Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia

Abstract

Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist in Phase 3 clinical development for the treatment of schizophrenia. Ulotaront was discovered through a unique, target-agnostic approach optimized to identify drug candidates lacking D2 and 5-HT2A receptor antagonism, while demonstrating an antipsychotic-like phenotypic profile in vivo. The mechanism of action (MOA) of ulotaront is thought to be mediated by agonism at TAAR1 and serotonin 5-HT1A receptors. Ulotaront has completed two Phase 2 trials (4-week acute study and 26-week open-label extension) which led to Breakthrough Therapy Designation from the US Food and Drug Administration for the treatment of schizophrenia. In the double-blind, placebo-controlled, acute study, ulotaront was associated with significant (p < 0.001) improvement in Positive and Negative Syndrome Scale (PANSS) total score (effect size [ES]: 0.45), with improvements vs. placebo also observed across secondary endpoints. Post-hoc analyses of the acute trial revealed additional evidence to support the effect of ulotaront on negative symptoms. In the 4-week study, ulotaront was well-tolerated, with an incidence of adverse events (AEs) numerically lower compared to placebo (45.8% vs. 50.4%; with a number needed to harm [NNH] for individual ulotaront AEs all > 40). The open-label extension demonstrated further improvement across schizophrenia symptoms and confirmed the tolerability of ulotaront, with a 6-month completion rate of 67%. Based on current data, ulotaront shows potential to be a first-in-class TAAR1 agonist for the treatment of schizophrenia with a safety and efficacy profile distinct from current antipsychotics.

TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding

“…TAAR1 agonists, including the Phase 3 clinical development candidate ulotaront, have recently emerged as a potential new treatment approach in schizophrenia and other psychiatric disorders including depression, anxiety and substance abuse [ 1 , 59 , 60 ]. Intriguingly, recent preclinical evidence has also identified TAAR1 as a novel regulator of metabolic control and a potential target for obesity and type 2 diabetes [ 16 , 17 , 61 , 62 ].…”

Novel Compounds in the Treatment of Schizophrenia—A Selective Review

“…A population analysis [ 95 ] of the pharmacokinetics of ulotaront based on eight studies concluded that ulotaront shows a good absorption profile and exhibits dose-dependency at 10 to 100 mg. The median time for the maximum concentration and the median effective half-life were estimated to be 2.8 and 7 h, respectively [ 93 ].…”

Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

“…Trace amine-associated receptor 1 (TAAR1) is a member of the G-protein-coupled receptor (GPCR) TAAR family enriched in the central nervous system and periphery, which could couple to diverse G protein subtypes (G s , G q , and G i1 ) by recognizing a spectrum of different endogenous amine-containing hormones and metabolites (EAHs and EAMs) and has been confirmed to be associated with cognition, mood, antidepressant, and schizophrenia treatment. − SEP-363856 was identified as a TAAR1-G s pathway agonist with beneficial effects in MK-801-induced schizophrenia-like rodent models via high-throughput phenotypic behavioral screening . Notably, SEP-363856 did not cause the cognitive impairment and other serious side effects associated with current antipsychotics targeting the D2R or 5-HT2AR. ,− In 2019, SEP-363856 was granted a breakthrough therapy designation for the treatment of schizophrenia with significant reduction in the Positive and Negative Syndrome Scale (PANSS) total score in clinical trials by the U.S. Food and Drug Administration (FDA). Unfortunately, the once-daily dose of SEP-363856 in acutely psychotic adults living with schizophrenia did not meet the primary end point in two therapeutic effect experiments of phase III.…”