Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study

Abstract

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors agonist, has demonstrated efficacy in the treatment of patients with an acute exacerbation of schizophrenia in a 4-week, double-blind, placebo-controlled study. The aim of this 26-week open-label extension study was to evaluate the safety and effectiveness of ulotaront (25/50/75 mg/d) in patients who completed the initial 4-week study. Of the 193 4-week completers, 157 patients (81.3%) continued into the open-label extension study; 66.9% were completers. Among all extension phase patients, treatment with ulotaront was associated with minimal changes in body weight (mean [SD] change from double-blind baseline: −0.3 [3.7] kg), cholesterol (median change, −2.0 mg/dL), triglycerides (median, −5.0 mg/dL), and prolactin (female, median, −3.4 ng/mL; male, median, −2.7 ng/mL). Movement disorder scales showed no extrapyramidal effects. Twenty-six weeks of extension phase treatment was associated with a mean (95% CI) observed change from open-label baseline in the PANSS total score of −22.6 (−25.6, −19.6; effect size, 1.46), and a mean (95% CI) change in the CGI-Severity score of −1.0 (−1.2, −0.8; effect size, 1.07). Long-term treatment with the TAAR1 agonist ulotaront, in the daily dose range of 25–75 mg, was characterized by a relatively high completion rate, an adverse event profile notable for the absence of extrapyramidal-related adverse effects, a low liability for adverse weight and metabolic effects, and no effect on prolactin levels. Additional studies are needed to further confirm the long-term efficacy and safety of ulotaront.

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia

“…Among the numerous compounds currently under investigation, the development of the selective GlyT1 inhibitor BI 425809 [97][98][99] and the TAAR1 agonist ulotaront (SEP-363856) [288][289][290][291] is the most advanced. The breakthrough therapy designation granted for both substances by the FDA enables regulatory monitoring of the approval process.…”

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

“…The published phase II or higher clinical trial evidence on TAAR1 agonists in schizophrenia currently only pertains to 2 studies that evaluated the efficacy and safety of ulotaront (Table 2). 23,42 Studies investigating ralmitaront in this patient population are currently still ongoing (refer to Ongoing Developments).…”

“…All published trials included adult patients with an acute exacerbation of schizophrenia. 23,42 Intervention Patients who received ulotaront in the SEP 361-201 trial were administered a 50 mg or 75 mg dose of the drug once daily orally. 23 In the SEP 361-202 trial, patients were treated with a 25 mg, 50 mg, or 75 mg once daily oral dose of ulotaront.…”

Emerging Treatments in Schizophrenia

“…At the 26-week endpoint, with all patients taking ulotaront, the pooled weight change was -0.3 kg, and lipid measures showed decreases or no change. 3 Additional adverse effects reported were generally mild, with headache and insomnia being most common.…”