Translational Pharmacology of PRAX-944, a Novel T-type Calcium Channel Blocker for the Treatment of Essential Tremor
Corey Puryear1, Liam Scott1, Gabriel Belfort1, Shane Raines1, Zoe Hughes1, Bernard Ravina1, Marion Wittmann1
1Praxis Precision Medicines
Objective:
PRAX-944 is a novel selective T-type calcium channel (TTCC) blocker in clinical development for the treatment of essential tremor (ET). We used sigma-power as a translational biomarker to assess whether pharmacodynamically-active doses of PRAX-944 would be well-tolerated in healthy participants, thus informing dose selection for future efficacy trials in patients with ET.
Background:
ET is the most common movement disorder with clear need for new therapeutic options. Mounting evidence suggests that tremor is caused by increased neuronal burst firing and oscillations in cerebello-thalamo-cortical circuitry, thought to be driven by TTCC activity. Furthermore, TTCCs regulate sigma encephalographic (EEG) power in the sigma band (11-15 Hz) during non-rapid eye movement sleep, representing a potential biomarker of central TTCC blockade.
Design/Methods:
Rodent harmaline-induced tremor and spontaneous locomotor activity were used to assess efficacy and tolerability of PRAX-944 (0.1-30 mg/kg, PO), respectively. Sigma-power was used as a translational biomarker of TTCC blockade following PRAX-944 treatment in rats and in a Phase 1 dose-escalating (5-120mg, qAM) clinical trial in healthy participants (ACTRN12620000675921).
Results:
In rats, PRAX-944 dose-dependently reduced tremor by 50 and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side-effects; these doses reduced sigma-power by 30-50%. In healthy participants given repeated PRAX-944 doses, sigma-power was similarly reduced by 34-50% at 10-100 mg, with no further reduction at 120 mg. All doses were well-tolerated. Additional exploratory analysis on awake EEG periods showed that gamma-power was also reduced in a dose-dependent manner.
Conclusions:
Administration of PRAX-944 in rats and humans produced strong and consistent effects on sigma-power, which may represent a robust and translatable biomarker of TTCC blockade. In rats, PRAX-944 reduced sigma-power at concentrations that reduced tremor without locomotor side-effects. In healthy participants, comparable sigma-power reductions indicate that TTCC blockade was achieved at well-tolerated doses that may hold therapeutic promise for tremor reduction in patients with ET.