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With a Leaner Structure and Maturing Technologies, Marina Looks to Rebuild

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With a portfolio of more mature technologies and increased interest in RNAi from the investment and pharmaceutical communities alike, Marina Biotech expects to rebuild itself as a leaner company with a greater focus on drug discovery, the struggling company’s top official said this week.

According to Marina President and CEO Michael French, the firm’s strategy of buying up attractive RNAi technologies put it under a financial burden it proved incapable of supporting, which contributed to its virtual shutdown last year.

But as sentiments regarding RNAi as a therapeutic modality improve, and having shed expenses associated with its predecessor company, Marina is now in a position to secure the funding needed to restart operations, he said.

Marina had been a promising player in the RNAi drugs space beginning in 2006 when intranasal drug-delivery firm Nastech Pharmaceuticals acquired Galenea as a way to give it a footing with the gene-silencing technology (GSN 2/23/2006).

Bothell, Wash.-based Nastech later transformed itself into MDRNA, dropping its legacy programs and focusing exclusively on RNAi. The company later replaced its leadership, bringing on Sirna Therapeutics veteran Michael French as its new president and CEO.

In 2010, MDRNA acquired Cambridge, Mass.-based Cequent Pharmaceuticals and its proprietary oral RNAi delivery technology, and once again changed its name — this time to Marina (GSN 4/1/2010). At the time, French said that the deal represented the latest step in the company’s “roll-up strategy” of bringing together complementary RNAi technologies under the same roof.

Indeed, under French’s leadership, Marina had been active in seeking out and acquiring various RNAi-enabling technologies. In 2008, the firm bought the intellectual property around RiboTask’s unlocked nucleic acids, which comprise an acyclic ribonucleoside analog in which the bond between C2' and C3' atoms is broken (GSN 10/23/2008). The resultant change in sugar structure is designed to make the analogs flexible and reduce the binding affinity of siRNA strands.

A few months after the Cequent transaction, Marina bought the IP of Novosom, including the patents and patent applications related to that company’s Smarticle liposome-based delivery technology (GSN 7/29/2010).

That same year, Marina also acquired Valeant Pharmaceuticals’ bridged nucleic acids, which it renamed conformationally restricted nucleotides (GSN 3/25/2010). According to the company, CRNs are nucleoside analogs in which the flexible ribose sugar is locked into a rigid conformation by a small chemical linker, boosting the thermal stability of a duplex RNA and increasing the affinity of single-stranded RNAs for their complementary targets.

Meanwhile, it was working on its own proprietary technologies, such as the so-called DiLA2 liposomal delivery vehicles.

“Pulling all these assets together and creating a broad nucleic acids drug-discovery engine … was always the vision,” French said. However, “the level of effort required to execute that strategy from a financial perspective … was probably too detrimental to the company.

“It was a good idea, and I still think it was a good idea, but it was harder to execute than I hoped it would be,” he added.

By mid-2012, with its familial adenomatous polyposis treatment CEQ508 midway through the first part of a phase Ib/IIa clinical trial and no sources of financing available, Marina was forced to shut its doors and halt the CEQ508 study (GSM 6/7/2012). It began selling off its equipment and laying off the majority of its employees shortly thereafter.

But Marina never quite gave up the ghost and continued to pursue the money it would need to restart. For instance, last December, it non-exclusively licensed the UNA technology to Tekmira Pharmaceuticals and last week announced that it had sold its UNA IP to startup Arcturus Therapeutics, while holding on to a non-exclusive license for its own purposes (GSN 8/15/2013).

The company also stands to receive milestones from microRNA drug developer Mirna Therapeutics and DNA-based drug firm ProNAi Therapeutics, both of which are using the Smarticle technology in clinical-stage programs.

In conjunction with the Arcturus deal, Marina announced that it is poised for a comeback, stating that it had amended a secured loan to extend its maturity date into early next year. It also expects to close before the end of this year either a partnership or financing arrangement that would enable it to move to restart operations in a new headquarters in Cambridge.

According to French, Marina long had designs on relocating to the Kendall Square area, and was only located in Bothell because of Nastech. However, the costs associated with the move delayed any such move.

But in its current state, Marina is for all intents and purposes a “Series A restart” with “nothing holding us to Seattle,” he said. Key personal have agreed to relocate, French said, and recent downsizing by companies including Alnylam Pharmaceuticals and Pfizer, which closed its Cambridge-based oligo therapeutics unit in 2011, have created in a pool of talent with nucleic acids experience from which to draw.

Still, French wants to make sure Marina’s regrowth happens in a measured fashion. He said the company will be considerably leaner than it was in the past, with about 15 to 20 employees for the foreseeable future versus the 60 staffers when he first come onboard.

At the same time, Marina anticipates using contract research organizations to continue the CEQ508 study, which could relaunch as early as the first quarter of next year and complete patient dosing in the phase Ib portion by the end of 2014.

Importantly, he said that the new Marina will have a much sharper focus on drug discovery than it did in the past, when it was spending a lot of time and resources on simply exploring and optimizing its various technologies.

“A lot of benchtop research was conducted from 2010 to 2012,” French said. Going forward, “we’ll be set up to exploit the drug-discovery aspects of the technologies [more] than trying to figure out what the technologies could do.”

Meanwhile, progress continues to be made by other players in the RNA therapeutics space — such as Alnylam, which has reported strong phase I data with its TTR-mediated amyloidosis treatment ALN-TTR02, and Isis Pharmaceuticals, which secured US Food and Drug Administration approval for its hypercholesterolemia treatment Kynamro — milestones French sees as helping Marina find funding and potentially, a partnership.

Indeed, investments in companies working with the technology have been on the rise lately, with publicly traded companies raising more than $230 million combined in the first part of this year alone (GSN 8/8/2013).

At the same time, big pharmas have shifted away from running oligo drug programs in-house and back toward the traditional model of partnering with smaller biotechs that handle early-stage development before taking over promising candidates for commercialization, French said.

It is in this climate, he added, that he aims to “take those steps forward that establish the first partnerships that … can rebuild value in the company.”

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