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Cash in Hand, Marina Aims at Rare Diseases with More than Just RNAi

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Having just closed its first financing transaction in two years, struggling Marina Biotech announced that it plans to continue looking beyond just RNAi and develop drugs using a number of different nucleic acid modalities. Unlike previous years, however, the company now intends to stick to rare diseases.

And while the company's orally delivered, RNAi-based familial adenomatous polyposis drug CEQ508 remains at the head of its pipeline, Marina anticipates that its nascent dystrophy programs will likely become its primary focus, President and CEO Michael French told Gene Silencing News this week.

Created out of the RNAi drug operations of now-defunct Nastech Pharmaceutical in 2010, Marina (then known as MDRNA) began building a portfolio of nucleic acid drug and delivery technologies under the leadership of French, who hoped the company's broad platform would attract pharmaceutical partners.

Yet deals failed to materialize, and in mid-2012 the company was forced to halt virtually all its operations under a severe cash crunch.

But late last month, Marina announced that it had found buyers for $6 million in convertible preferred stock. That transaction has now closed, giving the company enough funds to carry it through 2014 and setting it up to restart its drug-discovery and -development work.

At the same time, Marina has shifted away from large indications such as bladder cancer and hypercholesterolemia that it had once pursued in favor of going after small, rare diseases — a trend in the RNA drugs field that continues to grow amid successes by companies like Alnylam Pharmaceuticals.

By going after niche indications, French hopes that Marina will be able to secure the big pharma partner that has thus far eluded the company, potentially by the fourth quarter of the year.

"Pharma [has begun] to recognize the importance of the rare disease space," French said, noting that firms such as Pfizer, GlaxoSmithKline, Novartis, and Sanofi all have units dedicated to such indications.

And because many such disorders are caused by abnormalities in a single gene, "the targets in most of these things are pretty well defined," making them easier to go after with nucleic acid approaches than heterogenic conditions like diabetes, he added.

But unlike Alnylam, which remains a pure-play RNAi shop, Marina is sticking to its multiple drug modality plan, which French said has become an even more viable strategy in the years since the company first undertook it.

"We always thought that what the drug discovery and development sector needed was an integrated nucleic acid drug-discovery platform," French said. "When it got right down to it, nobody really cares how you get the job done, just that you get the job done. Big pharma doesn't care if it's an siRNA, a microRNA mimic, or an exon skipper; what they care about is the patient gets better."

When Marina first set out on this path, "only a couple of those modalities had made it into the clinic in a meaningful way," making them a hard sell to potential industry collaborators, he said. "Now … in 2014, mostly everything has made it into the clinic."

Indeed, an miRNA mimic is already in phase I testing with Mirna Therapeutics cancer drug MRX34, while Santaris Pharma has an miRNA inhibitor in phase II with its hepatitis C treatment miravirsen. Meanwhile, Alnylam's TTR-mediated amyloidosis drug patisiran has advanced into phase III, and Prosensa and GlaxoSmithKline have an exon-skipping drug in phase II for Duchenne muscular dystrophy.

Regardless of whether these and similar drugs prove effective, they have been shown to be safe, French said, which is "a huge de-risker for pharma."

As it goes after partnerships, Marina is also planning to restart its own drug-development programs, beginning with CEQ508, which is based on an oral delivery technology known as transkingdom RNAi, which involves using attenuated Escherichia coli to transcribe therapeutic shRNAs.

Before it halted its operations, Marina had completed a portion of a phase I trial for the drug, dosing two of four cohorts in a dose-escalation arm of the study. The company now plans to complete the phase I trial before year-end, hopefully generating proof of concept data on the transkingdom approach, French said.

But Marina's true interest going forward will be in muscular and corneal dystrophies, and it is here, too, that French sees the company's broad platform of technologies as coming into play.

"What Marina is bringing to the table is the ability to go after multiple mechanisms of action within a disease process," he said. With Duchenne muscular dystrophy, for example, "our lead [candidate] may be an exon skipper, but our backup might be … a messenger RNA translational inhibitor. … We're not having a failure of a modality causing the failure of the program."

Further enabling this approach is a suite of delivery and modification technologies including conformationally restricted nucleotides (CRNs), unlocked nucleobase analogs, and proprietary lipid nanoparticles dubbed Smarticles.

Given its limited resources, French said that Marina plans to conduct the bulk of its research and development through contract research organizations and academic collaborators, although there may be "some additional work we want to do as we look at delivery technologies and certain kinds of tissue systems … [or] the optimization of modification patterns with the chemistry."

With the $6 million stock sale only just having been consummated, work on Marina's internal programs has been very limited. However, the company has generated some data on CRN-modified mRNA translational blockers for myotonic dystrophy in collaboration with an undisclosed research group, and French said that the firm is aiming to generate in vivo proof-of-concept data by the end of the third quarter.

In line with its overall strategy, he said that animal studies will likely test an exon-skipping agent, the mRNA translational blocker, and possibly a steric blocker. "We'll put all of those in the same animal model and see which wins," he added. "We're going to try not to get wrapped around one technology as the final solution."

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