AAN 2026 Ulixacaltamide improves daily function in people with essential tremor

medwireNews: Ulixacaltamide, a selective T-type calcium channel modulator, significantly improves daily function in people with essential tremor with the treatment benefit sustained for up to 2 months, show topline findings from the ESSENTIAL3 study.

This is the “first positive phase 3 program for a drug in essential tremor,” said Jill Farmer (BoroNeuro, Hopewell, New Jersey, USA) at the 2026 AAN Annual Meeting in Chicago, Illinois, USA.

She highlighted that there is an “unmet need” for patients with essential tremor who are undertreated, citing that “fewer than half of patients seek treatment, and of those that do, less than 20% stay on therapy for more than 2 years,” and this is largely due to “the lack of efficacy and poor tolerability of what is available.”

The ESSENTIAL3 program consists of two 12-week studies of ulixacaltamide, which normalizes T-type calcium activity in the cerebello-thalamo-cortical circuit. The first is a placebo-controlled parallel study, and the second a randomized withdrawal study.

Farmer commented that the study findings were “meaningful and statistically significant showing consistency across studies, endpoints, and subpopulations.”

A total of 711 patients aged 18–85 years (mean age 68 years) who had experienced symptoms of essential tremor for at least 3 years (median 30 years) were enrolled, of whom 473 were randomly assigned to study 1 and 238 to study 2. If patients were already taking medications for essential tremor they had to be on a stable dose for at least 28 days.

The baseline Essential Tremor Rating Assessment Scale (TETRAS)–Activities of Daily Living (ADL) score was a mean of 30.8 points out of a possible 48.0 points. On the modified (m)ADL11, which encompasses 11 items of the TETRAS–ADL focused on activities affected by upper limb tremor, such as eating, drinking, dressing, and writing, the score was a mean of 18.6 points out of a possible 33.0 points.

Ulixacaltamide versus placebo

The patients in study 1 were randomly assigned to receive once daily oral ulixacaltamide hydrochloride 60 mg or placebo.

After 56 days of treatment, scores on the mADL11 improved significantly more among 199 available patients receiving ulixacaltamide than among 233 receiving placebo, with reductions from baseline of 4.3 points versus 1.7 points.

Significant improvements with ulixacaltamide compared with placebo were also seen for secondary endpoints at day 56, including the rate of disease improvement (least squares mean [LSM] reduction in slope of 2.27), and scores on the Patient Global Impression of Change (PGI–C; LSM reduction of 0.60 points) and the Clinical Global Impression of Severity (CGI–S; LSM reduction of 0.29 points).

The functional benefits with ulixacaltamide were “clinically meaningful and statistically significant […] irrespective of baseline demographics,” said the presenter, including whether or not patients were receiving concomitant essential tremor medications or taking propranolol.

Farmer noted that among the patients who were taking propranolol, “there was a compounded benefit” with the addition of ulixacaltamide.

Ulixacaltamide withdrawal

The patients in study 2 received ulixacaltamide in an 8-week lead-in phase. Of 147 participants, 80 responded to treatment, improving by at least 3 points on the mADL11. The mean improvement from baseline in mADL11 score among the 80 responders was 8.9 points, while TETRAS–ADL scores improved by a mean of 9.8 points.

The responders were then randomly assigned to continue taking ulixacaltamide or switch to placebo.

Farmer noted that “the significant gains realized during the blinded lead-in” were followed by “superiority of maintenance” during the randomized withdrawal phase.

Specifically, 55% of the 40 patients who continued to take ulixacaltamide for a further 4 weeks maintained their response on mADL11 compared with 33% of 40 patients who switched to placebo, giving a significant odds ratio of 2.7.

A significant benefit of ulixacaltamide over placebo was maintained across multiple measures of clinical improvement, including the mADL11, CGI–S, PGI–Severity, and PGI-C.

Across both studies the onset of treatment response happened “quite quickly,” said Farmer, with a difference compared with placebo seen from about day 14.

Ulixacaltamide response was also assessed across three different thresholds of minimal clinically important difference (MCID ≥x1, ≥x2, and ≥x3), and at the most stringent criteria of more than 3x MCID, a “remarkable proportion of patients are achieving and maintaining response,” noted the presenter, which “reflects robust and clinically meaningful effect.”

In terms of safety, “once-daily ulixacaltamide was generally well tolerated across studies,” she remarked.

Most adverse events (AEs) were mild to moderate, occurred in the titration phase, and self-resolved, with rates ranging from 37.7–46.8% with ulixacaltamide across the two studies, and from 33.3–38.0% with placebo.

The most frequent AEs in the ulixacaltamide group were constipation, dizziness, euphoric mood, brain fog, headache, paresthesia, and insomnia. There were no serious AEs and no significant drug–drug interactions.

Discontinuation of ulixacaltamide occurred in 35.6–38.1% of patients primarily due to dizziness and brain fog, and, again, mainly during the titration phase. Farmer noted that “in the real-world, we will likely be able to modify how quickly we titrate or change the dose that we use to mitigate any patient concerns.”

Concluding, Farmer announced that the study findings have led to a Breakthrough Therapy Designation being granted for ulixacaltamide in essential tremor, with “expected FDA approval in January 2027.”

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2026 AAN Annual Meeting; Chicago, Illinois, USA: 18–22 April