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
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.
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.
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).
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.
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.