Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Firm is upping its stake in pain medications.

Pfizer’s CEO Jeffrey Kindler stepped down this week. His resignation was mostly viewed as good news by investors who hope that the new leader, Ian Reed, previously head of the firm’s global pharmaceuticals division, will take bold action to revive the company.

Pfizer has been feeling a lot of pain in its pipeline, with cancer drug development taking multiple blows. In light of the number of drug failures over the last year, the firm is also probably wringing its hands over whether it can fill the revenue void created by the 2011 Lipitor patent expiry; in 2009, Lipitor accounted for almost 23% of the company’s total revenue, or $11.43 billion.

Pfizer is investing in the area of pain therapeutics. It already has two best-selling pain medications on the market: Lyrica, used to control seizures and to treat fibromyalgia, diabetic neuropathy, and herpes zoster; and Celebrex, a nonsteroidal anti-inflammatory.

In development Pfizer is covering a lot of bases with plans spread across a range of molecular targets, from an antinerve growth factor mAb, tanezumab, to tasocinib, a small molecule JAK inhibitor. Additionally Icagen, under a deal inked in 2007 with Pfizer, announced in November that Nav1.7, an ion-channel modulator, had been chosen for clinical advancement.

mAb against NGF

Last summer Pfizer suspended clinical trials with tanezumab in osteoarthritis pain. The decision was based on reports that patients experienced worsening of their condition. This included 16 patients who had radiographic evidence of bone necrosis that required total joint replacement, the investigators said. The company subsequently shut down trials in chronic low back pain and painful diabetic peripheral neuropathy at the FDA’s request. Investigations of the biologic in areas of high unmet medical need including cancer pain continue.

Pfizer halted the osteoarthritis trial a week after presenting data at the European League Against Rheumatism (EULAR) Congress 2010 showing the drug significantly reduced knee pain compared to placebo in osteoarthritis. Paradoxically, tanezumab seems to work too well as a painkiller. Nancy E. Lane, M.D., of the University of California Davis, Sacramento, and colleagues reported pain reductions of 45% to 62% in patients with knee pain due to walking who were given tanezumab versus 22% in those given placebo. Published in The New England Journal of Medicine, the study randomized 450 patients and was conducted over 16 weeks.

Dr. Lane noted, with regard to osteoarthritis patients in the long-term Phase III trial halted by Pfizer, “I believe that the apparent worsening of certain patients’ condition may be due to the fact that tanezumab works so well. People feel so much better that they become more active, putting increased stress on their already badly diseased joints.”

For her studies’ volunteers with walking knee pain she said, “The effects of tanezumab were remarkable. People on the drug went from having very limited activity to practically being on the dance floor. No medication available today has such dramatic results.”

Evidence suggests that tanezumab’s mechanism of action may not make sense from the perspective of unmitigated, progressive disease, even though it works against pain. Nerve growth factor (NGF), a regulatory protein that controls neuronal survival during development, mediates pain and weight loss in autoimmune arthritis. Function-blocking antibodies to NGF completely reversed established pain in rats with fully developed arthritis, but joint destruction and inflammation continued.

JAK and Ion Channels

Pfizer’s JAK inhibitor has had better luck in treating arthritis pain. Pfizer reported that tasocitinib significantly reduced the signs and symptoms of moderate-to-severe rheumatoid arthritis (RA), a primary endpoint. The drug, administered as monotherapy, also improved physical function versus placebo at three months. The drug did not meet a third primary endpoint of disease remission.

Another well-informed bet on a completely different kind of pain drug comes in the form of Icagen’s ion-channel modulators. On November 30, the partners reported that Nav1.7 was chosen to progress into Phase I trials. Richard Katz, M.D., Icagen’s CFO, says that the timeline for starting the Phase I trials will be up to Pfizer but thinks that they will begin either this year or early in 2011.

Icagen gained 96 cents a share to close at $2.18, up more than 75%, on the news. It also garnered a $1 million milestone payment from Pfizer.

Pfizer and Icagen are targeting three specific sodium ion channels for the treatment of pain and related disorders. This November the companies extended their agreement for an additional 15 months until December 2011, with Pfizer continuing to fund all R&D costs. Icagen could receive up to $359 million in research, development, regulatory, and commercialization milestones for each product, in addition to royalties on future sales.

Dr. Katz told GEN that NAV1.7, an ion channel that plays an important role in the detection, transmission, and cognitive recognition of pain signals, may provide a unique target for pain medication. “The NAV1.7 ion channel has been genetically linked to congenital indifference to pain.”

In 2006, he said, a research paper in Nature described a rare autosomal-recessive disorder, clinically characterized by insensitivity to all modalities of pain except neuropathic pain, in which recurrent injuries frequently go unnoticed. The disorder is linked to mutations in the SCN9A gene which encodes the alpha subunit of the NA1.7 ion channel, strongly expressed in nocioceptive neurons.

Icagen has been working on ion channels as potential novel drug targets for several years, Dr. Katz told GEN. “There are no drugs that work through this mechanism except Lidocaine, which acts as a nonspecific NAV blocker but can’t be used systemically. We have been working to identify this and other selective molecules that we believe are important in the transmission of pain signals.”

Marketed Assets

Pfizer inked another deal more recently to bolster its pain franchise. In October it bought King Pharmaceuticals, a diversified specialty pharmaceutical company, for $3.6 billion, a 40% premium over King’s market cap on October 11, the day before the announcement. King makes the morphine drugs Embeda and Avinza.

“There’s not a lot of research risk here,” noted Forbes reporter Matthew Herper. “This isn’t another biotechnology asset bringing fancy science. This is the push of big pharma into less financially risky specialty therapeutics that people have been predicting for a long time.” Pfizer, no doubt, hopes that such deals will provide it with a big enough safety net for its big push into gaining a financial upside from pain medicines.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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