Evaluate efficacy and safety of CX-8998 in essential tremor (ET) by baseline tremor severity.

CX-8998, a selective modulator of T-type calcium channels, was evaluated for treatment of ET in a 4-week, randomized, double-blind, placebo-controlled phase 2a trial (NCT03101241).

Adults with ET and score ≥15 on The Essential Tremor Rating Assessment Scale performance subscale (TETRAS-PS) were randomly assigned
to CX-8998 titrated to 10 mg BID or placebo. Changes from baseline to day 28 on TETRAS-PS, as rated in real time by the investigators (evaluated post hoc), and the activities of daily living subscale (TETRAS-ADL) were evaluated using analysis of covariance in the full analysis set (FAS), which included all participants who received study drug and had baseline and ≥1 postbaseline assessments. A prespecified analysis evaluated outcomes in subgroups defined by baseline TETRAS-PS scores at or below (less severe) and above (more severe) the median score.

Median investigator-rated baseline TETRAS-PS score was 27.5. Investigator-rated TETRAS-PS improved with CX-8998 treatment vs. placebo: Least squares (LS) mean differences from placebo (95% confidence interval [CI]) in change from baseline to day 28 were -2.0 (-4.0 to 0.0) in the FAS population (n=83); -1.2 (-3.1 to 0.6) in the less severe subgroup (n=44) and -3.5 (-7.4 to 0.4) in the more severe subgroup (n=39). For TETRAS-ADL, LS mean differences from placebo (95% CI) in change from baseline to day 28 were -2.9 (-5.8 to -0.1) in the FAS population; -1.6 (-4.7 to 1.4) in the less severe subgroup and -5.8 (-11.2 to -0.5) in the more severe subgroup. In both subgroups, adverse events were mostly mild to moderate.

For participants with more severe tremor at baseline, the treatment effect with CX-8998 may be larger in absolute value and therefore easier to detect relative to those with less severe baseline tremor.