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With Drugs in the Clinic, Gradalis Starts Looking to Partner Its Technologies

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With its core expressed RNAi technology under evaluation in several phase I and II cancer studies, Gradalis is setting its sights on transitioning from a company focused on a handful of drug candidates into one with a platform technology that can be partnered out to others working in the space, a company official said this week.

"To date, we've been a product company,” David Haselwood, Gradalis' head of business and corporate development, told Gene Silencing News this week. “We're now realizing we can also be a platform company ... [and are reaching] out to start expanding our base of collaborators.”

Such an effort includes not only looking for potential partners working in indications outside of Gradalis' core oncology interest, he said, but also ones that may want to use its RNAi and delivery technologies in non-human applications such as biologics manufacturing • similar to what Alnylam Pharmaceuticals is doing with its Alnylam Biotherapeutics initiative (GSN 11/19/2009).

Haselwood stressed, however, that this strategy is in its earliest stages, and that attracting partners will require Gradalis to be able to demonstrate the efficacy of its technologies with strong human data.

The firm's primary technology is its bi-functional shRNAs, which are designed to trigger both cleavage-dependent and cleavage-independent RISC-mediated inhibition of target mRNA and first entered clinical testing when Gradalis launched a phase I trial of its so-called FANG cancer vaccine in solid tumors in late 2009.

The vaccine expresses the immunostimulator recombinant human granulocyte-macrophage colony-stimulating factor, or GMCSF, which stimulates the immune system. It also expresses bi-functional shRNAs against furin, an enzyme responsible for lysing the components of the protein TGF-beta that are involved in cellular proliferation and differentiation.

With FANG, autologous tumor cells are transfected with the therapy, irradiated, then injected back into the patient. The GMCSF component recruits and activates antigen-presenting cells at the site of injection to promote antigen presentation, while the furin shRNA prevents the production of TGF-beta isomers, which cancer cells use to avoid detection and destruction by the immune system.

That phase I trial is ongoing, and Gradalis has since launched a series of phase II studies in high-risk stage IIIc ovarian cancer, advanced melanoma, and colorectal cancer.

Meantime, Gradalis also advanced another cancer drug into phase I testing for advanced and/or metastatic cancer. That agent is purely shRNA-based and is designed to inhibit stathmin-1, a protein that is mutated in about 65 percent of cancers and is linked to abnormal cell proliferation.

Unlike FANG, this drug is encapsulated in a proprietary fusogenic DOTAP-cholesterol cationic liposome delivery vehicle, which was developed by a privately held company called GeneExcel that Gradalis acquired, and injected intratumorally.

However, Gradalis ultimately aims to develop the stathmin-1 drug as an intravenously administered therapy, Haselwood noted. Once the ongoing phase I trial concludes this year, the company expects to launch a phase Ib trial that will examine the IV formulation's safety and tolerability, and then move into phase II efficacy studies, he said.

Should the phase Ib prove successful, Gradalis plans to move two additional IV-administered bi-functional shRNA drugs into the clinic. The first targets pancreatic and duodenal homeobox factor, or PDX-1, which is involved in pancreatic development and differentiation. According to Gradalis, over-expression of PDX-1 in pancreatic acinar cells results in acinar to ductal cell metaplasia, and is known to occur in a variety of other cancers.

The second targets K-RAS, a gene involved in tissue signaling but which is mutated in many cancers. According to Haselwood, this program is expected to be the first in which Gradalis explores a multiple gene-knockdown approach, combining shRNAs against up to five different K-RAS mutations into a single agent.

“An initial drug candidate in K-RAS would likely target a single, well-established mutation,” he explained, but a final product would likely have multiple targets.

Haselwood added that, in addition to its in-house liposome delivery vehicles, Gradalis also acquired from GeneExcel reversible masking and targeted delivery technologies that help the drug reach its target tissue and avoid clearance from the bloodstream, and which are incorporated into the company's drug candidates.

In 2010, GeneExcel founder and Baylor College of Medicine researcher Nancy Templeton published a report in Gene Therapy describing the use of these approaches to enhance the transfection efficacy of GeneExcel's delivery liposomes in vivo.

More recent data on the technologies, generated in a National Institutes of Health-sponsored study, are slated for publication, he noted.

Though Gradalis is still in the process of generating the clinical data that will be central to its effort to secure partnerships, one aspect of its business it feels is already well established is its intellectual property portfolio.

Earlier this year, the US Patent and Trademark Office issued the company a patent on the bi-functional shRNAs, which Haselwood said was an important validation of the uniqueness of the technology.

The patent, No. 8,252,526, is entitled “shRNA Molecules and Methods of Use.”.

Notably, expressed RNAi firm Benitec has publicly stated that Gradalis is using its own patented technology with its product candidates, namely the FANG vaccine. However, Haselwood pointed out that Gradalis currently does not have any business relationship with Benitec.

At the same time, Gradalis believes that it has the freedom to operate based on its existing IP, he said.

“We are always mindful ... of other people's intellectual property,” Haselwood added. However, “we have not felt the need at this point to license any additional technology ... when it comes to interfering RNA.”

Still, “should the need arise ... [licensing] would be something we'd obviously look at,” he added. "We're open to working with anybody.”

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