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.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.

SUMMARYObjective: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults. Methods: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded. Results: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (C max ), with all doses demonstrating rapid median time to C max (T max ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation. Significance: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.

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Background SEP-363856 is a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity. SEP-363856 showed significant antipsychotic efficacy in patients with schizophrenia, and a safety and tolerability profile similar to placebo and consistent with a non-D2 mechanism of action. Here, we examined measures of cognition and social functioning in schizophrenia patients receiving SEP-363856. Methods Patients aged 18–40 years with an acute exacerbation of schizophrenia were randomized, double-blind (DB), to 4-weeks of flexible-dose treatment with once daily SEP-363856 (N=120; 50 or 75 mg) or placebo (N=125). Patients (N=156) entering a subsequent 26-week open-label (OL) extension study were evaluated utilizing the Cogstate Brief Battery, administered at DB baseline and week 4, and OL baseline and weeks 12 and 26. Standardized z-scores were calculated for the Cogstate composite and subscale tasks (Detection task, Identification task, One Card Learning task, One Back task). The University of California San Diego Performance Based Skills Assessment (UPSA-B) scale was assessed at the same time-points, as were the following psychiatric scales: Positive and Negative Syndrome Scale (PANSS), the Brief Negative Symptom Scale (BNSS), the Montgomery–Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale, severity scale (CGI-S), and the Pittsburgh Sleep Quality Index global score (PSQI-global). Pearson correlation analyses were performed between DB baseline to Week 26 change in Cogstate composite and subscale scores and Week 26 change in the psychiatric scale scores. Results Small improvements, from DB baseline to Week 26, were observed in standardized scores on the Cogstate composite (+0.29), Identification task (+0.19), Detection task (+0.28); One Card learning task (+0.33); and One Back task (+0.33). Improvement from OL baseline at Week 26 was also observed on the mean [SD] UPSA-B total score (+6.2 [11.6]). At DB baseline, there were no correlations between CogState composite score and individual test scores with any of the psychiatric scales. Week 26 improvement in the following Cogstate composite and subscale tasks were correlated with Week 26 improvement in the following psychiatric scale scores: Cogstate composite score (PANSS total, r=-0.26; BNSS total, r=-0.31; CGI-S, r=-0.30; MADRS total, r=-0.23; PSQI-global, r=-0.23); Identification task (PANSS total, r=-0.30; BNSS total, r=-0.30), Detection task (BNSS total, r=-0.30; CGI-S, r=-0.28; PSQI-global, r=-0.23); One Card learning task (MADRS total, r=-0.29); and One Back task (PANSS total, r=-0.26). Discussion During 6-months of open-label extension treatment with SEP-363856, improvement in overall functioning was observed on the UPSA-B scale; and small but consistent improvement in cognition was noted in the Cogstate composite and subscale task scores. Endpoint reduction in the severity of schizophrenia-related symptomatology (eg, on the PANSS, BNSS, MADRS, insomnia) were associated with modest correlations, in the range of 0.2 to 0.3, in cognitive performance as measured by the Cogstate composite and subscale task scores.

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.

Treatment of adult MDD patients with escitalopram was significantly more likely to result in remission without concurrent AEs compared to treatment with current SNRIs. Study limitations include focus on only the initial 8 weeks of treatment and exclusion of trials for which individual patient data were not obtained.

By means of gene amplification, the authors have generated a high-producing hLL2-IgG clone suitable for production of the quantity of antibody necessary for clinical diagnostic and therapeutic trials of NHL patients.