ulotaront (SEP-363856) / Sumitomo Pharma, Otsuka, PsychoGenics - LARVOL DELTA

Next-Generation Pharmacotherapies for Unipolar Mood Disorders: A Leading Article on Phase II/III Drug Development Across Diverse Mechanisms. (PubMed, CNS Drugs) - "Following the US Food and Drug Administration (FDA) approval of esketamine and brexanolone in 2019, industry investment in therapeutics with novel mechanisms for mood and anxiety disorders has expanded, catalyzing a new wave of innovative interventions...The drug names discussed are ALTO-100, ALTO-203, ALTO-207, ALTO-300, BHV-7000, BI-1569912, BPL-003, COMP360, DT120, ELE-101, GATE-251, GH001, GM-1020, GM-2505, HLP003, MK-1942, NBI-1065845, NBI-1070770, NV-5138, PIPE-307, SEP-363856, SPT-300, VLS-01, and XEN1101. The US Clinical Trials registry (clinicaltrials.gov), MEDLINE, conference proceedings, and company communications such as press releases were consulted to obtain up-to-date trial information and reported outcomes. Overall, the therapeutic landscape shows an expanding range of clinical compounds under active development; nonetheless, persistent challenges remain, including approaches to therapeutics where functional unblinding may occur, the ways in which to..."

Journal • P2/3 data • Review • CNS Disorders • Mood Disorders • Psychiatry

A Trial of the Safety and Tolerability of SEP-363856 in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P3 | N=1120 | Not yet recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

New P3 trial • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

Design and synthesis of long-acting prodrugs of SEP-363856 with sustained antipsychotic-like activity. (PubMed, Bioorg Chem) - "In two mouse models of schizophrenia, SEP-363856 suppressed schizophrenia-like behaviors only through approximately 90 min, whereas prodrug 15 remained effective at later assessments up to approximately 150 min. These results collectively support prodrug design as a viable strategy for extending the antipsychotic-like effects of SEP-363856."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

A Trial of the Efficacy and Safety of a Fixed Dose of SEP-363856 in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P3 | N=384 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

New P3 trial • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

A Trial of the Efficacy and Safety of Fixed Doses of SEP-363856 in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P3 | N=576 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

New P3 trial • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

Antipsychotic-like effects of TAAR1 agonists and D2 receptor blockers are mediated through distinct modulation of striatal neuronal dynamics. (PubMed, Mol Psychiatry) - "Here we investigated the effects of TAAR1 agonists, RO5166017 and clinical drug candidate ulotaront, on in vivo calcium dynamics of D1- and D2-receptor expressing medium spiny neurons (MSNs) in freely behaving mice, under normal and phencyclidine (PCP)-induced, psychosis-like conditions. Although the established antipsychotics haloperidol and clozapine produced similar behavioral effects, their impact on striatal MSNs was distinct and lacked prominent state dependence. These findings provide new insights into the distinct neurocircuit changes associated with the antipsychotic-like effects of TAAR1 agonists, distinguishing them from D2 receptor-targeting treatments."

Journal • CNS Disorders • Psychiatry • Schizophrenia • MSN

TAAR1 as a Potential Alternate Molecular Target to GLP-1 for Novel Anti-diabetic, Anti-obesity Medications. (PubMed, Handb Exp Pharmacol) - "Comparisons with incretin mimetic therapies, including semaglutide - a glucagon-like peptide-1 (GLP-1) receptor agonist - reveal significant mechanistic overlap, alongside potential advantages including a more favourable metabolic safety profile. Collectively these findings position TAAR1 as a promising target with the potential to address both physiological and neurobehavioural aspects of metabolic disease."

Journal • CNS Disorders • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry • Schizophrenia • Type 2 Diabetes Mellitus

The use of artificial intelligence (AI) in neuropsychiatric drug discovery: current challenges and future directions. (PubMed, Transl Psychiatry) - "AI-driven platforms have been used to study behavioural data from preclinical models to identify novel clinical candidates in clinical trials (e.g., ulotaront, phase III). It is anticipated that the availability of large-scale multi-omics data ('big data') will likely increase in the future, allowing us to gain a better understanding of gene-associated mechanisms in psychiatry. Using AI-based technologies such as AlphaFold, future pharmacological targets will be identified based on gene expression data, and large libraries of chemical compounds will be screened rapidly to identify novel drug candidates, resulting in shorter pre-clinical phase with lower costs."

Journal • Review • Oncology • Psychiatry

Preclinical models of Non dopaminergic antipsychotics (CINP 2026) - "These findings are consistent with emerging clinical data on TAAR1 agonists such as ulotaront, although Phase 3 results remain mixed... TAAR1 agonists provide a mechanistically distinct alternative to D2 antagonists, with potential advantages in tolerability and metabolic profile. Preclinical models support their relevance for symptom domains inadequately targeted by current therapies. Further clinical investigation is warranted to clarify their therapeutic role and broader applicability, including in bipolar spectrum disorders."

Preclinical • Bipolar Disorder • CNS Disorders • Schizophrenia • DRD2

Ulotaront (SEP363856) Reduces Dopamine Release and Synthesis Capacity in Mice and Patients With Schizophrenia. (PubMed, Biol Psychiatry) - No abstract available

Journal • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

Medicinal chemistry advances of TAAR1 agonists: SAR, structural innovation, and mechanistic insights. (PubMed, Eur J Med Chem) - "However, only SEP-363856 and ralmitaront have advanced into clinical trials for schizophrenia to date, highlighting the considerable opportunities that remain for the development of TAAR1-targeted therapeutics. This review provides a comprehensive overview of TAAR1's structure, biological functions, and its connection to human diseases. Additionally, it summarizes the design strategies, structure-activity relationships, and pharmacological properties of TAAR1 agonists, aiming to guide future drug development and clinical applications."

Journal • Review • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Clinical Effects of Recently Developed Antipsychotic Drugs in Schizophrenia. (PubMed, Cent Nerv Syst Agents Med Chem) - "Promising new antipsychotic drugs include cariprazine, brexpiprazole, lumateperone, ulotaront, and xanomeline combined with trospium. Phase 3 clinical studies have shown therapeutic effects superior to those achieved with second-generation antipsychotic drugs."

Journal • CNS Disorders • Psychiatry • Schizophrenia

A Long-term Administration Trial of SEP-363856 in Patients With Schizophrenia (clinicaltrials.gov) - P3 | N=100 | Recruiting | Sponsor: Otsuka Pharmaceutical Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Psychiatry • Schizophrenia

Potential of Small Molecule TAAR-1 Agonists for the Therapy of Neurodegenerative Psychosis: A Medicinal Chemistry Perspective. (PubMed, Mini Rev Med Chem) - "Strategic bioisosteric replacements, such as methylene bridges and aminoethoxy chains, are highlighted for their role in enhancing metabolic stability. This robust pharmacophore underpins the rational design of advanced clinical candidates like Ulotaront, which demonstrate dual neuroprotective and symptomatic benefits over conventional antipsychotics, offering a clear roadmap for the development of next-generation TAAR-1-targeted therapeutics for complex neuropsychiatric disorders."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

SEP361-304: A Study of the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. (clinicaltrials.gov) - P3 | N=305 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | N=475 ➔ 305

Enrollment change • CNS Disorders • Psychiatry • Schizophrenia

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=929 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Long-term Administration Trial of SEP-363856 in Patients With Schizophrenia (clinicaltrials.gov) - P3 | N=100 | Not yet recruiting | Sponsor: Otsuka Pharmaceutical Co., Ltd.

New P3 trial • CNS Disorders • Psychiatry • Schizophrenia

Cortico-Striatal-Midbrain Circuit Dysregulation Underlying MK-801 Induced Impulsivity and the Ameliorative Effects of SEP. (PubMed, Adv Sci (Weinh)) - "Impulsivity is a core pathological feature of various psychiatric disorders including obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and schizophrenia, which is conceptualized as dysregulated motivational and inhibitory processes. Furthermore, this work confirms that the application of the trace amine-associated receptor 1 agonist SEP-363856 could correct the abnormal responses of NAc neurons and behavioral deficits. These findings elucidate the neural basis of impulsivity and support the potential therapeutic effect of SEP."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Mental Retardation • Mood Disorders • Obsessive-Compulsive Disorder • Psychiatry • Schizophrenia

The trace amine-associated receptor 1 regulates presynaptic dopamine function: evidence from preclinical studies and a phase 1b trial in patients with schizophrenia. (PubMed, Biol Psychiatry) - "TAAR1 regulates dopamine synthesis and release. Adjunctive ulotaront reduces presynaptic dopamine function and psychotic symptoms in schizophrenia. These findings support TAAR1 as a promising target for treating antipsychotic non-responsive schizophrenia and other dopaminergic disorders."

Journal • P1 data • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

A double-blind study on ulotaront's impact on weight-related parameters in schizophrenia patients with metabolic syndrome and prediabetes: Part II. (PubMed, Diabetes Obes Metab) - "Despite the sample size constraints due to early study termination, all key endpoint trends and statistically significant differences favoured ulotaront over previous antipsychotics, lending support that ulotaront may improve antipsychotic-induced weight-associated markers. Liver fibro-inflammation may serve as a potential marker for antipsychotic-induced MetSyn and prediabetes, and possible treatment target. Further research is needed to build on these findings."

Journal • CNS Disorders • Hepatology • Inflammation • Metabolic Disorders • Psychiatry • Schizophrenia

An open-label study on ulotaront's effects on insulin-glucose regulation in schizophrenia patients with metabolic syndrome and prediabetes: Part I. (PubMed, Diabetes Obes Metab) - P1 | "Despite limited sample size, primary endpoints favoured ulotaront over prior antipsychotics with respect to a reduction trend in glucose, c-peptide and insulin. The insulin response after a solid meal was nominally significant, suggesting that semi-chronic twice-a-day dosing of ulotaront might improve insulin dynamics in schizophrenia patients at high diabetes risk."

Journal • CNS Disorders • Metabolic Disorders • Psychiatry • Schizophrenia • Type 2 Diabetes Mellitus

Trace Amine-associated Receptors (TAARs): Candidate Targets in the Treatment of Bipolar Disorders. (PubMed, Actas Esp Psiquiatr) - "Ulotaront is a TAAR1 agonist that has advanced to Phase III with Food and Drug Administration (FDA) breakthrough status in schizophrenia...This constitutes a theoretical basis for transdiagnostic applications. The evidence particularly favors the TAARs as novel targets in the treatment of bipolar disorders, thus warranting a dedicated effort at drug discovery."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • General Anxiety Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry • Schizophrenia

A Trial of the Efficacy and Safety of SEP-363856 in Acutely Psychotic Participants With Schizophrenia (clinicaltrials.gov) - P3 | N=522 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Aug 2028 ➔ Oct 2026 | Trial primary completion date: Apr 2028 ➔ Oct 2026

Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry • Schizophrenia

A Clinical Study That Will Measure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P2/3 | N=434 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

An Extension Study to a Clinical Study That Will Continue to Evaluate the Effectiveness and Safety of SEP-363856 in People With Schizophrenia That Switch to SEP-363856 From Their From Their Current Antipsychotic Medication (clinicaltrials.gov) - P3 | N=75 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Enrolling by invitation ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia