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

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.

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies.

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.

Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers.

OBJECTIVE: 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 (Cmax ), with all doses demonstrating rapid median time to Cmax (Tmax ; 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.

Remission of major depressive disorder without adverse events: a comparison of escitalopram versus serotonin norepinephrine reuptake inhibitors.

OBJECTIVE: An antidepressant's tolerability, generally captured as the frequency and severity of adverse events (AEs), is often as important as its efficacy in determining treatment success. This study used a composite outcome - remission of major depressive disorder (MDD) without AEs - to compare the benefit-risk profiles of escitalopram versus the norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine extended release (XR). METHODS: Pooled data from three randomized, double-blind, multicenter trials were analyzed, in which patients with MDD were treated for 8 weeks with either escitalopram (n = 462) or an SNRI (n = 467). CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifiers: NCT00108979; NCT00384436. MAIN OUTCOME MEASURES: The composite outcome was defined as remission (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≤10) and concurrent absence of an AE. The proportions of remitted patients free of (1) any AEs, (2) moderate-to-severe AEs, and (3) study drug-related AEs were compared between treatment groups at each study visit and longitudinally across study visits common to all trials during the first 8 weeks of treatment. RESULTS: At endpoint (week 8), escitalopram-treated patients were more likely than SNRI-treated patients to experience remission free of any AEs (28.4 vs. 21.6%; p = 0.0179) and remission free of study drug-related AEs (45.2 vs. 36.8%; p = 0.0092). Compared to SNRI-treated patients, escitalopram-treated patients had 38% greater odds of remission free of any AEs, 28% greater odds of remission free of moderate-to-severe AEs, and 34% greater odds of remission free of study drug-related AEs (all p < 0.05). CONCLUSION: 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.

Target recognition and synaptogenesis by motor axons: responses to the sidestep protein.

Sidestep (Side) is a pivotal molecular player in embryonic motor axon pathfinding. But questions about its functional repertoire remain: (i) can Side permanently overturn targeting preferences? (ii) does it promote synaptogenesis, and (iii) can Side facilitate synaptic stabilization? To address these questions, Side was temporally and spatially misexpressed and the visible consequences for neuromuscular junction morphology were assessed. When Side was misexpressed either broadly or selectively in muscles during targeting in a wildtype background motor axon targeting preferences were permanently overturned. However the misexpression of Side in all muscles post-targeting neither changed synapse morphology, nor compensated for a lack of the synapse-stabilizing protein Fasciclin II (FasII). Rather Side appears to be dependent on FasII, instead of on intrinsic ability, for sustaining targeting changes. We propose that Side helps to bring motor axons to their correct muscle targets and promotes synaptogenesis, then FasII serves to stabilize the synaptic contacts.

Myoblast fusion in Drosophila.

Somatic muscle formation is an unusual process as it requires the cells involved, the myoblasts, to relinquish their individual state and fuse with one another to form a syncitial muscle fiber. The potential use of myoblast fusion therapies to rebuild damaged muscles has generated continuing interest in elucidating the molecular basis of the fusion process. Yet, until recently, few of the molecular players involved in this process had been identified. Now, however, it has been possible to couple a detailed understanding of the cellular basis of the fusion process with powerful classical and molecular genetic strategies in the Drosophila embryo. We review the cellular studies, and the recent genetic and biochemical analyses that uncovered interacting extracellular molecules present on fusing myoblasts and the intracellular effectors that facilitate fusion. With the conservation of proteins and protein functions across species, it is likely that these findings in Drosophila will benefit understanding of the myoblast fusion process in higher organisms.