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RXi Inks Deals with Mirna, Miragen to Examine Proprietary RNAi Molecules as miRNA Mimics

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By Doug Macron

RXi Pharmaceuticals this week said that it has struck two separate deals, one with Mirna Therapeutics and one with Miragen Therapeutics, to evaluate its proprietary RNAi molecules, dubbed rxRNAs, as therapeutic microRNA mimics.

And while RXi continues to bill itself as an RNAi drug developer, a company official indicated this week that the firm may expand its focus into the miRNA field as it works to meet its goal of defining its areas of therapeutic interest by the end of the second quarter.

Under the first deal, RXi and Mirna will evaluate whether rxRNAs can be used as miRNA mimics against targets in oncology, Mirna's core disease area. In the second arrangement, RXi will work with Miragen to develop rxRNAs as therapeutic miRNA mimics for cardiovascular and muscle diseases, fields in which Miragen specializes.

According to RXi President and CEO Noah Beerman, the primary focus of the deals is one particular type of rxRNA technology called self-delivering rxRNA, which may provide delivery advantages over alternative miRNA mimics.

The collaborations call for RXi to design sd-rxRNA molecules as miRNA mimics against a series of targets chosen by each of the three companies.

"We'll be doing the work to design those molecules, and then the majority of the in vivo and in vitro testing will be done by the partner company," he told RNAi News. Specific terms of the deals, including the financials, were not disclosed.

The sd-rxRNA technology was developed in collaboration with Advirna, a privately held biotech shop founded by RXi CSO Anastasia Khvorova, and fully acquired by RXi late last year (RNAi News 10/1/2009).

Although publicly available details about sd-rxRNAs are limited, RXi presented data earlier this year showing that the molecules were efficiently taken up by a variety of cells without the need for a delivery vehicle, and are effective in vivo when administered either systemically or locally (RNAi News 1/21/2010).

"We know that the sd-rxRNAs have the unique ability to be self-delivering and not require an additional delivery vehicle," Beerman said. This is "attractive in the traditional use of siRNAs, but we also believe … that it could be attractive in the development of microRNA mimics, as well."

Indeed, Mirna President and CEO Paul Lammers said that while his company has been conducting work in-house with lipid emulsions and with an undisclosed partner on nanoparticles for miRNA mimic delivery, "we have also been looking to see how we can work with other companies that have developed potential different ways of delivering [synthetic] microRNAs to target tissue."

He said that Mirna has the most data on the lipid emulsion approach, and because it is fully owned by the company, it is "ideally … the one we'd take forward" into the clinic. But the deal with RXi provides "a way to cover all bases," he noted. Mirna expects to file its first investigational new drug application in late 2011.

Similarly, the arrangement with RXi provides Miragen with a way to address potential delivery hurdles facing therapeutic miRNA mimics.

"When one thinks of microRNA mimicry, you run into a lot of the same inherent challenges you run into with an siRNA," Miragen President and CEO Bill Marshall told RNAi News. "What we've discovered through work on mimicry … is that the biggest challenge … is effective delivery of the molecules."

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Unlike Mirna, which has always been focused on miRNA mimic development, most of Miragen's work centers around miRNA inhibitors as therapeutic agents, and Marshall indicated that the company's first IND, the filing of which is expected to occur sometime next year, will likely be with such an agent.

"But there is some compelling biology at play with mimicry and we don't want to ignore that," he said.

"To balance the portfolio and bring up more targets we could bring forward, we definitely want to be at the cutting edge in terms of mimicry," Marshall noted. "At the end of the day, that means you either design double-stranded molecules that are more standard in their length and character to what an siRNA is, or you start looking at alternatives. We really want to start looking at alternatives [such as sd-rsRNAs] because you run into the delivery issues … [that] are potentially more significant with double-stranded triggers than some alternative structures."

Beyond RNAi?

Since it was spun out of CytRx in early 2007, RXi has expressed interest in a variety of different disease areas, but committed to none. This failure is something of which Beerman, who took the company's helm last November, said he is keenly aware and that charting RXi's course is a top priority.

Earlier this month, he said during a conference call held to discuss the company's fourth-quarter financial results that one of RXi's goals for the year is "refining [its] therapeutic focus" (RNAi News 4/1/2010).

This week, he told RNAi News that "this is a project that we've kicked off … and we will be announcing a more … focused strategy by the end of [the second] quarter."

Notably, an effort to develop a miRNA mimic could very well be among the "three or four therapeutic programs" the company plans to unveil, he said. However, he stressed that this is not necessarily going to be the case, and the fact that RXi is working with two miRNA drug shops is "not a reflection, one way or the other, of areas we may focus on."

The deals do, however, give RXi "the ability to leverage the [sd-rxRNA] technology into some really exciting areas," namely cardiovascular disease and oncology, he noted.

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