Novel Drug May Improve Daily Activities in ET: Phase 3 Trial

SEOUL, South Korea — A novel selective T-type calcium channel blocker/inhibitor was effective in improving multiple activities of daily living (ADL) in adult patients with essential tremor (ET), a new phase 3 trial showed.In Essential3 (E3) Study 1, which included more than 400 participants, those receiving ulixacaltamide 60 mg had significant improvement in all 12 ADL domains assessed at day 56 compared to those who received matching placebo.The largest improvements were in motor-intensive tasks, such as drinking, carrying dinnerware, pouring, and feeding oneself. Separation from placebo occurred by day 14 in all domains and continued through day 84.Patients with ET are often misinterpreted as being “a hearty bunch” because they commonly just manage and deal with the symptoms themselves rather than complain, even though ET is progressive in nature, said Jill Farmer, DO, a neurologist with BoroNeuro in Hopewell, New Jersey, and co-principle investigator of the E3 program which is funded by manufacturer Praxis Precision Medicines.“The medicines we had for it were not all that effective. But this new drug stands out because it is the only one that is mechanistically applicable to essential tremor,” Farmer told Medscape Medical News.Currently, ET is treated with drugs approved for other conditions, such as seizures, headache, and high blood pressure, Farmer noted. “As long as the FDA approves it, we could now have an effective treatment that is just for essential tremor,” she said.The findings were presented on October 5 at the International Congress of Parkinson's Disease and Movement Disorders (MDS) 2026.‘Dampening’ the Temor DriverET affects about 7 million US adults, with more than 85% of these reporting functional disability that affects their daily activities, the investigators noted.While composite ET-related ADL scores capture overall impairment, analyzing individual items can show which specific daily tasks improve with treatment, the researchers explained. Knowing which domains tend to improve first, and which lag behind, could also give a fuller picture of how treatment works in real-world settings, they added.Ulixacaltamide, which has received FDA Breakthrough Therapy Designation, is a selective T-type calcium channel inhibitor designed to suppress abnormal burst firing in in neurons along the cerebello-thalamo-cortical circuit, which is linked to tremor.“This medicine is essentially looking at the tremor driver in the brain. If we can modulate T-type calcium channels and dampen their activity, then we can dampen that tremor drive” and hopefully reduce tremor intensity, Farmer noted. “Patients want something that will just help them get through their day.”The E3 study program includes two simultaneous studies of ulixacaltamide in adults with ET. Preliminary topline results for both E3 Study 1 and Study 2 were released previously.The Study 2 was a stable-responder randomized withdrawal study with 238 patients who received ulixacaltamide for 8 weeks. The participants who showed a 3-point improvement from baseline on the Modified ADL11 (mADL11) were then randomized to receive either placebo or to continue receiving ulixacaltamide for an additional 4 weeks.Topline results for Study 2 showed that patients who stayed on ulixacaltamide held onto their gains significantly better than those switched to placebo during the randomized-withdrawal phase (P = .04), meeting its prespecified primary endpoint. A key secondary endpoint of rate of disease improvement during this same phase was also superior for the active-treatment group(P = .004).E3 Study 1, which was presented at MDS 2026, was a double-blind trial of adults aged 18-85 years who had ET for at least 3 years and were rated as having moderate-to-severe disability. All were randomly assigned to receive either ulixacaltamide 60 mg (n = 199; mean age, 67.9 years; 57.3% men; 98.5% White) or matching placebo (n = 233; mean age, 68.9 years; 56.0% men; 95.7% White) for 12 weeks.‘Granular Insight’The topline results for Study 1 had reported that the ulixacaltamide group had significant improvement from baseline to week 8 on the mADL11, the prespecified primary endpoint, of 4.3 points(P < .0001).Additional results from the poster presentation showed greater improvement for ulixacaltamide than placebo at day 56 at progressively higher bars for ADL response. Greater improvement for ulixacaltamide was also observed across all 12 ADL domains.Further, a higher proportion of ulixacaltamide-treated patients who had a baseline score of 3 or higher, signifying more significant disability, improved by at least 1 level compared to placebo across all individual ADL items. Steady movement to a near-normal level of functioning were observed for participants with baseline scores of 2 or higher.There was also a higher proportion of responders for the ulixacaltamide group than for the placebo group at day 56 on the Patient Global Impression of Change (PGI-C), the Patient Global Impression of Severity (PGI-S), and the Clinical Global Impression of Severity (CGI-S; P < .05 for all).Spearman r’s, relating the fraction of initially affected activities improved to global improvement in recipients of ulixacaltamide, were 0.64, 0.37, and 0.58 on the PGI-C, PGI-S, and CGI-S, respectively.Overall, the findings “demonstrate that clinically meaningful treatment benefits extend beyond upper-extremity motor tasks, complementing primary composite findings, and providing granular insight into the full breadth of potential therapeutic benefit,” the researchers wrote.Farmer reported that a long-term safety trial is currently underway. A Prescription Drug User Fee Act target action date for the drug is expected for January 29, 2027, the company reported.Promising, but EarlySteffen Paschen, MD, movement disorders specialist in the Department of Neurology at Kiel University in Kiel, Germany, said he found the investigators’ focus on ET-related ADL measures interesting.Paschen, who was not involved with the research, noted that although there were no tremor-related measures, the ADL outcomes did show a positive treatment response.“So I would say the data are promising, but it’s too early to compare it to other, established treatments for essential tremor,” he told Medscape Medical News.Head-to-head trials between ulixacaltamide and other first-line therapies, such as propranolol and primidone, could provide more information, Paschen said.With no advances in decades for new ET medications, Paschen said he is looking forward to examining new research and data that comes out about this new drug.The study was funded by Praxis Precision Medicines. Farmer reported having served as a consultant to Praxis Precision Medicines. Paschen reported having no relevant financial disclosures.