Translational Pharmacology of PRAX-944, a Novel T-Type Calcium Channel Blocker in Development for the Treatment of Essential Tremor.

Autor: Scott L; Praxis Precision Medicines, Boston, Massachusetts, USA., Puryear CB; Praxis Precision Medicines, Boston, Massachusetts, USA., Belfort GM; Praxis Precision Medicines, Boston, Massachusetts, USA., Raines S; Praxis Precision Medicines, Boston, Massachusetts, USA., Hughes ZA; Praxis Precision Medicines, Boston, Massachusetts, USA., Matthews LG; Praxis Precision Medicines, Boston, Massachusetts, USA., Ravina B; Praxis Precision Medicines, Boston, Massachusetts, USA., Wittmann M; Praxis Precision Medicines, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2022 Jun; Vol. 37 (6), pp. 1193-1201. Date of Electronic Publication: 2022 Mar 07.
DOI: 10.1002/mds.28969
Abstrakt: Background: Essential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello-thalamo-cortical circuitry and may be dependent on T-type calcium channel activity. T-type calcium channels regulate sigma band electroencephalogram (EEG) power during non-rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX-944 is a novel T-type calcium channel blocker in development for essential tremor.
Objectives: Using a rat tremor model and sigma-band EEG power, we assessed pharmacodynamically-active doses of PRAX-944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials.
Methods: Harmaline-induced tremor and spontaneous locomotor activity were used to assess PRAX-944 efficacy and tolerability, respectively, in rats. Sigma-power was used as a translational biomarker of T-type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants.
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 also reduced sigma-power by ~30% to 50% in rats. In healthy participants, sigma-power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated.
Conclusions: In rats, PRAX-944 reduced sigma-power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma-power indicate that robust T-type calcium channel blockade was achieved at well-tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
(© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE
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