• The Zalicus Ion channel technology 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 novel, oral, N-type calcium channel blocker in clinical development for chronic inflammatory and neuropathic pain and Z944, a novel, oral, T-type calcium channel blocker, in clinical development for the treatment of acute and inflammatory pain.

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.

N-type Calcium Channel Blockers

N-type, or neural-type, calcium channel blockers represent a new class of analgesics that are selective for pain signal transmission. The concentration of calcium entering certain nerve cells in the spinal cord is directly linked to pain signal transmission. This pathway has been targeted by commercialized products such as Prialt® and morphine-related drugs, both of which have been successful in treating severe and chronic pain but also have highly prohibitive routes of administration or side effects:

• Prialt is a peptide that must be delivered through a surgically implanted intrathecal pump (injected directly into the spinal cord), whereas Zalicus’ N-type calcium channel blockers are being developed in oral form.
  
• Morphine and other related drugs affect N-type calcium channels indirectly by binding to opioid receptors. When morphine activates these receptors, it not only inhibits N-type calcium channels to affect pain signaling, but also affects other processes, which leads to side effects such as sedation, motor impairment, addiction and gastrointestinal problems. N-type specific calcium channel blockers are believed to avoid these serious side effects.

T-type Calcium Channel Blockers

T-type, or transient-type (referring to the length of time activated), calcium channel blockers target low-voltage-activated, calcium channels. These channels have been recognized as critical components in numerous cell functions and have been implicated in the frequency and intensity of pain signals. Zalicus is investigating compounds to modulate T-type calcium channel signaling in the treatment of pain. Our orally-administered T-type calcium channel blockers have shown efficacy in animal models of acute and chronic pain, as well as other indications.

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 Na_V) 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 Na_V1.7 channel lead to the complete abolition of pain sensation while other gain-of-function Na_V1.7 mutations cause severe chronic pain syndromes. Further, in animal models it has been shown that the suppression of either Na_V1.7 or Na_V1.8 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 develop an in-house R & D program to design, characterize and develop novel, orally available agents that modulate the physiological functioning of Na_V1.7 and Na_V1.8 channels. The goal is to specifically target the increased firing and hypersensitivity in peripheral and spinal cord neurons that express Na_V1.7 and Na_V1.8 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 Na_V1.7 and Na_V1.8 channels has been generated. 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. By targeting  sodium channels in the peripheral and central nociceptive signaling pathways through a unique mechanism of action Zalicus has the opportunity to develop novel classes of safe and effective pain therapeutics.

Zalicus believes that the targeting of selective sodium channels both complements the existing N-type and T-type calcium channel pain programs and further by integrating many preclinical aspects of the programs, provides for cost-effective, value-added synergies to its drug discovery platform.