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Mirna Reports on Role of miR-34a in B Cell Lymphoma, Expands Planned Phase I Beyond Liver Cancer

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Mirna Therapeutics and collaborators at the University of Zurich reported last week that the company's therapeutic microRNA-34a mimic, dubbed MRX34, could inhibit tumor growth in an animal model of lymphoma, expanding the potential use of the agent to new cancer types.

According to the paper, which appeared in Leukemia, the investigators showed that diffuse B cell lymphoma can transform from an indolent to an aggressive state when miR-34 expression is lost. “By giving miR-34 back into tumors, you can control tumor growth and really inhibit their further development,” Mirna President and CEO Paul Lammers told Gene Silencing News.

This findings “open up, potentially … another option down the road for patients who have this kind of transition in these kinds of B cell lymphomas,” he said, adding that Mirna is continuing to explore different therapeutic opportunities for MRX34 as it preps for a phase I study of the drug next year.

“We have a development path, bringing MRX34 into the clinic … and a research path where we're trying to expand the potential clinical indications,” Lammer explained. “This paper is the first out of a series of experiments we're running, either in-house or with collaborators, looking at different tumor types in different models.”

MRX34, which is formulated with Marina Biotech's Smarticle liposome particle-based delivery technology, was originally under development for liver cancer based on strong preclinical data (GSN 11/17/2011).

“We did a lot of work in an orthotopic liver cancer [mouse] model … and we see dramatic results,” Lammer explained. “However, we have also now shown that we can see very effective biodistribution to other tissues, including tumors located in the lung [and] lymph nodes. Therefore, we have decided to switch our phase I program from liver cancer to an … all-comers” clinical study.

“That could be anything from lung to ovarian” cancer, he noted, adding that the company still expects “a number of patients with liver-based disease” to be enrolled in the trial. ”At the end, we'll see which tumors and locations are most amenable to the treatment.”

This will help guide patient population decisions for later investigation, including a planned 10-patient expansion to the phase I study following the establishment of a maximum tolerated dose for MRX34, Lammers said.

He said Mirna has contracted manufactures for both the miRNA mimic and the liposomal delivery formulation, and is on track to file an investigational new drug application by year end, putting the firm on course to launch the phase I study in early 2013.

Mirna has not provided guidance on when it might begin testing MRX34 in non-solid tumors, but Lammers said it remains committed to doing so, as evidenced by the Leukemia publication.

According to the paper, mouse models of B cell lymphoma received intravenous treatments of MRX34. Treated mice experienced an average reduction in tumor growth of 76 percent compared with controls, and none exhibited adverse effects or developed tissue abnormalities.

Additionally, treated tumors expressed elevated levels of miR-34a, and exhibited significantly higher apoptosis rates than control tumors, the paper's authors wrote.

“The results presented here illustrate how miRNAs could be harnessed in the future for the treatment of aggressive lymphoma for which other targeted treatment modalities are lacking,” they concluded.

“Suitable patient cohorts may be identified based on their lack of tumor cell intrinsic miR-34a expression,” they added, and treatment is not expected to have significant side effects given the normal expression of miR-34a in non-tumor tissues.

“We feel MRX34 has a lot of potential and we want to support that by doing the right type of in vivo experiments,” Lammers said.

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