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Dicerna Finds RNAi-Savvy Partner in Kyowa for Cancer Drug Program

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By Doug Macron

Dicerna Pharmaceuticals this week announced that it has signed a deal with Japanese pharmaceutical giant Kyowa Hakko Kirin to develop an RNAi-based cancer drug.

Having consummated the deal in December, Dicerna met its longstanding goal of forging at least one industry partnerships in 2009. At the same time, the company has found in Kyowa a big pharma ally with experience in the RNAi therapeutics field.

In mid-2008, Kyowa exclusively licensed the Asian market rights to Alnylam Pharmaceuticals' phase II respiratory syncytial virus drug ALN-RSV01 (see RNAi News, 6/19/2008). As such, "they actually know this field quite well," Dicerna's Chief Business Officer Martin Williams told RNAi News.

"One of the things that attracted us to them as a partner is that … we [won't] have to bring up the learning curve," he added. "They've already committed as an organization to RNAi as a therapeutic modality. That's huge and makes them a great partner. They understand the technology, [and] they understand the opportunities and hurdles."

Under the terms of the arrangement, Dicerna will receive from Kyowa $4 million upfront and up to $120 million in research funding and milestones in exchange for the exclusive rights to an undisclosed cancer target.

The companies will initially work together to select and optimize one of Dicerna's Dicer-substrate molecules — essentially 27-nucleotide long RNA duplexes capable of triggering an RNAi effect — against the target, a process Williams described as "a couple of years of intense collaboration."

"Once we have a lead candidate, it's handed off to Kyowa and they do the … work to take it towards the market," he said. However, Dicerna has the option to co-promote and share in the profits of the drug in the US on a 50/50 basis.

“This collaboration [aims] to reinforce the possibility of dsiRNA-based medicines by means of specific delivery to tumors or certain tissues," Etsuo Ohshima, managing officer and vice president of research at Kyowa said in a statement. "We believe that this endeavor to modulate intracellular targets can be complementary to our own antibody-based approach featuring Potelligent technology to cell surface targets."

According to Kyowa subsidiary BioWa, which holds rights to the technology, the Potelligent approach involves the removal of fucose from sugar chains on monoclonal antibodies, which results in "much higher antigen-dependent cellular cytotoxicity activity as compared to a highly-fucosylated conventional antibody."

After demonstrating that "the mechanism behind the enhanced ADCC of a low/no-fucose antibody was its increased affinity to FcγRIIIa, the major Fc receptor for ADCC in humans … our scientists strategically knocked out a gene called FUT8 that is responsible for the fucose addition to sugar chains in order to create a new production method for fucose-free antibodies in [Chinese hamster ovary] cells," BioWa noted.

The collaboration also allows for the partners to add up to around 12 new targets, each of which could be worth up to $120 million to Dicerna. According to Williams, Dicerna and Kyowa have already "mutually chosen" a number of other targets that are likely candidates for inclusion into the alliance.

And while all of these are oncology-related, he said, new targets could extend into other disease areas. He added that while it is not clear when the companies may add new targets to their partnership, he does not expect that such a move would be dependent on data from work done with the initial target covered by the deal.

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"Part of what's going on are internal discussions on their end about which targets to prioritize next," Williams said. "We may do some work on the first target before selecting the next, but equally, they might decide quite quickly to bring additional targets into the collaboration."

Importantly, none of the targets covered by the Kyowa agreement "overlap with the targets we have chosen for internal development," he noted, allowing Dicerna to pursue development of its lead in-house drug-development program in solid tumors.

Details about that internal target have not been publicly disclosed, but Dicerna CEO James Jenson told RNAi News that his company has "put a lot of effort into deciding what target we want to develop internally … [and] we've decided to minimize the risk of our proof-of-concept target by going after one that is already clinically validated … [with] clinically accessible issues and informative biomarkers."

In going after a target that is druggable by other modalities, Dicerna has made a sharp change in corporate strategy and is taking a path that other RNAi drug shops have been avoiding.

About a year ago, Jenson told RNAi News that Dicerna would be taking aim at targets not amenable to small molecules and biologics such as antibodies (see RNAi News, 1/29/2009). His comments came just days after Dicerna Chairman and Co-Founder Douglas Fambrough told attendees of the Center for Business Intelligence’s Executing on the Promise of RNAi conference that smaller RNAi drug shops should focus on undruggable targets in order to compete with larger, better-financed rivals in the space.

But to Jenson, there is still value to be found in such a target because while it is addressed by existing drugs, there is a "need [for] a next-generation therapy for reasons of either toxicity or drug resistance."

While he declined to provide a specific timeline on the program, Jenson said that it is on "an aggressive path" and is expected to reach the investigational new drug application-filing stage by the time Dicerna closes a soon-to-be launched financing round.

"In the next month or two, we're going to actively market a Series B raise of about $25 million, and [the IND] is a value proposition for that raise," he said.

Not only will the money from this financing provide Dicerna with the financial wherewithal to move its in-house drug program toward the clinic, but it is expected to help fund the company's ongoing efforts to develop a proprietary lipid-based nanoparticle drug-delivery technology, Jenson added.

Even so, Dicerna expects to continue pursuing industry alliances on a target-by-target basis, which "keeps our options open," Jenson said. "So we're not doing any big sector deals … and we are in discussions with companies for targets" in oncology and other indications.

"We're looking very aggressively," Williams added. "We're in advanced discussions with several other companies and are going to continue to pursue lots of other partnerships." He declined to provide guidance on when another deal might be struck.

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