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Pfizer Plans for First In-House RNAi Rx IND By 2011 as It Evaluates All Technologies

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With two RNAi-based therapies acquired from other companies already in the clinic, Pfizer is now aiming to have an entirely internally developed RNAi drug ready to enter human trials within three years, a senior company official told RNAi News last week.
 
“We have decided to set ourselves the goal of taking our first internally generated RNAi therapeutic into … an [investigational new drug application] filing by the end of 2011,” Art Krieg, CSO of Pfizer’s Research Technology Center, which oversees the company’s therapeutic RNAi activities, said. “We’ve picked our first targets, been doing our first gene walks and screening … [experiments, and] we’re setting up the animal models.”
 
He declined to name the indication for this initial drug candidate, but noted that Pfizer is “probably interested in the therapeutic areas that everyone else is with RNAi.” And, like most everyone else in the field, Krieg said Pfizer views effective delivery as perhaps the biggest factor in determining which diseases will be addressed first since “there are areas that clearly appear to be more challenging [in which] to develop than other areas.”
 
Though delivery tops everyone’s list when it comes to hurdles facing RNAi drugs, he added that Pfizer is also considering a variety of other issues, both scientific and commercial, as it hones in on its first in-house RNAi program.
 
“There is no approved RNAi drug,” Krieg said. “So for a new class of therapeutics where the safety hasn’t yet been established, I think you have to look very carefully at non-life-threatening indications” where unforeseen adverse events might not prove critical.
 
“Another part of our thinking in selecting indications is that right now the cost of goods for producing an RNAi [therapeutic] is quite high by drug standards,” he said. “If you have to deliver doses of several milligrams per kilogram, [the associated expense] could be prohibitive for a chronic indication.”
 
In facing these and related issues, Krieg said that Pfizer is maintaining an open mind as it evaluates all the different species of RNAi technologies and delivery approaches — a strategy made evident by Pfizer’s first two deals in the space.
 
In 2006, the company acquired from Quark Pharmaceuticals a preclinical siRNA designed to treat wet age-related macular degeneration, along with the rights to the drug’s target (see RNAi News, 9/28/2006). Based on technology Quark had licensed from Silence Therapeutics, the molecule features the company’s trademark blunt ends and alternating pattern of modifications. Renamed PF-4523655, the drug is now in phase I/II testing.
 
Then, early this year, Pfizer picked up the worldwide rights outside of Asia to Tacere Therapeutics’ expressed RNAi-based therapy for hepatitis C, TT-033, marking the first time a big pharma had put its support behind a drug based on this alternative approach to RNAi (see RNAi News, 1/10/2008). This drug could reach the clinic as early as next summer.
 
Evaluating solutions to the delivery issue both internally and through discussions with a number of potential industry collaborators, Pfizer has not “limited [its] thinking to any single approach or strategy,” Krieg said.
 

“Because we have not made a very large strategic investment specifically in RNAi technology, we don’t feel limited to that approach for manipulation of gene expression … [and] could also consider antisense approaches … [if they] turned out to be of similar efficacy.”

“We’re thinking about the 21-mer RISC substrate RNAi [molecules] with or without overhangs, about the Dicer-substrate design, [about] expressed RNAi,” he said, adding that “we believe there could be different optimal indications for each of those different strategies.
”We’re still in the learning and evaluating phase,” he said. When it comes to RNAi, “our philosophy … is to operate in a biotech-like model, which to us means that instead of making a huge investment in a new area of technology that you don’t understand, you get into the science first and foremost and develop enough of an understanding of the science yourself to help guide your investment strategy.”
 
As a result, Pfizer has yet to follow the lead of peers such as Roche, Novartis, and Takeda Pharmaceutical, which each took broad and expensive licenses to Alnylam Pharmaceuticals’ RNAi platform technology and intellectual property in order to jumpstart their efforts with the gene-silencing technology (see RNAi News, 9/9/2005, 7/12/2007, and 5/29/2008).
 
And while Pfizer is sanguine about the therapeutic potential of RNAi, it is also open to the notion that there may be better alternatives out there at the moment.
 
“Because we have not made a very large strategic investment specifically in RNAi technology, we don’t feel limited to that approach for manipulation of gene expression … [and] could also consider antisense approaches … [if they] turned out to be of similar efficacy,” Krieg said.
 
And antisense has a lot in its favor, he noted, including “fewer issues with formulation and complicated delivery systems,” as well as a potentially reduced cost of goods “with a single-stranded oligo that may be shorter” than an RNAi oligo.
 
At the same time, Krieg said Pfizer has its eye on the microRNA field, although the company has yet to make any formal decision on whether to extend its reach into this area.
 
“MicroRNAs are a very interesting and exciting area of biology, and I think anyone interested in nucleic acid drugs as we are would want to think very hard about the possible therapeutic applications there,” Krieg said. Still, “we haven’t reached a conclusion yet on what sort of investment we should make in that area, or even whether we should invest in that area.
 
“I’d say we’re still in a very early, exploratory phase,” he added.
 
Banking on Experience
 
Over the past year, there have been several reports suggesting that unintended immune responses, rather than a true RNAi mechanism, are at work with many of the molecules designed to harness the gene-silencing technology.
 
Last month, for example, a research group from Tekmira Pharmaceuticals reported that the previously demonstrated antiviral effects of siRNAs targeting influenza in a mouse model appear to have actually been the result of immune responses triggered by the duplexes.
 
In March, a team of investigators led by the University of Kentucky’s Jayakrishna Ambati published data indicating that all siRNAs, including two currently in clinical trials for wet AMD, suppress neovascularization regardless of their sequences or targets due to the activation of a cellular immune response.
 
Having joined Pfizer when the big pharma acquired Coley Pharmaceutical, a company he co-founded and focused on developing drugs that modulate toll-like receptors, Krieg said he is well-aware of the immunostimulatory potential of RNA.
 
“We have a great deal of respect for the immune effects of RNA because we’ve been working on that for over five years” at Coley, where researchers have identified RNA motifs capable of activating various TLRs including TLR3, which was implicated in the Ambati paper, he noted. 
 
In light of this experience, Krieg said that he views a “huge amount” of the literature describing the in vivo efficacy of RNAi as resulting, at least in part, from immunostimulatory effects of the RNAi rather than a true RNAi mechanism. As a result, one of the challenges for Pfizer is to “try to work out for ourselves in the different models that we’re considering how much of the activity is RNAi-mediated and how much is immune-mediated,” he said.
 
According to Krieg, growing concerns over RNAi’s immunostimulatory potential is reminiscent of the early days of antisense.
 
“In the late 1980s, you had four antisense companies established with a lot of fanfare [over their] rational approach to drug design, and so forth and so on,” he said. “Very quickly, it became apparent that the antisense oligos had a lot of non-specific immunostimulatory effects that turned out to be due to CpG motifs and other backbone effects that we now know activate TLR9.”
 
As a result, many of the early reports of antisense’s in vivo efficacy were actually due to immune effects. “I think the same thing has happened to a certain degree in the RNAi field,” he said.
 
In the end, however, Krieg expects these issues will be overcome through the use of chemical modifications and appropriate delivery systems.
 
“Chemical modifications make it easy to avoid” immune responses, he noted. “All you have to do is make 2’-O-methyl or some of the other modifications at just a few points in the oligo … and you can really make immune stimulation a non-issue.”
 
Meanwhile, “we’ve discovered that some delivery systems deliver the RNA much more into the endosomal compartment [where TLRs reside] whereas other delivery approaches can more or less bypass the endosomal compartment” in order to sidestep immune responses.
 
Krieg also said that in certain cases he sees the potential for combining RNAi and immune effects to improve therapeutic efficacy.
 
“One of the tricky things in accomplishing this, however, is that the immune stimulatory effects of the RNA do differ between rodents and primates,” he cautioned. “So you have to be careful in your interpretation of rodent data [so as] not to believe what you see in rodents is what you’re going to get in primates.”
 
Another potential roadblock is that the optimal dosing schedules for an RNAi drug may be different from what is optimal for inducing a desired immune response.
 
So the hurdles to such a combination therapy are “not trivial,” he said. “But at least in some of the animal models, we and others have found that combining immune stimulation and RNAi may be of benefit.”

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