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MDRNA Begins Primate Studies in Liver Cancer Program, Adds Bladder Cancer to Pipeline


By Doug Macron

This story has been updated to include company comment on its newly announced bladder cancer program.

MDRNA has begun non-human primate studies within its lead liver cancer program with the goal of selecting a lead drug candidate by the end of the year and potentially filing an investigational new drug application by late 2010, a company official said last week.

At the same time, the company has expanded its pipeline to include bladder cancer after achieving positive results in rodent studies conducted through a partnership with the University of British Columbia, and could file an IND from this program as early as the end of 2011, the official added.

MDRNA also reported its second-quarter financial results last week, posting a nearly 50 percent drop in its net loss despite decreased revenues. The company attributed the improvement to decreased costs following its completed transition from the clinical-stage intranasal drug-delivery shop Nastech Pharmaceuticals to a preclinical RNAi-therapeutics developer.

Although it had initially intended to pursue a variety of different indications (see RNAi News, 8/7/2008), earlier this year MDRNA said that it would work exclusively on liver cancer as a way to conserve cash in a difficult economy (see RNAi News, 3/26/2009).

That sharpened focus appears to have paid off. Speaking last week during a conference call held to discuss MDRNA's second-quarter results, CSO Barry Polisky noted that the company has been able to demonstrate "efficient delivery and effective knockdown of multiple targets in rodents," including an in-house rodent model of the liver cancer.

In February, the company reported that its UsiRNAs — duplex siRNAs modified with non-nucleotide acyclic monomers, called unlocked nucleobase analogs, in which the bond between two adjacent carbon atoms of ribose is removed — were capable of triggering significant inhibition of apolipoprotein B in a rodent model.

A few months later, the company said that UsiRNAs were able to inhibit expression of the blood-clotting factor Factor VII in rodents by more than 90 percent with a duration of effect lasting up to 28 days.

"We've demonstrated that our DiLA2 [liposomal delivery] platform is well-tolerated and safe in rodent models, and … we have established a robust and scalable process [that] results in manufacturing reproducible lots of formulated UsiRNAs with long-term stability," Polisky noted. As such, "we're talking the next logical step and evaluating our proprietary compounds in non-human primates."

These "non-terminal" primate studies, he noted, are designed to give a better indication of the tolerability of the company's formulated RNAi drugs and to provide functional target-knockdown data.

Specifically, MDRNA will evaluate the effect of its UsiRNAs to inhibit Factor VII, an "easily measured target in monkeys," he said. "We're going to be able to get some idea of the tolerance and safety of the material in non-human primates … [as well as] some functional information on the knocking down of a particular gene that is expressed in the liver.

"These are experiments that are designed to broaden our understanding beyond rodents, where we have seen very good behavior of these materials and potent knockdown of the target," he added. "We want to simply determine that we can see the same thing in a non-human primate."

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Should the primate work goes well, Polisky said that MDRNA expects to have initial data within about four weeks, and will announce the preliminary findings "later in this quarter."

In response to a financial analyst's question during the conference call, he said that MDRNA expects to have identified a lead candidate for the liver cancer program by the end of 2009, a timeline that reflects the benefits of the company's liver-cancer model and "the anticipated results from the non-human primate studies."

As a result, "we should be able to have IND-enabling data and preparations completed by the end of 2010," although he cautioned that this timeline is optimistic and assumes that "everything went very smoothly and according to plan."

Meanwhile, MDRNA has formally expanded its pipeline just months after cutting loose a number of drug-development programs in order to streamline its operations.

"Recently, our UsiRNAs and delivery systems have demonstrated early but encouraging results in a rodent model of human bladder cancer where we've shown significant knockdown of human survivin messenger RNA present in the tumor" with no apparent cytokine induction, Polisky said.

Also driving MDRNA's interest in bladder cancer is that the disease "offers the opportunity for local delivery," Polisky told RNAi News this week. In light of the challenges of systemic RNAi drug delivery, being able to administer a therapeutic directly to the target tissue, in this case through a urinary catheter, "has a lot of appeal for us."

He added that MDRNA plans to continue its bladder-cancer collaboration with researchers at the University of British Columbia, and could potentially file an IND for a bladder cancer drug by late 2011 or early 2012. "We're still in early pre-clinical development … [however, and] it's a bit difficult to pin this down precisely," he stressed.

About a year ago, MDRNA's former CSO and Chairman Steven Quay, who had been a co-founder of Nastech, said that the company had a bladder cancer drug under development that targeted survivin, a member of the inhibitor of apoptosis family; polo-like kinase 1, a gene linked to solid-tumor growth; and epidermal growth factor receptor, a cell-surface receptor that is over-expressed in many cancers.

Polisky told RNAi News that the company continues to evaluate all three targets in the current bladder cancer program, but that the drug's ultimate target or targets have not been determined.

"They are on the table … but I wouldn't say we've made a final decision on what our targets are going to be," he said. And while it is very possible that a drug candidate will be a cocktail of siRNAs against multiple targets, "it's still too early to make any kind of statements there."


For the three-month period ended June 30, MDRNA's net loss fell to $7.5 million, or $0.21 per share, from $14.3 million, or $0.48 per share, the year before.

Revenues in the quarter, derived primarily from licensing fees from Novartis and Roche (see RNAi News, 4/19/2009), slipped to $300,000 from $800,000 in the same period a year earlier.

Research and development spending declined almost 50 percent in the second quarter, to $4.3 million from $8.5 million. Selling, general, and administrative expenses, meantime, slipped to $2.3 million from $3.8 million, reflecting headcount reductions associated with the transition from Nastech and cost-cutting efforts.

As of June 30, MDRNA had roughly $9.4 million in cash and cash equivalents, which CEO Michael French said during last week's call will be sufficient to fund operations for about six months.

He added that the company continues to expect to be able to sign additional money-generating partnerships in the future, although he did not provide specific details, as it leverages its forthcoming non-human primate data.

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