Breakthrough Clinical Results
Praxis Precision Medicines announced positive topline results from two pivotal Phase 3 studies (Essential3 program) of ulixacaltamide HCl in patients with essential tremor (ET). Study 1 met its primary endpoint, showing a statistically significant improvement in the Modified Activities of Daily Living 11 (mADL11) score at Week 8 compared to placebo. Study 2 also met its primary endpoint, demonstrating superior maintenance of effect with ulixacaltamide versus placebo during the randomized-withdrawal phase. Ulixacaltamide was generally well-tolerated. Praxis plans to request a pre-NDA meeting with the FDA and intends to submit the NDA by early 2026.
Key Highlights
- Ulixacaltamide showed statistically significant improvement in mADL11 score in essential tremor patients in Phase 3 trials.
- Study 1 demonstrated a 4.3-point improvement in mADL11 at Week 8 (p<0.0001).
- Study 2 showed superior maintenance of effect with ulixacaltamide versus placebo (p=0.0369).
- Praxis plans to submit an NDA to the FDA by early 2026.
Incidence and Prevalence
Essential Tremor Prevalence: Brazilian Study Findings
According to a 2014 study conducted in Bambuí, Brazil, the prevalence rate for essential tremor was 7.4% in a community-dwelling elderly population aged ≥64 years.
In this Brazilian study, essential tremor was one of the most commonly identified causes of tremor, along with parkinsonian tremor and enhanced physiological tremor.
The research found no gender differences in prevalence rates for all types of tremor, including essential tremor. However, the age-specific prevalence of tremor increased with advancing age for both men and women.
The study also noted that patients who had Parkinson's disease with tremor were older than those who had essential tremor.
This research examined 1186 inhabitants aged ≥64 years using a 2-phase methodology where participants who screened positive for tremor were examined by specialists.
While this study provides valuable insights into essential tremor prevalence in an elderly Brazilian population, it represents just one geographic region rather than global estimates.
Key Unmet Needs for Essential Tremor Based on Recent Publications
Diagnostic Challenges
Recent publications highlight significant diagnostic challenges in Essential Tremor (ET), with traditional assessment methods being time-consuming, subjective, and requiring in-person visits. There is a pressing need for improved accessibility in ET assessment, particularly in remote or resource-limited settings. The field requires cost-effective, scalable, and reliable solutions that can be deployed across various healthcare environments.
Treatment Limitations
A critical unmet need is the lack of curative treatments or medications that can slow disease progression. Current medications improve tremor in only approximately 50% of patients, highlighting a substantial treatment gap. Research indicates different pathophysiologies may exist in ET patients based on their response to first-line therapy (beta-blockers), suggesting the need for personalized treatment approaches.
Emerging Diagnostic Approaches
To address diagnostic limitations, novel approaches are emerging: - A deep learning-based approach using handwriting images for remote assessment (88.44% accuracy) - Multivariate pattern analysis combined with resting-state functional MRI to identify diagnostic biomarkers - Frequency-dependent brain activity measures (ALFF, ReHo, DC) as potential biomarkers
Treatment Gaps
For patients with medication-refractory tremor, options include deep brain stimulation and thalamotomy, which provide adequate control in approximately 90% of patients. However, comparative studies between treatment options are lacking, with limited long-term efficacy data for newer interventions. Botulinum toxin (BTX) shows promise but faces limitations, with studies showing a gap between clinical improvement and patient-perceived benefit.
Alternative Therapies
Research on vibrational therapy (Vilim Ball) shows mixed results, with some patients reporting improvement while others experienced no benefit or worsened symptoms. In an extended safety study, 48 out of 51 patients reported improvement in tremor symptoms, suggesting potential as an alternative treatment option.
Diagnostic Biomarkers
Studies show that significant discriminative features for ET are mostly located in the cerebello-thalamo-cortical pathway. ET patients show decreased glucose metabolism in specific brain regions compared to healthy controls. Research on rest tremor in ET patients (present in 47.9%) indicates a need for better diagnostic markers to distinguish ET from Parkinson's disease.
Targeted Populations
Recent research focuses on patients with: - Medication-refractory tremor requiring surgical interventions - Proximal upper limb tremor treated with incobotulinumtoxinA - ET patients with rest tremor who may be at risk for developing Lewy body disease - Patients who do not respond to first-line therapies like propranolol
The field is moving toward precision medicine approaches for ET, recognizing the heterogeneity of the condition and the need for tailored therapeutic strategies based on individual pathophysiology.
Recent Studies
Recent Essential Tremor Studies: Interventions and Outcomes
Cerebellar Repetitive Transcranial Magnetic Stimulation (rTMS)
A randomized sham-controlled trial evaluated the efficacy of cerebellar rTMS for essential tremor. The study included 45 patients divided into active (23) and sham (22) groups. The active group received 12 sessions of 1-Hz rTMS at 90% of resting motor threshold over 4 weeks. Results showed significant reductions in Fahn-Tolosa-Marin tremor-rating scale (FTM) subscores A and B and total score in the active group, with effects lasting up to 3 months (p=0.031 and 0.011). The global assessment score was significantly higher in the active group (p>0.001). The study concluded that low-frequency rTMS demonstrated relative safety and long-lasting efficacy.
Transcutaneous Peripheral Nerve Stimulation (TPNS)
A prospective, open-label study evaluated a novel TPNS device used by ET patients at home for 7-10 days. In 17 patients with evaluable data, the dominant-hand Performance Subscale improved from 14.1 to 11.4 (p=0.0002). Activities of Daily Living (ADL) and modified ADL scores improved from 29.9 to 20.7 and 34.8 to 24.8, respectively (both p<0.001). Improvement was reported for 82% of patients on both Patient and Clinician Global Impression questionnaires. The AI-controlled device showed promise as a safe and effective treatment with only one adverse event (skin reaction in a patient with adhesive allergy).
IncobotulinumtoxinA for Proximal Upper Limb Tremor
A double-blind, randomized, placebo-controlled cross-over trial evaluated incobotulinumtoxinA for proximal upper limb tremor in 20 adult patients. Secondary outcomes showed a mean reduction in TETRAS score of -1.05 (95% CI -1.99 to -0.13) and Fahn-Tolosa-Marin tremor rating scale of -6.84 (95% CI -12.37 to -1.31) in the treatment group. However, there was no significant improvement in the primary outcome (Goal Attainment Rating Scale) or patient-rated outcome scores. Single dose injections were effective in reducing objective measures of proximal upper limb tremor and function.
Deep Brain Stimulation (DBS)
A 2018 prospective observational study evaluated directly targeting the dentato-rubro-thalamic tract (DRTt) in 20 consecutively enrolled intention tremor patients. The mean age was 66.8 years with mean tremor duration of 16 years. Mean voltage for the left electrode was 3.4 V and right electrode was 2.6 V. Improvement in arm tremor amplitude from baseline after DBS was significant (P<0.001). Direct targeting of the DRTt was found to be an effective strategy for tremor suppression.
In another case, DBS targeting the ventral intermediate nucleus (VIM) of the thalamus for cerebellar tremor resulted in the TRS total score decreasing by 64.06% during 18-month follow-up, with significant improvement in quality of life.