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

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2/3 | N=1030 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Nov 2025 ➔ Feb 2026 | Trial primary completion date: Nov 2025 ➔ Feb 2026

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

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.

New P3 trial • CNS Disorders • Psychiatry • Schizophrenia

Novel pharmaceutical treatment approaches for schizophrenia: a systematic literature review. (PubMed, Eur J Clin Pharmacol) - "Novel treatments for schizophrenia show promise in managing both positive and negative symptoms, with generally favorable safety profiles. Future studies should focus on large-scale, long-term trials to refine their efficacy, safety, and clinical applicability."

Journal • Review • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Mental Retardation • 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 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Feb 2025 ➔ Feb 2026 | Trial primary completion date: Feb 2025 ➔ Feb 2026

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

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2/3 | N=1030 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: May 2025 ➔ Nov 2025 | Trial primary completion date: May 2025 ➔ Nov 2025

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

Triangulating evidence from the GALENOS living systematic review on trace amine-associated receptor 1 (TAAR1) agonists in psychosis. (PubMed, Br J Psychiatry) - "This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry • Schizophrenia

SEP-363856 attenuates CUMS-induced depression-like behaviours and reverses hippocampal neuronal injuries. (PubMed, World J Biol Psychiatry) - "The 10 mg/kg dosage of SEP-363856 and fluoxetine significantly improved depressive-like behaviours as assessed by the SPT, OFT, EPM, TST, and FST. The antidepressant-like effects of SEP-363856 are linked to increased hippocampal neurotrophic factors, decreased hippocampus neuronal lesions, and activation of the IGF-1Rβ/PI3K/AKT signalling pathway. The latter may serve as a novel drug target for the treatment of depression."

Journal • CNS Disorders • Depression • Psychiatry • IGF1 • SYP

Unlocking the secrets of trace amine-associated receptor 1 agonists: new horizon in neuropsychiatric treatment. (PubMed, Front Psychiatry) - "Recent cryogenic electron microscopic (cryo-EM) structures of human and mouse TAAR1 (hTAAR1 and mTAAR1, respectively) in complex with agonists and G proteins have revealed detailed atomic insights into the binding pockets, binding interactions and binding modes of several agonists including endogenous trace amines (β-phenylethylamine, 3-Iodothyronamine), psychostimulants (amphetamine, methamphetamine), clinical compounds (ulotaront, ralmitaront) and repurposed drugs (fenoldopam). The in vitro screening of drug libraries has also led to the discovery of novel TAAR1 agonists (asenapine, guanabenz, guanfacine) which can be used in clinical trials or further developed to treat different neuropsychiatric conditions...In this review, we discuss the emergence of structure-based approaches in the discovery of novel TAAR1 agonists through drug repurposing strategies and structure-guided designs. Additionally, we discuss the functional selectivity of TAAR1 signalling, which..."

Journal • Review • Bipolar Disorder • CNS Disorders • Cognitive Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia

Trace amine-associated receptor 1 agonists for the treatment of negative symptoms of schizophrenia: a review (ECNP 2024) - "Ulotaront (SEP-363856) and ralmitaront (RO6889450) are two TAAR1 agonists in clinical trials. Based on data from preclinical and clinical trials, TAAR1 agonists may be beneficial in reducing negative symptoms of schizophrenia. Placebo-controlled studies focusing on negative symptoms in appropriate patient populations are important to determine the place of ulotaront in the future treatment of schizophrenia."

Review • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities. (PubMed, Med Res Rev) - "Notably, the sigma-2, 5-HT2A, and α1A receptor antagonist roluperidone, as well as a fixed-dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5-HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small-molecule entities and fixed-dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Pharmacological Treatment of Cognitive Impairment Associated With Schizophrenia: State of the Art and Future Perspectives. (PubMed, Schizophr Bull Open) - "In particular, the effects on CIAS of antipsychotic medications, anticholinergic medications, benzodiazepines, which are currently commonly used in the treatment of SSD, and of iclepertin, d-serine, luvadaxistat, xanomeline-trospium, ulotaront, anti-inflammatory molecules, and oxytocin, which are undergoing regulatory trials or can be considered as experimental agents, will be reported and discussed. Some molecules that are currently being investigated in Phase 2 and Phase 3 trials have provided very promising preliminary results, but more information is currently required to assess their effectiveness in real-world contexts and to provide clear recommendations regarding their use in clinical practice. The results of ongoing and future studies will reveal whether any of these molecules represents the awaited pharmacological game-changer in the treatment of CIAS."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data. (PubMed, Wellcome Open Res) - "Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. PROSPERO-ID: CRD42023451628."

Journal • Retrospective data • Review • Anesthesia • CNS Disorders • Psychiatry • Schizophrenia

Ligands of the trace amine-associated receptors (TAARs): A new class of anxiolytics. (PubMed, Pharmacol Biochem Behav) - No abstract available

Journal • Review • Mood Disorders • Psychiatry

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms. (PubMed, PCN Rep) - "One noteworthy candidate is Ulotaront (SEP-363856), an agent acting as a TAAR1 agonist with 5-HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side-effects. Similarly, MIN-101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)-approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor-positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK-653 (NBI-1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric..."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry • Schizophrenia

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis. (PubMed, Biomedicines) - "In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder...Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression."

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

SEP-363856 exerts neuroprotection through the PI3K/AKT/GSK-3β signaling pathway in a dual-hit neurodevelopmental model of schizophrenia-like mice. (PubMed, Drug Dev Res) - "This study aimed to evaluate the impact and underlying mechanisms of SEP-856 on SZ-like behavior in a perinatal MK-801 treatment combined with social isolation from the weaning to adulthood model (MK-SI). In addition, SEP-856 can reduce the release of proinflammatory factors in the MK-SI model, promote the expression of BDNF and PSD-95 in the hippocampus, correct the Bax/Bcl-2 imbalance, turn on the PI3K/AKT/GSK-3β signaling pathway, and ultimately help the MK-SI mice's behavioral abnormalities. SEP-856 may play an antipsychotic role in MK-SI "dual-hit" model-induced SZ-like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro-inflammatory substances in the hippocampal region, and subsequently initiating the PI3K/AKT/GSK-3β signaling cascade."

IO biomarker • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Oncology • Psychiatry • Schizophrenia • BAX • BCL2 • DRD2 • IL1B • IL6 • TNFA

Trace amine associated receptor 1: predicted effects of single nucleotide variants on structure-function in geographically diverse populations. (PubMed, Hum Genomics) - "Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies."

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

A Clinical Study That Will Evaluate How Well SEP-363856 Works and How Safe it is in People With Schizophrenia That Switch to SEP-363856 From Their Current Antipsychotic Medication (clinicaltrials.gov) - P3 | N=101 | Completed | Sponsor: Sumitomo Pharma America, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jul 2024 ➔ Apr 2024 | Trial primary completion date: Jul 2024 ➔ Apr 2024

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

Beyond dopamine: Novel strategies for schizophrenia treatment. (PubMed, Med Res Rev) - "We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT-1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5-HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments. (PubMed, Pharmacopsychiatry) - "Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Ulotaront in the Treatment of Schizophrenia: Post-Hoc Analyses of Two 6-Week, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trials (ASCP 2024) - P3 | "A large PBO effect was observed in both studies (most notable in D1) which may have masked the ability to detect a significant efficacy signal for ULO. Patients enrolled pre-COVID demonstrated notably larger effect sizes for ULO, though this finding may be due to geographic factors, as most pre-pandemic patients were recruited in the US. Initiation of a new AP or a dose increase for ongoing AP just prior to study entry appears to have contributed to a lack of drug-placebo separation."

Clinical • P3 data • Retrospective data • CNS Disorders • Psychiatry • Schizophrenia • PRL

Ulotaront Delays Gastric Emptying Time in Schizophrenia Patients with Metabolic Syndrome (NCT05402111) (ASCP 2024) - P1 | "Patients were required to maintain a stable dose and regimen for one of 4 antipsychotics as treatment for schizophrenia at the time of screening (risperidone, olanzapine, quetiapine, or aripiprazole). : Following a single-dose of 150 mg ulotaront, gastric emptying was delayed (T1/2 = 145 ± 17 min; median ± SE) compared to patients receiving a single dose of their prior antipsychotic drug (125 ± 4 min, p-value 0.0028). The median percent gastric retention post-dose (1h, 2h, 4h) was 2024 ASCP Annual Meeting greater following ulotaront (83%, 66%, 17%) compared to prior antipsychotic (76%, 51%, 7%, respectively). : Ulotaront significantly delayed gastric emptying following a single dose."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Effect of Ulotaront on Brain Dopamine Synthesis Capacity in Subjects with Schizophrenia on Stable Doses of a D2 Antipsychotic: Results of an 18F-DOPA Pet Study (ASCP 2024) - "In a mouse model, ketamine-induced elevations in DA synthesis capacity were reduced by single doses of ulotaront (3 mg/kg i.p.) with no effect on baseline DA synthesis capacity [2]. Consistent with preclinical findings, this study found that 14 days of treatment of patients with schizophrenia with ulotaront added to a stable dose of a D2 antipsychotic resulted in potentially clinically meaningful reductions in dopamine synthesis capacity in the striatum that were correlated with a reduction in the severity of the PANSS-positive subscale score. These results, despite stable baseline treatment with a D2 antipsychotic, provide confirmation of the potential efficacy of the novel TAAR1 agonist mechanism of action of ulotaront. Learning Objectives • Elevated striatal dopamine levels are associated with symptoms of psychosis as well as severity of illness in schizophrenia."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

A Randomized, Double-Blind, Active Comparator-Controlled, Phase 3 Study to Evaluate the Long-Term Safety and Tolerability of Ulotaront in Patients with Schizophrenia (ASCP 2024) - "The results of this study extend the findings from a previously-reported 6-month Phase 2 study to 52 weeks [4], demonstrating that long-term treatment with ulotaront is safe and well-tolerated with no unexpected adverse effects for this novel TAAR1 agonist class drug. The notable lack of adverse effects of ulotaront on lipids and glycemic indices, and the significant reduction in weight and waist circumference, are consistent with preclinical research suggesting that ulotaront improves glycemic control and reduces body weight in rodent models of diabetes, obesity, and iatrogenic weight gain [2]. Learning Objectives • Long-term treatment (52-weeks) with ulotaront, an investigational trace amine-associated receptor 1 (TAAR1) agonist with 5-HT1A activity, was safe and well-tolerated with no unexpected adverse events in patients with schizophrenia."

Clinical • P3 data • CNS Disorders • Insomnia • Mood Disorders • Psychiatry • Schizophrenia • Sleep Disorder

The trace amine-associated receptor 1 agonists - non-dopaminergic antipsychotics or covert modulators of D2 receptors? (PubMed, J Psychopharmacol) - "Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments."

Journal • Cardiovascular • CNS Disorders • Psychiatry • Schizophrenia • DRD2