Building a Greater Understanding of Ulixacaltimide’s Impact in Essential Tremor

Marcio Souza

Essential tremor (ET) is the most common movement disorder, affecting nearly 7 million people in the US alone, including approximately 2 million diagnosed patients. There is currently only 1 approved medication for ET, propranolol, a beta blocker approved by the FDA in 1967, that offers some relief for patients. Ulixacaltamide (Praxis Precision Medicines), 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 circuit, has shown promise as a potential therapy for ET.

In early August, the company announced positive data from a randomized withdrawal sub-study and long-term extension of its pivotal, phase 2b Essential1 study (NCT05021991), in which treatment with the agent resulted in maintained or improved efficacy, as demonstrated by changes in the modified Activities of Daily Living 11 (mADL11) scale, the primary end point. During the initial 8-week double-blind period, patients treated ulixacaltamide demonstrated a mean improvement of 3.09 (95% CI, 0.98-5.2) points on mADL11. After continuing on to the 6-week open-label extension (OLE), patients gained an additional mean improvement of 1.7 points in mADL11, totaling 4.81 (95% CI, 2.38-7.23) at 14 weeks. Above all, the therapy continued to show a safety profile that was consistent with previous observations.

Following the announced results, NeurologyLive® reached out to Praxis to learn more about the ulixacaltamide, and the reasons behind why it can be an effective therapy for ET. Marcio Souza, president and chief executive officer of the company, provided answers on the study, including how they might shape future phase 3 trials. Additionally, he spoke on the unmet needs of patients with ET, and the research that remains to be done.

NeurologyLive^®: How significant is it that additional benefits were seen after the double-blind period?

The continued improvement in the Modified Activities of Daily Living 11 (mADL11) score we saw in the extension study further demonstrated ulixacaltimide's potential long-term durability in patients who have remained on drug from baseline and a similar response in patients who transitioned from placebo to ulixacaltamide. The ongoing results reinforce our clinical hypothesis based on the signal that we saw in the primary readout of the study in March. Additionally, there were no new safety signals and there was no change to the overall safety results. We see this as a meaningful clinical benefit for patient as current medications for essential tremor are associated with limited efficacy and poor tolerability. In fact, approximately 40% of ET patients discontinue pharmacotherapeutic treatments for ET within two years due to the toxicity and poor efficacy of current treatment options.

What about ulixacaltamide’s mechanism of action makes it a promising therapy for essential tremor?

T-type calcium channels are gatekeepers of neuronal firing patterns in the Cerebello-Thalamo-Cortical circuit. Abnormal burst firing in this circuit is correlated with tremor activity. Ulixacaltamide is designed to inhibit T-Type calcium channels and neuronal misfiring. The molecule is highly selective for T-type calcium channels and potent across all three T-type isoforms.

How will data from the sub-study help guide the upcoming phase 3 trial?

Patients who switched from ulixacaltamide to placebo experienced an average loss of effect in their mADL11 per week of 47%. Patients who remained on ulixacaltamide had an average improvement of 6% per week. The results from the sub-study supported a number of proposed design elements for the upcoming Phase 3 randomized withdrawal study, including the responder criteria and feasibility of rescuing patients with ulixacaltamide. Additional study design elements will be discussed in more detail at our upcoming R&D portfolio event slated for October 2nd.

What are some of the greatest unmet needs for patients with essential tremor?

Essential tremor is the most common movement disorder but often goes undiagnosed, misdiagnosed and untreated. Patients with ET face a number of challenges that significantly disrupt daily life. As an action-oriented tremor, ET makes basic tasks that those without the condition may take for granted such as speaking, dressing, eating, drinking, brushing your teeth, writing more difficult. Because of this, almost all ET patients suffer from at least one comorbid condition such as depression, anxiety, sleep disorders and cognitive dysfunction.

What goals are the team hoping to reach with the phase 3 study?

Innovation in ET is long overdue. There are no medications designed specifically to treat ET and the last medication for the condition was approved almost 40 years ago. Our Phase 3 program is comprised of two complementary 12-week studies both with the Modified Activities of Daily Living 11 score as the primary endpoint. We hope to glean additional data on the safety and efficacy of ulixacaltamide and are on track to submit a New Drug Application to FDA in 2025.