$ZLCS Discovery Technologies Calcium and Sodium Channel

$ZLCS Discovery Technologies Calcium and Sodium Channel Blockers Ion Channel Expertise The Zalicus approach to Ion channel discovery identifies state-dependent Ion channel modulators to achieve analgesic efficacy with superior selectivity and safety profiles Increased (high-frequency) neuronal activity in neuropathic pain drives channels into an inactivated channel state that can be selectively antagonized by our compounds Compounds designed to target the inactivated channel state will selectively modulate neurons undergoing high-frequency firing while sparing low-frequency firing neurons where channels may be predominantly in the closed state. The Zalicus Ion channel targets are well-validated in the treatment of pain. Zalicus has multiple Ion channel compounds undergoing clinical and preclinical safety and efficacy evaluation including Z160, a first in class, oral, state dependent, selective N-type calcium channel blocker in Phase 2 clinical development for chronic neuropathic pain and Z944, a novel, oral, T-type calcium channel blocker, in Phase 1 clinical development targeting further development in pain. Calcium Channel Blockers N- and T-type calcium channels have been recognized as key targets in the therapeutic inhibition of a broad range of cell functions. Specifically, for pain indications, these calcium channels have been recognized as critical for controlling the entry of calcium into neurons. When a pain signal is initiated from the skin, muscle or other organ, the channels open and calcium concentration increases, triggering the release of neurotransmitters from synaptic vesicles to relay the signal to the brain where it is perceived as pain and also increasing the general excitability of neurons to affect the intensity of the pain signal. Zalicus has utilized its rational drug design processes to successfully discover high affinity, selective and orally available compounds that block N- and T-type calcium channels and that show promise for further development as therapies for pain. Calcium channels are involved in the control and regulation of many critical cell pathways and are attractive drug targets. In order to carry out the multiple physiological functions that calcium channels help regulate, the human genome encodes distinct types of calcium channels. Of particular relevance for pharmaceutical development, each of the different types of calcium channels is known to perform distinct physiological functions and offers the opportunity to target specific drugs to specific calcium channels and human disease indications. However, because of the ubiquity of the genetically related calcium channel family members, compounds with low specificity for their targets have the potential for cross-reactivity leading to potential side effects. As a result, compounds with high specificity for specific subtypes of calcium channels are very important in the development of product candidates that will be both safe and efficacious. Improved Calcium Channel Blockers through Electrophysiological Screening Zalicus has created a differentiated model for the discovery of new calcium channel blocking compounds that overcomes the serious issue of selectivity in calcium channel blocker drug discovery. Zalicus has utilized an electrophysiological screening process to generate drug candidates with much greater levels of specificity than other systems. This approach enables the discovery of targeted state and frequency dependant blockers and it is anticipated that by improving selectivity, compounds with greatly enhanced safety and tolerability profiles can be developed. Zalicus (formerly Neuromed) was the first company to discover that the various calcium channels in the nervous system are encoded by a family of distinct genes, and, recognizing the potential pharmaceutical significance of the N-type and T-type calcium channels, Zalicus devised innovative screening platforms and discovered initial proprietary calcium channel blocker product candidates. Building on this work, Zalicus is currently pursuing calcium channel programs targeting the N-type and the T-type calcium channel gene subtypes and may potentially develop mixed N/T-type calcium channel product candidates. Sodium Channel Blockers In addition to the N-type and T-type calcium channels being targeted for pain, Zalicus has been actively pursuing another class of Ion channel for pain drug discovery and therapeutic intervention. Sodium channels (abbreviated NaV) crucially regulate pain signaling by mediating sodium ion currents that contribute to the excitability of both peripheral pain-sensing neurons and also neurons within the spinal cord that relay pain signals to the brain. Several distinct types of sodium channels are important for setting the threshold and influencing the frequency, sustainability and intensity of pain signaling. Of the ten sodium channel genes found in humans, the Nav1.7 and Nav1.8 types are of particular interest related to multiple chronic pain conditions as they are validated in both humans and commonly used preclinical models. For example, in humans naturally occurring loss-of-function genetic mutations in the NaV1.7 channel lead to the complete abolition of pain sensation while other gain-of-function NaV1.7 mutations cause severe chronic pain syndromes. Further, in animal models it has been shown that the suppression of either NaV1.7 or NaV1.8 channels reduces various kinds of acute and neuropathic pain. Addressing these attractive targets for pain intervention, Zalicus has utilized its considerable expertise in Ion channels to design, characterize and develop novel, orally available agents that modulate the physiological functioning of NaV1.7 and NaV1.8 channels. The goal is to specifically target the increased firing and hypersensitivity in peripheral and spinal cord neurons that express NaV1.7 and NaV1.8 and that are associated with chronic inflammatory and neuropathic pain. Representing the considerable progress that Zalicus has made to date, a pipeline of preclinical agents shown to affect NaV1.7 and NaV1.8 channels has been generated and is being studied as part of our collaboration with Hydra Biosciences. A number of these new compounds have been found to both reduce the excitability of neurons and to reverse pain hypersensitivity in animal models of acute and neuropathic pain. Zalicus hopes that targeting sodium channels in the peripheral and central nociceptive signaling pathways through a unique mechanism of action will lead to novel classes of safe and effective pain therapeutics. Zalicus believes that the targeting of selective sodium channels complements the existing N-type and T-type calcium channel pain programs. Terrance P. Snutch, PhD, FRSC, DSc (hon) Dr. Snutch, a Senior Scientific Advisor to Zalicus and the founder of Neuromed, is a professor in the Michael Smith Laboratories at the University of British Columbia. He was the first scientist in the world to describe the molecular basis for clinically important calcium channels in the cardiovascular, endocrine and nervous systems. Dr. Snutch's contributions have been recognized internationally with numerous awards, including the International Albrecht Fleckenstein Award, the Killam Research Prize, the Steacie Prize, and induction into the Royal Society of Canada. He was named 2004 Researcher of the Year by BC Biotech and has received the BC Innovation Council's New Frontiers in Research Award. Most recently, Dr. Snutch received an Honorary Doctorate of Science from Simon Fraser University.