ET is among the most prevalent of movement disorders in adults. Propranolol is the only medication approved for the treatment of ET. The T-type calcium channel is a mediator of subthreshold oscillations and excessive rhythmicity in pathophysiologic states found in tremor and is highly expressed in functional tremor network regions. Tremor-related oscillations are a neuronal signature for ET and T-Type calcium channels play a critical role in their generation. CX-8998 is a potent, selective, and state-dependent small molecule modulator of T-Type calcium channels.

To determine the efficacy of CX-8998 in patients with moderate to severe essential tremor (ET) with inadequate response to standard of care anti-tremor medications. 

We recently completed a randomized, double-blind, placebo-controlled, parallel-group study (NCT03101241) of 95 patients with ET. Following consent and screening, subjects were randomized to receive either CX-8998 (titrated to 10mg BID) or placebo for 28 days. Clinical rating scales, patient-reported outcomes and digital markers were collected at baseline (visit 1), day 15 (visit 3) and day 28 (visit 4).

Investigator-rated TETRAS (The Essential Tremor Rating Assessment Scale) Performance Subscale (p=0.017), TETRAS-ADL (p=0.049), TETRAS total score (p=0.007) and Clinician Global Impression of Improvement (p=0.001) significantly improved. Centrally video-rated TETRAS Performance Subscale (primary endpoint) did not reach significance due to methodological issues. The significant differences on the TETRAS-ADL were confirmed by goal attainment scaling (GAS; p=0.034) and supported by the subject’s impressions of improvement (PGIC; p=0.089). Digital spirography using iMotor was qualified as a digital marker in a subset of patients.

The study achieved proof-of-concept in ET and identified key pivotal study design parameters including primary and secondary efficacy endpoints, patient population, dose and titration scheme. Further studies are needed to evaluate the efficacy of CX-8998 in ET patients. These results are expected to enable late-stage development of CX-8998 in ET.