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Mirna Reports Preclinical Data on Lead miRNA Replacement Drug, Focusing on Upcoming Phase I

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Mirna Therapeutics this week announced new preclinical data on its lead microRNA replacement therapy, MRX34, which the firm says further validates the drug candidate's potential as a treatment for solid tumors.

The data were presented at the Keystone Symposia's Non-Coding RNAs in Development and Cancer conference.

Meantime, having recently closed a $34.5 million Series C round of financing (GSN 10/25/2012), the company is well funded to meet is goal of filing an investigational new drug application for MRX34 before the end of the first quarter, Mirna President and CEO Paul Lammers told Gene Silencing News.

But despite the cash infusion, Mirna isn't rushing other pipeline candidates, which are all oncology related, into the clinic, he noted.

In addition to the miR-34a mimic that forms the basis of MRX34, Mirna is also developing synthetic versions of let-7 and miR-16, among other miRNAs.

And while these earlier-stage programs have thus far yielded promising data, focusing the lion's share of its research and development muscle on advancing MRX34 through phase II is expected to provide “clear human proof of concept with a tumor suppressor replacement therapy approach,” Lammers said. Once that is done, Mirna will be better equipped to go ahead with the rest of its pipeline since all the candidates will use the same delivery technology and will follow essentially the same development path.

Helping push MRX34 to the head of Mirna's pipeline is a growing body of evidence linking miR-34a to various cellular processes implicated in cancer. Most notably, the miRNA family has been shown to play a key role in the p53 tumor suppressor pathway.

However, recent work conducted at Mirna indicates that the miRNA represses the expression of more than 20 oncogenes, and inhibits processes vital for cancer cell viability, cancer stemness, metastasis, and chemoresistance, the company said this week.

Similar findings have come out of the lab of Harvard University researcher Judy Lieberman, who reported in 2011 that miR-34a targets genes involved in growth factor signaling, including ARAF and PIK3R2, and cell cycle progression at various stages of the cell cycle.

Such data suggest that a miR-34a mimic may offer therapeutic benefit in a range of cancers. Mirna previously reported that MRX34 could significantly inhibit tumor growth in a mouse model of liver cancer (GSN 11/17/2011), and has shown that the agent could be reduce lung tumor burden in mice when delivered systemically (GSN 3/23/2011).

Last year, Mirna and collaborators also reported that the drug could inhibit tumor growth in a model of diffuse B cell lymphoma (GSN 5/3/2012).

Contributing to MRX34's positive effects in animal models are the liposomes being used to deliver it. As reported by Gene Silencing News, Mirna licensed Marina Biotech's Smarticle technology about a year ago, ending a longstanding search for a delivery vehicle for its drug candidates (GSN 1/5/2012).

According to Lammers, new data from mouse, rat, and non-human primate studies show that Smarticles offer efficient delivery with no immune stimulation. These experiments also confirmed that any observed toxicity was a result of the liposomes and not the miR-34a payload, with similar side effects observed following treatment with MRX34 and a negative control.

Pointing out that liposomes are employed in a number of currently marketed cancer drugs, he said that the side effects have all been “in line with the guidance on liposomes that the [US Food and Drug Administration] has issued.”

Also reinforcing the safety of the Smarticle technology are clinical data from ProNAi Therapeutics, which is developing single-stranded DNA oligonucleotides as therapeutics. Late last year, the company announced that its lead candidate, which is delivered using Smarticles, caused no significant side effects in a 22-patient phase I trial — results that Lammers called “very encouraging for us.”

Aside from the apparent safety of the Smarticle technology, he said that Mirna has found it to enable effective distribution of MRX34 in rodents and monkeys to not only the liver and spleen, where lipids naturally aggregate, but also to lymph nodes in the thorax and abdomen, and tumors in the lung and colon.

“That bodes well for our phase I cancer patient profile,” Lammer said.

The planned study of MRX34 will enroll patients with primary liver cancer or advanced solid tumors with liver involvement. The first part of the trial will examine escalating doses of the drug in around 30 patients. However, once the maximum tolerated dose is identified, Mirna plans to enroll an additional 18 patients with different types of cancer as part of an enrichment phase that will test the drug's effect in tumors outside of the liver, depending on the outcome of the first part of the trial.

In particular, Mirna thinks miR-34a is very involved in non-small cell lung cancer, Lammer said. “We hope that we can drive enough microRNA copies into the lung tumor to see an effect.” If so, “we may decide to have more patients with lung cancer included [in the enrichment phase] without the liver metastasis requirement.”

Mirna continues to weigh the possibility of running a phase Ib trial of MRX34 as part of a combination therapy with standard cancer drugs, but Lammers said this week that the company is sticking to its plan of pushing the drug forward as a standalone treatment for cancer.

Any phase Ib study will depend on “what tumors we get enrolled in the [phase I] and the responses we see, if any,” he said. “In phase I, we have to be realistic about how many patients we will see because it's an advanced cancer patient population. That's just the way oncology drug development works.”

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