By Doug Macron
Following the issuance of a US patent last week covering modifications used to minimize off-target effects of siRNAs, Silence Therapeutics' top official said that players in the RNAi drugs field are becoming increasingly aware that the company is a key licensing partner.
Silence also continues to view its delivery technology platform, which was bolstered by its acquisition of Intradigm early this year (GSN 12/17/2009), as a hot commodity that will drive big pharma partnerships, CEO Philip Haworth told Gene Silencing News.
Last week, the US Patent and Trademark Office disclosed that it had issued US patent No. 7,750,144, entitled, "Methods and Compositions for Enhancing the Efficacy and Specificity of RNA Silencing."
Based on the work of University of Massachusetts Medical School researcher Phillip Zamore, and exclusively controlled by Silence for therapeutic applications, the IP claims "methods of enhancing the efficacy and specificity of RNA silencing," as well as ”compositions for mediating RNA silencing," its abstract states.
The patent "generally claims methods of producing double-stranded … agents having decreased off-target silencing activity through certain structural modifications," Silence noted.
To Silence CEO Philip Haworth, the patent, along with a related US patent — No. 7,732,593 — issued earlier this year, "is going to prove to be a very significant IP asset, not just for Silence but for the space, in general."
The siRNA design rules covered by the Zamore IP "are fairly complex … [and relate to] a number of variations in different parts of the sequence [that] have different properties and different levels of utility," Haworth said this week. "But ultimately, the mismatching of bases within the double-stranded RNA is a fairly commonly used technique to [enhance] sequence potency and limit some of the off-target effects."
As RNAi drug candidates move through pipelines and information about their structures becomes available, Silence expects to find that "a number of the sequences in the clinic use these mismatches to increase their insertion of the antisense into RISC or change some of the off-target effects.
"I can't confirm that, but certainly I think these criteria have been deployed quite widely in our estimate," he added. As a result, Silence expects that a number of different companies will need to take a license to its IP.
"As the big pharma guys start to bring more into the clinic, there will be a recognition that this technology is something that is useful to them, and they're going to start talking to us about it," he said. "And we're not going to deny it to people, we're just going to find the right price for a particular transaction."
But Silence also expects that big pharma will be interested in alliances, not just IP licensing deals.
When the company acquired Intradigm, Haworth touted the merged company's portfolio of RNAi drug-delivery technologies, which include the so-called AtuPlex system used in Silence's systemically administered, phase I cancer drug Atu-027, as a resource that would be attractive to potential partners.
"By bringing together a comprehensive platform of siRNA-delivery and -development technologies, we believe [the new company] will be a partner of choice for those seeking to develop RNAi therapeutics," Silence Chairman Iain Ross added in a statement at the time.
Now that the integration of the two companies is essentially complete, "we are working on some discussions now" over new deals, Haworth said, pointing out that Silence extended its ongoing siRNA delivery collaborations earlier this year with Dainippon Sumitomo Pharma and AstraZeneca (GSN 4/1/2010).
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And this week, Silence announced that that AstraZeneca has decided to extend for another year the companies' ongoing research and development collaboration, under which they are identifying and optimizing five novel siRNAs for respiratory and oncology indications (GSN 7/12/2007).
Meanwhile, Silence is also on the lookout for a company interested in collaborating on Atu-027, he said.
The drug is a modified, blunt-ended siRNA that targets PKN-3, a protein kinase that company researchers have linked to tumor growth and metastases, and is formulated with the AtuPlex technology. It entered phase I testing about a year ago (GSN 7/9/2009).
According to Haworth, Silence does not anticipate moving the drug into phase II on its own since it doesn't have the resources as a small company to sufficiently fund later-stage clinical development.
"It's necessary to invest in this program appropriately to do the right clinical studies [and] you need … more resources behind it to do it right," he said. While biotech companies are "great at investing, discovering, and doing some early development, we always find ourselves in the position where you get to later-stage clinical development and you start to have to compromise the integrity of the clinical plan because of the expense.
"There are very few examples where that works out well for the drug," he noted.
And while Silence wouldn't necessarily rebuff offers to partner on Atu-027 by itself, Haworth said he hopes that the drug would be part of a bigger partnership package that includes additional cancer targets.
"We would … pitch a broader deal as part of the Atu-027 program, in part because it's just much more interesting science if you start to think about a strategy to exploit the delivery system" as a whole, he explained.
"Pharma companies say … 'I want exclusivity to the target. I want to make sure you don't make a sequence against this target with somebody else,'" he said. "And we understand that, and with small molecules that would be the normal protocol. But in this particular context, they'd be better off saying, 'I want rights to your endothelial cell delivery technology, and I'll pick the targets later.'
"One or two targets to the endothelial cell is one or two out of 50, and many of these pathways are complementary or overlapping," he added. "I think we add more value to our partners if we say, 'You can take the delivery system exclusively [for a class of targets], because if it works, you've got [a number of different] products you can think about. If I give you the target [alone], you've got [just] that.'"
Still, Haworth understands that this might be a tough sell.
"That big-picture view is still, I think, a struggle for the pharma guys to accept just yet," he noted. But "we're getting there."
Although Silence's AtuPlex technology has thus far shown promise in delivering siRNAs to endothelial cells, Haworth said that success for the company will require it to show that it is more than a one-trick pony.
"We pitch ourselves as a delivery platform company, and we need to demonstrate to the world that that platform has multiple dimensions," he said. "One of the strongest ways to do that is move them forward in the development process."
As such, he does not expect that the company's next investigational new drug application will be for a product based on a new delivery approach.
"For us to keep re-applying [the AtuPlex] system isn't the best use of funds … [so] we're evaluating other INDs with different delivery systems," he said. Among the research programs Silence has disclosed is one in acute lung injury, and Haworth said that pulmonary delivery is a project "we're very excited about."
He said that it is unclear when Silence would file its next IND, but that a decision on a drug candidate could be made before the end of this year.