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In Changing RNAi Rx Guidance, Pfizer Becomes Latest Big Pharma to Shift Expectations

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By Doug Macron

When Pfizer pulled back from a commitment to file an investigational new drug application on an RNAi candidate next year, it joined a small but growing list of big pharmas that have ostensibly run into difficulties developing the gene-silencing technology for therapeutic applications.

At the same time, a handful of RNAi drug shops have found forging alliances with pharmaceutical firms to be challenging, in some cases and on several occasions missing previous partnership guidance.

As reported by Gene Silencing News last month, Pfizer amended its previous plans to submit an IND for an internally generated RNAi therapeutic by the end of 2011 (GSN 10/28/2010). Instead, the company now expects its Research Technology Center will file an IND next year for "an in-house nucleic acid drug," RTC CSO Art Krieg said.

Although Krieg said that Pfizer did not make the decision because of any unforeseen troubles making RNAi work in a therapeutic context, he noted that other technologies, including antisense and immune stimulatory CpGs, may prove to be more commercially promising at this stage of the game.

Krieg's disclosure comes just a few months after Tekmira Pharmaceuticals President and CEO Mark Murray announced that partner Roche would miss its goal of filing an IND on its first RNAi drug candidate before the end of this year (GSN 8/19/2010).

About a year ago, Gene Silencing News reported that Roche aimed to file the IND in 2010, and that the drug would be delivered using Tekmira's stable nucleic acid lipid particles — now simply known as lipid nanoparticles — rather than an in-house delivery technology (GSN, 10/1/2009).

Lou Renzetti, global head of RNA therapeutics for Roche, said at the time that using the Tekmira technology "would give us a chance to get a first-in-human study [underway], monitor target knockdown," and examine pharmacokinetics and pharmacodynamics with the RNAi agent.

But in August, Murray noted during Tekmira's second-quarter financials conference call that "Roche has recently provided guidance to us that they are not going to meet their previous stated objective of filing an IND by year end."

He added that it was difficult to know "the extent of the issue prompting the delay," and that Roche hadn't "told us clearly" what is going on. A Roche spokesperson confirmed the delay to Gene Silencing News but declined to elaborate.

And while Merck has never provided specific guidance or much detail on any of its RNAi drug programs since acquiring Sirna Therapeutics in 2007 for more than $1 billion, the lack of any siRNA drugs in the big pharma's formal pipeline has not gone unnoticed by industry watchers.

At the time of the acquisition, Sirna had a number of candidates moving through its pipeline including a hepatitis C treatment and a permanent hair removal compound, both slated to move into human trials by the end of 2007. Sirna had also out-licensed a phase I wet age-related macular degeneration drug, dubbed Sirna-027, to Allergan

Since then, Merck has remained tightlipped on any siRNA programs it might be advancing internally, although Gene Silencing News learned that the company later shut down the dermatology unit developing the hair removal drug (GSN 1/24/2010) and that it passed on re-acquiring the rights to Sirna-027 after Allergan dropped the medicine on poor phase II results (GSN 5/28/2009)

Meantime, Merck officials have publicly made statements seemingly designed to cool enthusiasm over the therapeutic potential of RNAi.

Notably, in late 2008, Alan Sachs, vice president of RNA therapeutics at Merck Research Laboratories, said during a keynote presentation at the second Drug Information Association Oligonucleotide-based Therapeutics Conference that while the technology is a "game-changer," the anticipated commercial success of RNAi-based drugs is "going to take time" as technological hurdles are addressed (GSN 10/3/2008).

And at industry conferences, a common theme of Sirna/Merck presentations has been the use of RNAi for target identification and validation, rather than as a therapeutic approach.

Falling Short

The seemingly measured approach that some pharmaceutical firms are now taking with regards to their in-house RNAi efforts may also be extending outward, impacting potential alliances with pure-play RNAi firms.

For instance, Alnylam Pharmaceuticals, which has been highly adept at striking deals with big pharmas including Merck, Novartis, Roche, and Takeda Pharmaceutical, has had problems recently meeting its own partnership guidance.

In early 2009, Alnylam officials said that the company expected to ink at least two industry partnerships over the course of that year (GSN 1/15/2009), but secured none. And around a year later, President and COO Barry Greene said that the firm expects to "form additional alliances in 2010," but did not provide specific guidance.

However, in a corporate update released in January, Alnylam said it remains committed to its so-called RNAi 2010 plan (GSN 1/10/2008), which requires the company to establish at least three new alliances during the year.

Tellingly, later Alnylam began categorizing deals with its microRNA joint venture Regulus Therapeutics and its Alnylam Biotherapeutics biologics manufacturing initiative as company partnerships.

Another firm to face difficulties finding partners is RXi Pharmaceuticals.

Since it was spun out of CytRx in 2007, RXi has provided varying guidance on partnering. In late 2008, the company's then-CFO Stephen DiPalma said that RXi's first industry tie-up would happen before the end of that year.

A deal never materialized, and RXi is still chasing its first alliance with a bigger player. In April, the company's new CEO, Noah Beerman, said during a conference call that one or more deals would be forged before the end of 2010 (GSN 4/1/2010).

Also falling short of partnering expectations has been Calando Pharmaceuticals, a subsidiary of Arrowhead Research, that has the distinction of advancing the first formulated RNAi drug into the clinic with its phase I cancer therapy CALAA-01 (GSN 6/5/2008).

Despite its successes with the drug, including the publication of phase I data showing that it could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism when delivered intravenously (GSN 3/25/2010), Calando has never been able to find a partner — a key goal for Arrowhead as it struggles financially.

Earlier this year, however, Arrowhead President and CEO Christopher Anzalone confirmed in a letter to company shareholders that the company expects to find an ally for Calando before the end of 2010 (GSN 9/30/2010).

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