Ulixacaltamide

Ulixacaltamide (developmental codes PRAX-944 and Z-944) is an investigational new drug developed by Praxis Precision Medicines for the treatment of essential tremor (ET).^[1] It is a small molecule designed to selectively inhibit T-type calcium channels, reducing the abnormal neuronal burst firing in the cerebello-thalamo-cortical (CTC) circuit that is believed to cause tremors.^[2]

In October 2025, the drug met its primary endpoints in the pivotal Phase 3 Essential3 clinical program.^[3] Following these results, the U.S. Food and Drug Administration (FDA) granted ulixacaltamide Breakthrough Therapy Designation in December 2025.^[4] In February 2026, the company submitted a New Drug Application (NDA) to the FDA, which was accepted for review in April 2026 with a target action date of January 2027.^[5]

Ulixacaltamide is being developed specifically for the treatment of essential tremor in adults. If approved, it would represent a new pharmacological class of treatment for the condition, distinct from the current standard-of-care agents such as propranolol (a beta-blocker) and primidone (an anticonvulsant).^[2]

In December 2025, the FDA granted the drug Breakthrough Therapy Designation, a status intended to expedite the development and review of drugs for serious conditions where preliminary clinical evidence indicates the drug may demonstrate substantial improvement over available therapies. The designation was supported by Phase 3 clinical results demonstrating superiority over propranolol, the only currently FDA-approved pharmacologic treatment for essential tremor.^[6][4]

Ulixacaltamide is a selective blocker of T-type calcium channels (Cav3.1, Cav3.2, and Cav3.3 isoforms).^[2]

Research suggests that the involuntary rhythmic shaking characteristic of essential tremor is driven by abnormal oscillatory activity within the cerebello-thalamo-cortical circuit. Specifically, T-type calcium channels play a key role in generating "burst firing" patterns in neurons within this pathway. By inhibiting these channels, ulixacaltamide is designed to suppress this pathological burst firing and reduce tremor amplitude without causing the widespread central nervous system depression often associated with non-selective treatments.^[7]

The compound was originally discovered by Zalicus Inc. (formerly Neuromed) and was known as Z-944.^[8] It was later acquired by Praxis Precision Medicines and renamed PRAX-944.

The drug's efficacy was evaluated in the Phase 2 "Essential1" study, which showed improvements in daily living activities scores.^[7]

In 2025, Praxis completed the "Essential3" Phase 3 program, which consisted of two concurrent decentralized studies. Topline data from the program were presented at the American Academy of Neurology (AAN) Annual Meeting in April 2026:^[6]

• Study 1 (Parallel Group): A 12-week randomized, double-blind, placebo-controlled trial enrolling 473 adults. The study met its primary endpoint, demonstrating a statistically significant and rapid improvement in the Modified Activities of Daily Living (mADL11) score from baseline to day 56 for patients on ulixacaltamide (mean change of -4.3 points) compared to placebo (-1.7 points; p<0.0001).
• Study 2 (Randomized Withdrawal): An 8-week blinded lead-in period followed by a 4-week randomized withdrawal phase. This study also met its primary endpoint, showing that 55% of patients maintained their clinical response upon re-randomization to ulixacaltamide compared to 33% of those switched to placebo (p=0.037, Odds Ratio=2.7).

These positive results followed a February 2025 interim analysis by an Independent Data Monitoring Committee (IDMC) that had initially recommended discontinuing the study due to perceived futility. Praxis elected to continue the trial, ultimately achieving statistical significance in the final readout.^[9]

Following the Phase 3 results, Praxis submitted a New Drug Application (NDA) to the FDA in February 2026.^[10] On April 14, 2026, the FDA formally accepted the application for review and set a Prescription Drug User Fee Act (PDUFA) target action date of January 29, 2027, with no plans to hold an advisory committee meeting.^[5]

In Phase 3 clinical trials, once-daily ulixacaltamide was generally well-tolerated, with no drug-related serious adverse events or significant drug-drug interactions reported. Most adverse events occurred during the initial dose titration period, were mild to moderate in severity, and resolved quickly. The most common treatment-emergent adverse events (occurring in ≥10% of patients) included constipation, dizziness, euphoric mood, "brain fog" (cognitive disturbance), headache, paresthesia, and insomnia. Treatment discontinuations in the active group were primarily driven by adverse events, most commonly dizziness and brain fog.^[6]