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Review
.2023 Oct;273(7):1543-1556.
doi: 10.1007/s00406-023-01580-3. Epub 2023 May 10.

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

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Review

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

Eric D Achtyes et al. Eur Arch Psychiatry Clin Neurosci.2023 Oct.

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.

Keywords: Schizophrenia; Serotonin 5-HT1A; Trace amine-associated receptor 1.

© 2023. The Author(s).

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Conflict of interest statement

Dr. Achtyes has served on advisory boards or consulted for Alkermes, Atheneum, Janssen, Karuna, Lundbeck/Otsuka, Roche, Sunovion and Teva. He has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, National Network of Depression Centers, Neurocrine Biosciences, Novartis, Otsuka, Pear Therapeutics, and Takeda. He serves as an advisor to CAPNOS Zero, the World Psychiatric Association and Clubhouse International, and the SMI Adviser LAI Center of Excellence (all unpaid). Drs. Hopkins, Dedic, Dworak, Zeni, and Koblan are employees of Sunovion Pharmaceuticals Inc.

Figures

Fig. 1
Fig. 1
Discovery and characterization of ulotaront.A Ulotaront discovery. Ulotaront was discovered through a unique, target-agnostic approach designed to identify drug candidates that lack D2 and 5-HT2A receptor antagonism but retain an antipsychotic-like behavioral profile in vivo.B Ulotaront mouse SmartCube® profile. Ulotaront demonstrated a predominantly antipsychotic-like behavioral profile (drug signature), with some secondary anxiolytic and antidepressant-like activity.C In vitro target profiling of ulotaront (SEP-363856). Additional in vitro and in vivo pharmacological studies showed that agonism at TAAR1 and 5-HT1A receptors contribute to the efficacy of ulotaront [32, 35].D2 dopamine D2 receptor,5-HT1A and 5-HT2A serotonin 1A and 2A receptor subtypes,ADHD attention deficit disorder with hyperactivity. *Antipsychotic (purple) and high-dose antipsychotic (dark purple); **antidepressant (green) and high-dose antidepressant (dark green)
Fig. 2
Fig. 2
Significant improvement in PANSS total score during 4 weeks of treatment with ulotaront (50–75 mg/day) [69]
Fig. 3
Fig. 3
Ulotaront (50–75 mg/day) efficacy in schizophrenia symptom domains in a randomized clinical trial.A Ulotaront was associated with significant improvement at Week 4 (effect size vs. placebo) across multiple measures of negative symptoms [70].B Forest plot of endpoint effect sizes for UPSM-transformed PANSS factors: ulotaront vs. placebo [69]
Fig. 4
Fig. 4
Improvement in PANSS total score during 26 weeks of treatment with ulotaront (50–75 mg/day) [74].PANSS positive and negative syndrome scale,DB double blind,OL open label,BL baseline
Fig. 5
Fig. 5
Second generation class-related D2 antipsychotic adverse events based on FAERS data (n = 11 antipsychotics). The x-axis is the fold-increase in disproportional reporting of each AE. The y-axis is the cumulative proportion of patients with class-specific AEs that meet the threefold EBGM threshold [77].EBGM Empirical Bayes Geometric Mean,FAERS Food and Drug Administration Adverse Event Reporting System (FAERS) data
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