Z944: a first in class T-type calcium channel modulator for the treatment of pain.

Abstract

Zalicus, Inc. is a small, publicly-traded biotech company in Cambridge, Massachusetts. The potential target for neuropathic pain lies in the T-type calcium channels, members of the low-voltage activated channel family. By opening at relatively negative membrane depolarizations, T-type channels can act as modulators of the threshold of the action potential by increasing the calcium current, leading to further depolarization of the cell and activation of other calcium channels, and ultimately, sodium and potassium channels. This is a target that is widely expressed in both the peripheral as well as the central nervous system (Zamponi et al., 2009). It is known that T-type calcium channel blockade can modulate pain behavior and disrupting this mechanism can reduce pain in neuropathic, inflammatory, and visceral pain models. There is evidence that the calcium channel protein itself as well as the current that is delivered by this channel is increased in certain pain models (Marger et al., 2011). Another important feature of this target is its central action. There are three subtypes of the T-type calcium channel, denoted Cav3.1, 3.2, and 3.3. They are expressed in different places in the thalamus, the cerebellum, and other parts of the brain. It is thought that they participate in the regulation of connectivity or crosstalk between the sensory nervous system and the cortex by promoting thalamic neuron burst firing and network oscillations important for relay and interpretation of signals to and by the cortex. A number of central nervous system (CNS) diseases have been linked to aberrant thalamocortical oscillations (thalamocortical dysrhythmia), and there is evidence that T-type calcium channel mutants can play a role in hyperexcitability disorders, for example, epilepsy syndromes. Some approved anticonvulsants also hit the T-type channel as part of their polypharmacology. Zalicus' approach has been to discover and develop a small molecule blocker of T-type calcium channels as a potential therapeutic for pain. The medication, Z944, is a novel, oral, state-dependent, selective T-type calcium channel blocker. This blocker has >150-fold selectivity vs. non-T-type voltage-gated ion channels and has been shown to inhibit native neuronal T-type currents at high potency. The blockade of Cav3.2 by Z944 is more pronounced during high-frequency firing and may provide some advantage to the molecule by selectively targeting a pathological state of the channel (Short et al., 2013). A phase 1, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of oral Z944 in healthy male subjects in the fed and fasted states using an immediate release formulation showed that the medication was safe and well tolerated. Mild and expected CNS side effects were observed; no serious adverse events were reported. A phase 1b clinical study utilized a state-of-the-art experimental clinical model measuring Laser-Evoked Potentials (LEP) from skin irritated following topical application of capsaicin (modeling neuropathic pain signaling and central sensitization) or exposure to UV light (modeling inflammatory pain signaling). Healthy volunteers received 20, 40, and 80 mg doses split in four administrations every 2 h vs. placebo. The data showed that Z944 reduced peak-to-peak amplitudes of LEPs from both capsaicin and UV irritated skin models and reduced subjective Visual Analog Scale (VAS) pain scores in both skin types. The noted adverse events were generally mild to moderate and primarily central nervous system related. No serious adverse events occurred in this study. On the basis of these findings, several modified release formulations of Z944 are currently being advanced in clinical development for pain indications.