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Suvecaltamide Metabolites Are CaV3 Modulators and Contribute to Pharmacological Effect

E. Brigham, W. Zeng, N. Shanks, M. Lee (Palo Alto, USA)

Meeting: 2024 International Congress

Abstract Number: 1532

Keywords: Essential tremor(ET), Pharmacotherapy, Tremors: Treatment

Category: Tremor

Objective: To determine the potency-concentration relationships and combined pharmacological effects for suvecaltamide and its 2 active metabolites (JZZ05000034=M01, JZZ05000035=M02; total active moiety [TAM]).

Background: T-type calcium (CaV3) channels regulate neuronal excitability and are thought to play a key role in mediating pathological tremor-producing oscillations in conditions like essential tremor (ET). Suvecaltamide (JZP385), a potent, selective CaV3 modulator, improved function in adults with moderate-to-severe ET in a phase 2 study (T-CALM/NCT03101241).

Method: Automated patch-clamp recordings in HEK293 cells stably overexpressing human CaV3 subtypes were used to generate steady-state inactivation curves with/without treatment with analytes (suvecaltamide, M01, or M02); concentration-response curves used protocols enriching for resting or inactivated channel states. Off-target effects were tested in enzyme and receptor binding panels.

Results: All analytes inhibited all CaV3 channels in a concentration- and state-dependent manner [table 1] and slowed recovery from inactivation. Selectivity (<50% [10 µM]) was demonstrated for all targets/analytes except suvecaltamide at CB2 receptor (IC50=5.3 μM) and M01 at human PPAR-gamma (54% at 10 µM) and guinea-pig adenosine transporter (IC50=2.9 µM), which are not likely to be relevant at projected therapeutic doses.

Conclusion: Suvecaltamide and its active metabolites demonstrate selective, state-dependent modulation of all CaV3 subtypes with markedly higher affinity for partially inactivated channels. Modelling TAM shows that, at clinically relevant concentrations, suvecaltamide and its metabolites may selectively inhibit channels enriched under hyperexcitable conditions (eg, pathological neuronal firing) while sparing channels involved in normal signalling, which may contribute to a more optimal clinical profile. Two ongoing phase 2 studies are evaluating suvecaltamide in adults with moderate-to-severe ET (NCT05122650) or residual Parkinson’s disease tremor (NCT05642442).

Table 1

Table 1

To cite this abstract in AMA style:

E. Brigham, W. Zeng, N. Shanks, M. Lee. Suvecaltamide Metabolites Are CaV3 Modulators and Contribute to Pharmacological Effect [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/suvecaltamide-metabolites-are-cav3-modulators-and-contribute-to-pharmacological-effect/. Accessed July 9, 2025.
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