslo. It is majority owned by the Norwegian firm Biomedical Innovation, he said.

"Right now, we have three or four groups [from different academic institutions] that are contributing the [research] projects" that make up siRNAsense's pipeline, Amarzguioui noted. Through Biomedical Innovation, siRNAsense has the right to evaluate each group's RNAi research and, should the work appear promising, take licenses to further develop and commercialize it.

Although siRNAsense's website indicates that the company's pipeline includes programs in heart disease and neuroscience, cancer "is the major focus right now," Amarzguioui said. However, "as a company we do not envision being restricted [to this indication]. The [ultimate] focus will be RNAi applied to any field of medical interest."

"We don't necessarily want to take [a drug candidate] all the way to a clinical stage. We are currently evaluating potential exit strategies, even during early product development."

Researchers affiliated with siRNAsense are currently developing siRNAs targeting prostate-specific genes for prostate cancer, DNA repair genes for combination therapy with existing chemotherapeutics, and tissue factor for metastases — the company's most advanced effort.

"Tissue factor is a trigger of blood coagulation," Amarzguioui said. "But it has more recently been associated with various processes in cancer development."

According to Amarzguioui, siRNAsense researchers have identified siRNAs that target tissue factor and transfected them into B16 melanoma cells, which were then administered via tail-vein injections into mice. The researchers found that mice receiving the siRNAs experienced delays in pulmonary metastasis versus mice that received inactive siRNA sequences.

Most recently, the researchers conducted more "clinically relevant" experiments, he said, in which untransfected B16 cells were administered intravenously to mice, followed by multiple intraperitoneal injections of liposomally complexed siRNA. They found that a single dose of the siRNA could inhibit lung colonization and increase survival in the mice.

"We saw about a four- or five-fold inhibition [of the number of lung tumors in treated animals] at the 100 microgram dose," Amarzguioui said. "The effect was dependent on the timing of treatment," he added, noting that this "window of opportunity was not surprising since these are circulating cells. Treatment while the cells are still in circulation seems to have a more dramatic effect."

These data have been accepted for publication in an undisclosed peer-reviewed journal, he said. They were also presented earlier this month at Gene Expression System's RNAi 2006 Boston meeting in Waltham, Mass.

"The next step [in the tissue factor program] is establishing a true metastases model," Amarzguioui said. Based on his presentation at the RNAi 2006 Boston conference, this will involve examining the siRNA's efficacy in mouse and human cell xenograft models of distant metastases from primary solid tumors. Additionally, the safety of the RNAi treatment will be evaluated to ensure that tissue factor levels do not fall below the level needed for normal hemostasis.

As siRNAsense's drug-development programs move forward, the company expects that collaborations will become increasingly important. For example, Amarzguioui said siRNAsense is currently looking for the best delivery technology for its tissue factor-targeting siRNA, including ones developed by other parties.

"Right now, we are considering different options, and ideally [this would be] a collaboration with an [academic] group or company specializing on delivery," he said.

Additionally, siRNAsense expects to forge alliances to help develop and market its products.

"We don't necessarily want to take [a drug candidate] all the way to a clinical stage," he said. "We are currently evaluating potential exit strategies, even during early product development. So if a project appears to be interesting enough, we will be pursuing either a product co-development deal or a straight [out-licensing arrangement] with a partner that would be interested in taking it further."

Such a deal might not be too far down the road, Amarzguioui added.

"What we have at this point [in the tissue factor program] could be of interest to a partner," he said. "Preliminary contacts have been made … [but] whether to pursue them depends on whether it makes business sense or not. That's a decision that would have to be made for each project."

The earlier a deal is struck, however, the faster a drug is expected to move down the development pipeline, he said. For example, in the company's tissue factor program, "If we do all the work ourselves, we're possibly talking about two years" until phase I studies, he said. "With more resources and a collaboration, that could be less time."

— Doug Macron ([email protected])

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