Objective: In this study, we utilized preclinical data to establish predicted human therapeutic exposures of the potent, selective and state-dependent Cav3 channel antagonist, CX-8998, currently in Phase 2 clinical studies for essential tremor and Parkinson’s disease tremor.

Background: Cav3 is a mediator of subthreshold oscillations and excessive rhythmicity in pathophysiologic states found in tremor and is highly expressed in functional tremor network regions. Rodent models of tremor show enhanced Cav3 currents and burst-firing. Selective targeting of Cav3 channels has the potential to provide symptomatic benefit in conditions where Cav3 is an important component of disease pathophysiology.

Methods: We have investigated the potency and efficacy of CX-8998 and other Cav3 antagonists in rat preclinical models dependent on elevated Cav3 activity including harmaline induced tremor and the WAG/Rij genetic model of spontaneous absence seizures. Dose and time dependent effects of Cav3 antagonists on tremor and seizure were objectively quantified using measures of tremor power and electrocorticogram recordings.

Results: Cav3 antagonists suppressed both tremor and accumulated time in seizure in a dose and time dependent fashion. CX-8998 showed robust activity following single oral doses of 1-10 mg/kg with exposure response analysis indicating an effective plasma concentration threshold of 150-350 nM CX-8998 in rat. Adjusting for species differences in plasma protein binding predicts a human therapeutic plasma concentration range of 300-700 nM. Comparison of Cav3 antagonist potencies suggests that CX-8998 will result in substantially greater target engagement at achievable CNS concentrations compared to less potent and selective Cav3 antagonists zonisamide and ethosuximide.

Conclusions: Cav3 antagonists, including CX-8998, show robust efficacy in preclinical models dependent on Cav3 pathology including tremor and epilepsy. Evaluation of preclinical efficacy and pharmacology data for CX-8998 supports an achievable effective human plasma concentration range and suggest the potential for improved Cav3 target engagement compared to less potent and selective antagonists.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/therapeutic-exposures-of-cx-8998-a-potent-selective-and-state-dependent-cav3-channel-antagonist-in-development-for-essential-tremor-and-parkinsons-disease-tremor-in-cav3-driven-neurological-models/