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PhaseRx Inks Tech-Evaluation Deal with Monsanto as It Advances Liver Cancer Program

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PhaseRx announced this week that it has signed an RNAi delivery technology-evaluation deal with ag-bio giant Monsanto, a key step forward in the startup's effort to license out its core technology in areas outside its focus on human therapeutics.

According to PhaseRx, Monsanto will test the delivery technology for its potential in agricultural applications. The company said it will receive an undisclosed amount of funding during the evaluation period, but specific terms of the arrangement were not made public.

A Monsanto spokesperson confirmed that the company was testing PhaseRx's technology for use in its various RNAi-based programs, but did not provide additional details.

As reported by Gene Silencing News, Monsanto recently announced that it is moving four product candidates incorporating RNAi through its pipeline (GSN 1/17/2013). These include pest-resistant corn, pesticides, and plant virus-control agents, as well as bee health products through its Beeologics unit.

PhaseRx was founded in 2006 to advance an RNAi delivery approach developed in the labs of University of Washington researchers Patrick Stayton and Allan Hoffman. That technology, dubbed Smart polymers, consists of linear polymers that incorporate targeting ligands; chemistries for RNA association, shielding, and endosomal release; and an siRNA payload.

The polymers are designed to mimic the cellular-entry activity of viral glycoproteins, PhaseRx President and CEO Robert Overell explained.

“About half of mammalian viruses get into cells through the endosomal route,” he said. “The ones that do have a conditionally membrane-active peptide in their envelope, which is hydrophilic at physiologic pH and hydrophobic and membrane-destabilizing at endosomal pH.”

The Smart polymers take the same approach, starting off hydrophilic and then becoming hydrophobic following endocytosis, which enables them to pass out of the endosome and into the cytoplasm.

According to a 2010 publication by Stayton, Hoffman, and colleagues in Biomacromolecules, the Smart polymers are composed of a positively charged block of dimethylaminoethyl methacrylate, which mediates siRNA binding, and a pH-responsive endosome-releasing block composed of DMAEMA, propylacrylic acid, and butyl methacylate.

“These polymers spontaneously form spherical micelles in the size range of 40 nm,” which were unaffected by the addition of siRNAs, the paper's authors wrote. In lab tests, greater than 90 percent of cells transfected with the polymers contained fluorescently labeled siRNAs, which dispersed throughout the cellular cytoplasm.

Although it had initially planned to focus on licensing the Smart polymer technology to other companies for use within their own RNAi drug pipelines, the company later shifted its strategy to include in-house drug development, Overell said. With that new course set, PhaseRx has two liver cancer drug candidates in its pipeline, and expected at least one to yield an investigational new drug application filing by mid-2014.

The first program focuses on beta-catenin, a known oncogene that has been associated with a variety of cancers including colorectal, ovarian, and liver cancers, he noted.

The second is targeting the tyrosine kinase Met, which has been linked to cellular transformation, motility, and survival. While not an undruggable target by traditional therapeutic modalities, “kinase inhibitors have not done very well in [hepatocellular carcinoma], so we believe RNAi therapeutics represent a very interesting modality to go after what is a quite well-validated target,” he added.

As this work progresses, PhaseRx is still keeping an eye out for those who may be interested in using the Smart polymers for other applications, and the deal with Monsanto represents the first such arrangement.

PhaseRx also hopes to find a partner for its liver cancer programs, ideally upon the completion of IND-enabling studies. If it should fail to do so, however, “we're perfectly willing to do [a phase I study] by ourselves, if that's what it takes,” Overell said.

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