Objective: To evaluate efficacy of ulixacaltamide, a selective T-type calcium channel modulator, versus placebo in adults with essential tremor (ET) as monotherapy and as add-on to propranolol in ESSENTIAL3 Phase 3 Study 1 (NCT06087276).

Background: Propranolol remains the only FDA-approved oral ET treatment, yet it is either contraindicated or provides inadequate control to the majority of patients. Ulixacaltamide targets T-type calcium channels in the cerebello-thalamo-cortical circuit, a key tremor network, through a mechanism distinct from beta-adrenergic antagonism, supporting the potential for efficacy independent of propranolol use.

Method: Essential3 Study 1 was a decentralized, randomized, double-blind, placebo-controlled phase 3 trial. Adults with moderate-to-severe ET (modified Activities of Daily Living scale, 11- item version, mADL11 ≥12) were randomized 1:1 to ulixacaltamide QD or placebo for 12 weeks. The primary endpoint was change from baseline in mADL11 at Day 56. Key secondary endpoints included Patient/Clinical Global Impression (PGI-C and CGI-S) change from baseline at Day 56. Pre-specified subgroup analyses examined the treatment effect of ulixacaltamide stratified by propranolol use.

Results: Among mITT participants (N=199 ulixacaltamide, N=233 placebo), mean age was 68.4 years (57% male), with ~35% using propranolol at baseline, balanced across arms. Overall, Study 1 met the primary endpoint (mADL11 change in favor of ulixacaltamide −2.57; 95% CI −3.62, −1.53; p<0.0001) and key secondaries: PGI-C −0.60 (p<0.0001), CGI-S −0.29 (p=0.0007). Onset of effect was rapid and robust at Day 14 (−2.65; p<0.00001). In the propranolol subgroup, results were statistically significant with an mADL11 change of −3.00 (p=0.0005), representing effect size d ≥ 0.6. Ulixacaltamide demonstrated consistent superiority with no treatment-by-subgroup interaction. Sensitivity analyses confirmed robustness of findings.

Conclusion: Ulixacaltamide demonstrated superiority over placebo both as monotherapy and as add-on to propranolol across all endpoints. The effect observed in the propranolol subgroup supports the potential for mechanistic complementarity between T-type calcium channel modulation and beta-adrenergic antagonism. These data position ulixacaltamide as a meaningful option for the full ET treatment-seeking population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ulixacaltamide-demonstrates-superiority-over-placebo-as-monotherapy-and-as-add-on-to-propranolol-in-essential-tremor-phase-3-essential3-study-1/