Until recently, pain management has been dominated by traditional therapeutic modalities, including opiates and

nonsteroidal antiinflammatory drugs. Recent innovations in pain management have been led by new treatments such as triptans and COX-II inhibitors. Still, side effects of current drugs may prove unacceptable to some patients, and thus, pain management remains an under-served medical need.

Pain therapeutics represent a multi-billion dollar market. Demographics, physician prescribing patterns and novel products are expected to spur significant growth in the pain market over the next decade.

Pain disorders are classified into several categories based upon their cause. Neuropathic pain is a particularly severe pain disorder that results from damage to the central and peripheral nervous systems. Inflammatory pain results from the effects of inflammatory mediators and cellular debris that are released into surrounding tissues as the immune system is activated, whether appropriately to fight infection, or inappropriately, e.g, as in autoimmune disorders, such as rheumatoid arthritis. Both neuropathic pain and inflammatory pain are types of chronic pain.

Ion channels play an important role in the detection, transmission and cognitive recognition of pain signals. Ion channels are critical at each step in the pain pathway, including the detection of local stimuli, the transmission of the electrical impulses to the brain and the interpretation of electrical impulses as pain signals. The underlying mechanism through which ion channels are involved in the sensation of pain is through the modulation of the level of excitability of specialized nerve cells in the pain pathway. Consequently, we believe that by selectively modulating particular ion channels in the pain pathway, the detection, transmission or cognitive recognition of pain can be reduced.



We have identified several ion channel targets including sodium channels, calcium channels and potassium channels, that are expressed in pain pathways in both the central and peripheral nervous systems. For several of these targets, we have identified lead compounds with in vivo efficacy in animal models of pain disorders. For

example, in our multi-target sodium channel pain program, Icagen has identified selective compounds which demonstrate efficacy in animal models for neuropathic and inflammatory pain.

In August 2007, we entered into a collaborative research and license agreement with Pfizer for the discovery, development, manufacture and commercialization of compounds and products that modulate three specific sodium ion channels as new potential treatments for pain and related disorders. Under the terms of the agreement, we and Pfizer are combining resources to identify compounds that target these three ion channels in a global research and development collaboration. We and Pfizer have formed a joint research committee to monitor and oversee the collaboration.

The ion channel targets included in the collaboration are important in the generation of electrical signals in nerve fibers that mediate the initiation, transmission and sensation of pain. In preclinical studies, compounds identified by us have demonstrated efficacy in pain models. We have also established a broad portfolio of intellectual property in this area, covering multiple promising compounds targeting sodium channels.

Under the terms of the collaboration, we have granted Pfizer a worldwide exclusive license, with the right to grant sublicenses, to our patent rights and know-how with respect to drugs arising from the collaboration. In addition, we have granted Pfizer the first right to enforce our intellectual property rights in order to protect these drugs and have retained a right to enforce our intellectual property rights. Pfizer is responsible for funding all aspects of the collaboration and for worldwide clinical development and commercialization of drugs arising from the collaboration.