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Abbott's Decision to Partner With Dharmacon Came After 18-Month Industry-Wide Evaluation

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When Abbott signed its multi-year siRNA drug-discovery collaboration with Dharmacon, it marked the culmination of a one-and-a-half year effort to evaluate RNAi as a therapeutic modality, according to an official from the healthcare giant.

And now that it has officially jumped into the RNAi-based therapeutics pool, Abbott may start signing more partnerships in the field.

Last week, Dharmacon and Abbott announced that they will collaborate to identify therapeutic siRNAs for multiple indications, with an initial focus on cancer (see RNAi News, 7/6/2006). Under the deal, Dharmacon will optimize siRNAs for therapeutic use, while Abbott will handle all drug development and commercialization efforts.

Though Abbott had long been using RNAi for target validation, its interest in the gene-silencing technology for therapeutic uses began fairly recently, according to Bill Kohlbrenner, director of cancer research at Abbott and project leader for the Dharmacon collaboration.

"About a year and a half ago … we initiated a task force, which I headed, that evaluated the technology for therapeutics," Kohlbrenner told RNAi News this week. "We looked at the entire field, visited companies, [and] evaluated the technology with the goal of identifying opportunities that might complement our commercial interests.


"The big issue for us [before signing the Dharmacon deal] was understanding the potential to identify viable delivery strategies. … What we see on the horizon is promising."

"As a result of that analysis â€" and a lot of internal discussion and evaluation â€" we thought [RNAi] was definitely an area from which new therapies could emerge," he said.

Asked why Abbott chose to partner with Dharmacon after discussing potential deals with numerous other companies in the RNAi field, Kohlbrenner said that it was a matter of familiarity and complementarity.

"What attracted us to Dharmacon is that we did have a track record with them," he said, referring to a 2003 deal under which Dharmacon built an siRNA library covering 4,000 genes for use by Abbott in drug target identification. Additionally, "Dharmacon has a highly focused and productive research group that we think we can work well with to address any technical issues that come up.

"We have very much the same mindset about how to approach research and address technical issues in developing therapies," he added.

Taking the Plunge

While many of the big pharmaceutical players continue to maintain a wait-and-see position on RNAi as a therapeutic, Kohlbrenner said that rapid gains in the field made it clear to Abbott that the technology had potential and that its biggest hurdle â€" delivery â€" could be overcome.

"The big issue for us [before signing the Dharmacon deal] was understanding the potential to identify viable delivery strategies," he explained. Delivery "is an obvious limitation … [but] what we see on the horizon is promising. We believe that … ultimately it will be possible to deliver siRNAs for a variety of diseases."

Though big pharma has started to warm up to the idea of RNAi as a therapeutic modality, most continue to maintain a wait-and-see stance on the gene-silencing technology.

Of the top 20 pharmaceutical firms by revenues, only five have publicly disclosed programs exploring the development of RNAi-based drugs: GlaxoSmithKline (see RNAi News, 4/6/2006); US-based Merck (see RNAi News, 7/6/2006); Novartis (see RNAi News, 9/9/2005); Eli Lilly (see RNAi News, 1/30/2004); and most recently, Abbott (see RNAi News, 7/6/2006).

The other 15 â€" Pfizer, Sanofi-Aventis, Johnson & Johnson, AstraZeneca, Bristol-Myers Squibb, Roche, Wyeth, Takeda, Boehringer-Ingelheim, Schering-Plough, Bayer, Novo Nordisk, Schering, Sankyo, and Germany's Merck â€" are either continuing to steer clear of RNAi as a therapeutic or have not disclosed work in the field.

Under their collaboration, Dharmacon will help Abbott develop drug-delivery approaches for its siRNA-based drug candidates, but Kohlbrenner suggested that with "a variety of companies working on" solving the delivery problem, Abbott won't limit itself to in-house delivery solutions.

"There are several [delivery technologies] out there," he said. "There's nanoparticle technology, there are some that call themselves nanoparticles with cationic polymers, [there are] the lipoplexes â€" we've evaluated all of those.

"I think there are a lot of plusses and minuses with each of the technologies, [and] our job is going to be to identify those that are best to deliver siRNAs for [the] cancers we're interested in," he added. "If we can find partners who could bring technologies that complement our needs … we would consider [deals] to access required technologies."

Ultimately, though, it is not clear where Abbott finds its delivery answer, Kohlbrenner said, noting that "it's still early days. When we advance our collaboration with Dharmacon and [determine] precisely the direction we're going in, I think the delivery piece will fall into place," he said. "We're going to be very deliberate about this and find the best technology to put together the best therapy."

New Technology, Old Targets

With cancer first up in its RNAi drugs program with Dharmacon, Abbott is taking aim at a disease area with great money-making potential but one in which it has no therapeutic experience. Currently, Abbott has no oncology drugs on the market, and last autumn a US Food and Drug Administration advisory panel recommended the agency reject the company's investigational prostate cancer therapy Xinlay.

The company does, however, sell a number of cancer diagnostics, and RNAi could prove key for Abbott in becoming a well-rounded player in oncology.

"Our original thought was … [that] siRNA and RNAi might have potential in virology, which we believe it does," Kohlbrenner said. "As we began exploring [the technology, we saw it] clearly has potential in a variety of areas â€" cancer being a big area of our interest."

"We're aware of a number of key proteins, key gene products, [associated with cancer but] hard to drug with small molecules," he said. Small-interfering RNAs "provide an opportunity of modulating all these targets and potential combinations of these targets that should provide some novel opportunities."

Which cancers Abbott will target with siRNAs have yet to be determined, however.

"As part of our collaboration [with Dharmacon] and as part of our internal efforts, we're looking at which cancers to go after, [but] it's too early to identify where we'll be headed," Kohlbrenner noted. "We certainly feel the technology has a lot of potential in a variety of areas, and we're looking for the best approaches and the most appropriate cancers."

This is not to say that Abbott won't potentially explore the potential of RNAi beyond cancer, he added.

"We're not going to limit this to oncology," he said. "Oncology is just the best therapeutic area to launch this [effort], to explore the potential [of RNAi], and understand what the challenges are going to be."

Once work with siRNAs in cancer is underway, "we're hoping that … the insights we get from working with Dharmacon and potentially other partners will [allow us] to really understand where we could apply [RNAi]. If … opportunities [in other therapeutic areas] present themselves, we'll move forward. Again, it's still too early to make a call about where we're going to be and when we're going to be there."

- Doug Macron ([email protected])

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