Objective: An innovative, multi-study Phase 3 program to definitively assess safety and efficacy of ulixacaltamide in essential tremor (ET).

Background: Phase 2 studies of ulixacaltamide, a selective T-type calcium channel blocker, have demonstrated improvement in TETRAS Activities of Daily Living (ADL) measures and favorable tolerability. Findings from the Essential1 Phase 2 study (NCT05021991) provided confidence in a modified ADL scale (mADL11) as a robust endpoint for assessing meaningful benefit in ET, demonstrating early clinical benefit at 8 weeks and long-term durable benefit. Incorporating learnings from Essential1 and FDA guidance, the Essential3 program (NCT06087276) addresses critical trial design considerations to facilitate definitive assessment of the safety and efficacy of ulixacaltamide in adults with ET.

Method: The Essential3 program uses an innovative, decentralized trial design including functionally relevant endpoints and disease-appropriate analyses and is optimized to: minimize variability due to disease heterogeneity and temporal fluctuation; mitigate placebo effects and potential confounds; and maximize speed, efficiency, accessibility and diversity. Two simultaneous, 12-week, decentralized, pivotal studies will combine in-home and telehealth visits to assess efficacy of ulixacaltamide (60 mg QAM) vs. placebo, and maintenance and durability of effect in responders following randomized withdrawal (RW). Participants have the option to participate in a long-term safety study up to ~1 year. Essential3 aims to recruit ~600 adults aged 18–85 years with ET (symptoms for ≥3 years; no more than 1 ET medication for ≥1 month before screening), with over 3,000 referrals meeting pre-qualifying eligibility criteria as of March 2024.

Results: Primary endpoints in the two studies are change from baseline to Day 84 in mADL11 (TETRAS-ADL items 1-11 with modified score), and the proportion of participants maintaining response following RW, respectively. Secondary endpoints include responder rates and mADL11 change after 12 weeks, change in TETRAS-ADL, clinician and patient measures of severity, and safety assessments. Enrollment commenced in 4Q2023 with topline results expected in 2H2024.

Conclusion: In addition to providing evidence of ulixacaltamide safety and efficacy, the Essential3 program is expected to set the foundation for future clinical trial design in ET and other neurologic disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/essential3-an-innovative-multi-study-phase-3-program-to-evaluate-the-efficacy-and-safety-of-ulixacaltamide/