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Pfizer Amends In-House RNAi Rx Guidance

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By Doug Macron

Pfizer has stepped back from its goal of filing an investigational new drug application on an internally developed RNAi drug by the end of next year as it evaluates alternative technologies, Gene Silencing News has learned.

The big pharma's Research Technology Center still anticipates filing an IND before the end of 2011, but now expects it to be for "an in-house nucleic acid drug" in 2011, rather than one necessarily based on RNAi.

In late 2008, RTC CSO Art Krieg told Gene Silencing News that Pfizer planned on filing an IND on its "first internally generated RNAi therapeutic" within three years (GSN 9/11/2008). But last week on the sidelines of the Oligonucleotide Therapeutics Society's 6th annual meeting in Dana Point, Calif., he said that the company is now considering other therapeutic approaches.

"Although we started out with the mission of developing RNAi, we realized as we progressed … that there are also opportunities in many other areas," including antisense, immune stimulatory CpGs, and alternative splicing approaches, Krieg explained.

Krieg joined Pfizer after its acquisition of CpG drug developer Coley Pharmaceuticals, which he co-founded. At the time, "we recognized that it was possible to have an IND [for an RNAi drug] in 2011 if everything went well," he said. "And I still think it's definitely possible for us."

"But we don't want to meet a deadline" just for the sake of doing so, Krieg noted. "We want to make sure it still makes clinical sense in terms of the therapeutic potential, and it has to make commercial sense, ultimately."

For instance, in treating a chronic but non-life-threatening disease, "we wouldn't want to use a technology that requires IV infusion every week or couple of weeks," as in the case of an siRNA. "We'd rather use something that you could give by subcutaneous administration [such as antisense] because that's much more commercially acceptable for those kinds of indications.

"Ideally, what we'd like to do is match up the different oligonucleotide applications to the best clinical areas," he said.

Pfizer's in-house work with RNAi and other nucleic acid technologies is being conducted "in parallel," Krieg noted, but he declined to speculate on which approach is most likely to yield the 2011 IND, stating that "we haven't said publicly yet what we think we will take into the clinic" first.

"We have a goal, but lots of things could go wrong with that," he added. "We know the failure rate in drug development is very high, so I would continue to say that everything would have to go right for us to meet that goal."

Pfizer's decision to potentially advance another nucleic acid-based drug before an RNAi one isn't entirely unexpected given comments that Krieg made in 2008 to Gene Silencing News.

Although he said that the 2011 IND would be for an RNAi therapeutic, at that time he emphasized the company's interest in alternative technologies, namely antisense.

And indeed, last week at the OTS meeting, he highlighted the advances made in the antisense field in recent years by companies including Isis Pharmaceuticals.

"When antisense first started back in the late '80s, no one believed that the phosphorothioate backbone was still going to be in use in five or 10 years," he said. "We're actually still using phosphorothioate, but together with other modifications. And I think those modifications on top of the phosphorothioates … is a kind of advance in technology that makes antisense competitive with RNAi for some applications.

"Although [antisense] may not be as potent … [for] a simple subcutaneous injection [for instance] rather than an IV infusion, it opens the door to a lot of applications." This, in turn, raised Pfizer's interest in the application even though the company has never worked in the field before, he noted.

At the same time, having acquired Coley and brought Krieg on board, it is no surprise that the company would aim to leverage the immunostimulatory expertise gained through that transaction.

One RNAi-related field that Pfizer continues to take a wait-and-see stance on is microRNAs.

In 2008, Krieg told Gene Silencing News that although the small, non-coding RNAs are "very interesting and exciting," the company had not "reached a conclusion yet on what sort of investment we should make in that area."

Last week, he echoed that sentiment, stating that "we're following the microRNA field with great interest," but cautioning that Pfizer's activities in the space remain exploratory.

"It's really exciting … but we still have not made a commitment [to miRNAs] internally," he said.

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