Objective: To characterize the in vitro T-type calcium (Ca_V3) channel target pharmacology and in vivo anti-tremor profile of suvecaltamide (JZP385, CX-8998).

Background: Ca_V3 channels, a family of 3 low-voltage–activated calcium channels, help to set the excitability and oscillatory activity of neurons and are highly expressed in brain regions mediating excessive rhythmicity in essential tremor (ET). Suvecaltamide, a selective Ca_V3 modulator, reduced tremor severity and improved function in participants with moderate to severe ET in a phase 2a clinical study [1]. The present nonclinical studies investigated the mechanism of action of suvecaltamide.

Method: Currents were recorded from HEK293 cells stably overexpressing human Ca_V3.1, 3.2, or 3.3 using a QPatch 48X automated patch clamp system (Sophion Bioscience A/S). Steady-state inactivation curves were generated for each Ca_V3 subtype with and without suvecaltamide (n=4‒17/treatment group); concentration-response curves were generated using protocols that enriched for resting or inactivated channel states (n=3‒9/treatment group). Using a piezoelectric sensor cage system (Signal Solutions), harmaline-induced tremor (9–12 Hz) was quantified in male rats (n=8‒24/group) administered suvecaltamide (0.1–10 mg/kg, oral) or vehicle pre- or post-harmaline (10–15 mg/kg, intraperitoneal).

Results: Suvecaltamide hyperpolarized the midpoint of voltage-dependent channel inactivation by −6 to −18 mV relative to vehicle for all Ca_V3 subtypes. Suvecaltamide inhibited all Ca_V3 subtypes in a concentration- and state-dependent manner, with low nM potencies, and was 7- to 19-fold more selective for the inactivated Ca_V3 channel state. In rats, suvecaltamide administered either pre- or post-harmaline dose-dependently reduced tremor vs vehicle, with robust inhibition observed at ≥1 mg/kg. Plasma concentrations of suvecaltamide that reduced tremor were consistent with those achieved at steady state in humans at projected therapeutic doses.

Conclusion: Suvecaltamide inhibited all Ca_V3 subtypes with low nM potency in a state-dependent manner and effectively reduced tremor in rats when administered orally pre- or post-harmaline, supporting the continued development of suvecaltamide for the treatment of ET. An ongoing phase 2b trial will further evaluate the safety and efficacy of suvecaltamide for adults with moderate to severe ET [2].

References: 1. Papapetropoulos S, Lee MS, Versavel S, et al. A phase 2 proof-of-concept, randomized, placebo-controlled trial of CX-8998 in essential tremor. Mov Disord. 2021;36(8)1944-1949.
2. ClinicalTrials.gov. A study to assess the safety and efficacy of JZP385 in the treatment of adults with moderate to severe essential tremor (ET). Available at: https://clinicaltrials.gov/ct2/show/NCT05122650. Accessed February 25, 2022.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-characterization-of-suvecaltamide-for-essential-tremor/