Praxis Precision Medicines announced positive topline results from its Essential3 Phase 3 program evaluating ulixacaltamide in essential tremor (ET), marking a potential breakthrough for the most common movement disorder affecting approximately seven million Americans. The company reported statistically significant improvements across all primary and key secondary endpoints in both pivotal studies.
Study Design and Patient Population
The Essential3 program (NCT06087276) employed an innovative decentralized design conducted across all 50 U.S. states, allowing participants to complete visits from their homes. The program included two simultaneously enrolled studies with participants allocated in a 2:1 blinded randomization.
Study 1 was a double-blind, parallel-group, placebo-controlled trial that enrolled 473 patients randomized 1:1 to receive either ulixacaltamide or placebo for 12 weeks. Study 2 was a stable-responder randomized withdrawal study enrolling 238 patients who received ulixacaltamide for 8 weeks, with responders then randomized to continue treatment or switch to placebo for an additional 4 weeks.
Patients in the Essential3 program had been living with essential tremor for an average of 30 years with worsening symptoms. The trial's recruitment demonstrated significant unmet need, with over 200,000 people expressing interest in participating during just 15 months of recruitment.
Primary Efficacy Results
In Study 1, patients treated with ulixacaltamide showed a mean improvement from baseline in the Modified Activities of Daily Living 11 (mADL11) score of 4.3 points at Week 8 compared to 1.7 points with placebo (p<0.0001). The effect was sustained from Week 2 throughout the 12-week dosing period.
All key secondary endpoints in Study 1 achieved statistical significance, including rate of disease improvement over 12 weeks (p<0.0001), Patient Global Impression of Change (PGI-C) with scores of 3.3 versus 3.9 for placebo (p<0.0001), and Clinical Global Impression of Severity (CGI-S) showing -0.41 versus -0.12 change from baseline (p=0.0007).
Study 2 met its pre-specified primary endpoint, with 55% of patients in the ulixacaltamide arm maintaining response versus 33% in the placebo group (p=0.0369, OR=2.7 CI 1.06-6.92). The first key secondary endpoint evaluating rate of disease improvement during the randomized-withdrawal phase also demonstrated superior effect for ulixacaltamide (p=0.0042).
Safety Profile
Ulixacaltamide was generally well tolerated over 12 weeks of treatment with no drug-related serious adverse events and no deaths reported. The most common treatment-emergent adverse events (≥10% of patients) included constipation, dizziness, euphoric mood, brain fog, headache, paresthesia, and insomnia.
In Study 1, 94.9% of ulixacaltamide patients experienced any treatment-emergent adverse event compared to 75.6% on placebo. Drug-related adverse events leading to discontinuation occurred in 27.0% of ulixacaltamide patients versus 1.7% on placebo, with dizziness and brain fog being the most common reasons for discontinuation.
Clinical Significance and Expert Commentary
"This is incredibly exciting news, for the first time we have a medication designed specifically for our ET patients," said Dr. Salima Brillman, Founder of Parkinson's Disease and Movement Disorders Center of Silicon Valley and co-lead investigator. "Ulixacaltamide represents more than data on a chart - it is a real opportunity to help people regain their independence and improve their daily functioning in meaningful ways."
Dr. Alexander Shtilbans from Hospital for Special Surgery and Weill Cornell Medicine noted the clinical meaningfulness of the results: "These results show clinically meaningful improvements in tremor control and daily function for adults with ET. These results give hope that ulixacaltamide could be widely used in people suffering from this condition."
Addressing Unmet Medical Need
Essential tremor represents a significant unmet medical need, with propranolol being the only FDA-approved pharmacotherapy despite offering limited efficacy and poor tolerability. The drug is also contraindicated for comorbidities affecting a significant portion of the ET population. Patient surveys indicate that up to 77% feel their ET is inadequately controlled and up to 50% aren't receiving treatment.
U.S. neurologists surveyed indicated that 85% of their visits are for patients seeking treatment, yet 40% of their patients receive no treatment. An estimated minimum of 2 million patients are actively seeking treatment, representing a multi-billion dollar commercial opportunity.
Mechanism of Action and Development
Ulixacaltamide is a differentiated and highly selective small molecule inhibitor of T-type calcium channels designed to block abnormal neuronal burst firing in the Cerebello-Thalamo-Cortical (CTC) circuit correlated with tremor activity. The drug represents the most advanced program within Praxis's Cerebrum™ small molecule platform.
Regulatory Timeline
Praxis has submitted a pre-NDA meeting request to the FDA and plans to submit the New Drug Application by early 2026, pending agreement with the agency. The company intends to share additional data from these studies at upcoming medical conferences and in peer-reviewed publications.
"We look forward to the opportunity to have a pre-NDA meeting with the FDA soon to discuss the potential NDA," said Marcio Souza, president and chief executive officer of Praxis Precision Medicines.
