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Marina Takes Aim at Big Pharma Partnerships with RNAi Alternatives


By Doug Macron

While it intends to maintain its focus on its core RNAi technology, Marina Biotech is working to position itself as a go-to partner for big pharmas by also offering capabilities in antisense and microRNAs to hit so-called undruggable targets, the company's top official said this week.

“Diversity is critical to success,” French said during a presentation at the BIO CEO and Investor conference in New York. Just as “no one single delivery technology is going to solve everything, no one single modality approach in the RNA and RNAi sector” is going to be the sole answer.

Since its transformation in 2008 from nasal drug-delivery shop Nastech Pharmaceutical to the pure-play RNAi therapeutics company MDRNA (GSN 8/7/2008), Marina has been steadily building a portfolio of different technologies that it is betting will provide multiple avenues to approach disease targets.

Internally, the company has developed UsiRNAs, duplex siRNAs that are modified with non-nucleotide acyclic monomers, and the so-called DiLA2 platform for creating liposomal delivery vehicles. Meanwhile, it has also looked beyond its own walls for promising technologies.

For instance, last April it acquired Cequent Pharmaceuticals and its orally delivered transkingdom RNAi technology (GSN 4/1/2010), and three months later picked up Novosom's Smarticle drug-delivery liposomes (GSN 7/29/2010).

During his presentation, French also highlighted Marina's conformationally restricted nucleotide technology, which essentially comprises nucleotide analogs to which the C2' and C4' carbon bonds of the ribose ring are linked.

Similar to Santaris Pharma's locked nucleic acids, CRNs are designed to have increased hybridization affinity, but differentiate themselves from LNAs by a longer linker and an oxygen atom in a different location, according to Marina.

CRNs, French said, will be key to Marina's bid to look beyond RNAi because they give the firm the opportunity to develop single-stranded oligos, which can be used as antisense molecules, as well as microRNA inhibitors and mimics.

With a stable of different, albeit related, RNA technologies, Marina is “providing … choices for pharma,” he said. Drug development “is not one size fits all; we're tired of trying to get round pegs in square holes. You have to be able to provide multiple RNA and RNAi-based therapeutic choices ... so that [potential pharma partners] can choose the one that best suits the therapeutic indication.

“It is unnecessary for us to go down an siRNA pathway and take on the challenges of delivery if a single-stranded approach will work,” French added. “Likewise, if a single-stranded approach won't work, we understand that we will need to take on the challenges of delivery if we want to get that bigger bang for our buck out of a potent pathway like RNAi.”

Having a breadth of technologies with which to work may also help Marina deal with the slowing enthusiasm that the RNAi field has been experiencing recently, he indicated. Despite pullbacks in in-house RNAi-related research and development by giants such as Roche (GSN 11/18/2010), pharmas still have an appetite for RNA-based medicines, as evidenced by Pfizer's decision to expand its LNA alliance with Santaris last month despite having shuttered its own oligo therapeutics unit (GSN 1/6/2011 & 2/3/2011).

“When pharma comes with an undruggable target ...we'd love to be in a position … to give them modality options versus what they're up against now,” he told Gene Silencing News. “If they go and partner with an siRNA company, it's only siRNA. Why not provide a single-stranded option that doesn't [have] delivery challenges?”

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At the same time, Marina is not losing focus on its own efforts, French said, adding that “every company has to be pursuing something and taking it forward.”

Earlier this month, the company licensed the rights to its preclinical bladder cancer program — formerly its flagship effort — to Switzerland's Debiopharm, which will take over all the program's development and commercialization responsibilities (GSN 2/3/2011). With Cequent's familial adenomatous polyposis therapy CEQ508 on track to enter the clinic this year, there are suddenly holes in Marina's pipeline that the firm is aiming to fill.

A likely candidate is the company's liver cancer program, which had at one time been the frontrunner among Marina's preclinical compounds, French said, but, with an eye to additional partnerships in the future, “we'll spend some time … to look at … what some of the opportunities might be in selecting additional candidates we feel pharma will find very attractive.”

It is possible that a single-stranded oligo could move into formal development, but French said it might make more sense to advance a technology the company has more experience with, such as the tkRNAi approach.

For example, it “would be in our best interest from a strategic perspective” to find another indication where CEQ508 would be appropriate, he said, “because we have safety data on that and we know we can move that forward.” Additionally, “it would be great to show proof of concept and further demonstrations of capability [with the Cequent technology] in something big ... [like] a metabolic disorder that can be attacked via the [gastrointestinal] tract.”

Cequent had already been conducting work on a tkRNAi-based treatment for inflammatory bowel disease, and an option Novartis acquired to one specific target from that program remains in effect, and French said that
obesity is an attractive indication.

Yet, orphan diseases such as FAP remain a “great opportunity” for small companies like Marina, he said, noting that the US Food and Drug Administration recently awarded CEQ508 orphan-drug status, and that the company remains interested in marketing the drug itself should it be approved (GSN 4/8/2010).

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at dmacron [at] genomeweb [.] com.