Therapeutic Potential of Ulotaront for Neuropsychiatric Disorders: Comparison
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SEP-363856 (International Nonproprietary Name: Ulotaront) is an investigational antipsychotic drug with a novel mechanism of action that does not involve antagonism of dopamine D2 receptors. Ulotaront is an agonist of trace amine-associated receptor 1 and serotonin 5-HT1A receptors, but can modulate dopamine neurotransmission indirectly. In 2019, the United States Food and Drug Administration granted Breakthrough Therapy Designation for ulotaront for the treatment of schizophrenia.

  • SEP-363856
  • antipsychotic agents
  • dopamine
  • schizophrenia
  • ulotaront
  • trace amine-associated receptor 1
  • TAAR
  • neuropsychiatric disorders

1. Introduction

Schizophrenia is a chronic psychiatric disorder that affects about 1% of the population worldwide and is characterized by continuous or relapsing episodes of psychosis. The major manifestations of schizophrenia include positive symptoms (hallucinations, various delusions, paranoia, and disorganized thinking), negative symptoms (social withdrawal, decreased emotional expression, anhedonia, alogia, and avolition), and cognitive deficits (deficient memory and impaired attention and executive functions) [1]. It is believed that the major contributors to the neuropathophysiology of this disorder are excessive dopaminergic activity and deficits in cortical glutamatergic neurotransmission, but it appears to be much more complex, involving structural and molecular changes throughout brain circuits involving alterations in other neurotransmitters, monoamines, and their derivatives [2][3][4][5][6][7][8][9][10][11].
Following the serendipitous discovery of the antipsychotic action of chlorpromazine in the 1950s, many antipsychotics have been introduced into clinical practice. However, all of them essentially share the same mechanism(s) of action, involving antagonism or partial agonism of the dopamine D2 receptor (D2R). Traditionally, antipsychotics are divided into two generations. The drugs of the first generation (‘typical’) are thought to work mainly by the blockade of D2R and often induce extrapyramidal symptoms in patients. The drugs of the second generation (‘atypical’) share the ability to block the serotonin receptor 2A subtype (5-HT2A), in addition to D2R, and their safety profiles are sometimes better. Additionally, some clinicians distinguish atypical antipsychotics that are partial D2R agonists, such as aripiprazole, brexpiprazole, cariprazine, and lumateperone, as a third generation of these drugs. However, the efficacies of typical and atypical antipsychotics do not differ strongly and mostly affect positive symptoms, with negative symptoms and cognitive deficits remaining essentially untreatable [12][13]. Additional limitations in the clinical use of both first- and second-generation antipsychotics include adverse effects, particularly extrapyramidal motor effects and metabolic dysregulations, which often lead to nonadherence to treatment [14]. Pimavanserin, a 5-HT2A serotonin receptor blocker, is the only antipsychotic without D2R antagonistic properties, but it failed in schizophrenia trials and is currently approved only for Parkinson’s disease psychosis [15]. Therefore, there is an urgent need for new medications with novel mechanisms of action that do not involve D2R and/or 5-HT2A serotonin receptor antagonism for the treatment of schizophrenia.
One of the approaches used to develop such drugs is the target-agnostic in vivo phenotypic drug discovery protocol [16]. Sunovion Pharmaceuticals partnered with PsychoGenics Inc. to use its proprietary, high-throughput SmartCube® platform that combines in vivo behavioral testing with artificial intelligence to phenotypically discover potential anti-psychotics. This approach resulted in the discovery of the antipsychotic-like profile of the Sunovion Pharmaceuticals compound ulotaront (INN; developmental codes: SEP-363856, SEP-856). By testing the radioligand binding profile, ulotaront was initially characterized as a serotonin 5-HT1A agonist; however, follow-up functional studies revealed the potent agonistic action of the compound at Trace Amine-Associated Receptor 1 (TAAR1), its potency being one order of magnitude higher than that at the serotonin 5-HT1A receptor [17].
Identified in 2001, Trace Amine-Associated Receptors (TAARs—six functional receptors found in humans: TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) comprise a family of G protein-coupled receptors that are clustered in a chromosomal region associated with schizophrenia [18][19][20]. While TAAR2-TAAR9 receptors were initially considered as a new class of olfactory receptors sensing innate odors mediated by volatile amines [21], recent observations indicate that at least some of these receptors are expressed also in the limbic brain areas and involved in emotional regulation and adult neurogenesis [22][23][24]. The best-studied receptor is TAAR1, which is expressed in part within the dopaminergic neuronal circuitry and can be activated by a variety of monoaminergic compounds, including trace amines, amphetamines, and monoamine metabolites. TAAR1 is emerging as a promising new target for psychiatric disorders [25][26][27]. Pharmacological or genetic targeting of TAAR1 revealed that stimulation of TAAR1 suppressed dopamine-dependent behaviors, while TAAR1 deficiency potentiated them [26][28][29]. This modulation likely involves the regulation of striatal presynaptic and postsynaptic D2R function via D2R-TAAR1 heterodimerization and modulation of the beta-arrestin2-dependent Akt/GSK3beta signaling cascade [30][31][32]. Thus, instead of acting on D2R directly, ulotaront may affect its functions indirectly through activation of the TAAR1 heterodimer, thereby providing a novel opportunity to bias D2R signaling [33].
TAAR1 seems to affect the function of the other critical brain neurotransmitters. A distinct pattern of expression of TAAR1 in the pyramidal neurons of layer V of the prefrontal cortex (PFC) was detected, and altered subunit composition and deficient functionality of the glutamate NMDA receptors in the PFC and striatum were found in mice lacking TAAR1 [34][35]. These studies indicate that TAAR1 plays an important role in the modulation of dopamine-related processes in the striatum and NMDA receptor-mediated glutamate transmission in the PFC. TAAR1 is also found in the serotonergic dorsal raphe nucleus (DRN) and regulates serotonin transmission [28]. By modulating dopamine, glutamate, and serotonin transmission, selective TAAR1 agonists have shown potential antipsychotic, antidepressant, and pro-cognitive effects in several experimental animal models [36][37]. Thus, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of neuropsychiatric disorders related to aberrant frontostriatal circuitry. Based on the preclinical studies, it might be expected that TAAR1 could be a potential drug target for several neuropsychiatric disorders, including schizophrenia, depression, bipolar disorder, generalized anxiety disorder, addiction, ADHD, Alzheimer’s disorder, etc. [29][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52].
To date, two TAAR1 agonists, ralmitaront (F. Hoffmann La-Roche, phase 2, Clinical-Trials.gov identifier: NCT03669640) and ulotaront (SEP-363856, 1-[(7S)-5,7-dihydro-4H-thieno [2,3-c]pyran-7-yl]-N-methylmethanamine, Sunovion Pharmaceuticals, phase 3, described below), are undergoing clinical trials in schizophrenia treatment. In 2019, based on the results of a phase 2 clinical trial, ulotaront was awarded FDA Breakthrough Therapy Designation for schizophrenia treatment due to its demonstrated efficacy and greatly reduced side effects compared to current treatments [53][54].

2. Preclinical Pharmacology

2.1. In Vitro Pharmacological Studies in Heterologous Cellular Cultures

In an initial radioligand binding screening assay, ulotaront (at 10 µM) showed >50% inhibition of specific binding at the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2, 5-HT7, α2A, α2B, and D2R receptors. Ki values varied from 0.031 to 21 µM. In follow-up functional assays, it was identified as an agonist of the human TAAR1 receptor, with an EC50 of 0.14 ± 0.062 μM and an Emax of 101.3 ± 1.3% (means ± SEMs), and the 5-HT1A receptor, with an EC50 of 2.3 ± 1.40 μM and an Emax of 74.7 ± 19.60%. Weak effects on all other targets (the 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2, 5-HT7, α2A, α2B, and D2 receptors) were observed only at high micromolar concentrations. In D2R receptor functional assays, ulotaront exhibited weak partial agonist activity, with EC50 values of 10.44 ± 4 µM (cAMP, Emax = 23.9% ± 7.6%) and 8 µM (β-arrestin recruitment, Emax = 27.1%). At 100 µM, 34% ± 1.16% inhibition was seen in the cAMP assay, and no antagonism was seen at concentrations up to 100 μM in the β-arrestin recruitment assay. Low potency partial agonist activities were also observed at the 5-HT1B (EC50 = 15.6 ± 11.6 μM, Emax = 22.4% ± 10.9%), 5-HT1D (EC50 = 0.262 ± 0.09 μM, Emax = 57.1% ± 6.0%), and 5-HT7 receptors (EC50 = 6.7 ± 1.32 μM, Emax = 41.0% ± 9.5%). In a functional assay of 5-HT2B activity, ulotaront showed no agonism up to a concentration of 100 µM. Little to no activity was detected at the 5-HT2A receptor, with 29.3% agonism seen only at the highest tested concentration of 10 μM. Ulotaront did not show activity in any of the studied enzymes up to a concentration of 100 µM [17]. Intriguingly, a more recent study involving an alternative in vitro cellular method of detecting TAAR1 activity revealed a more potent (EC50 of 38 ± 11 nM, Emax = 109% ± 3%) agonistic action of ulotaront, thereby revealing a higher selectivity level with respect to 5-HT1A activity [55].

2.2. Studies on Neuronal Tissues

To evaluate the mechanisms responsible for the action of ulotaront at the neuronal level, whole-cell patch-clamp recordings in isolated mouse brain slices of the dorsal raphe nucleus (DRN), where cell bodies of serotonin neurons are located, and the ventral tegmental area (VTA) containing cell bodies of mesolimbic dopaminergic neurons were performed. Ulotaront induced inhibitory responses in DRN neurons, and this effect was attenuated by the 5-HT1A antagonist WAY-100635 but not by the TAAR1 antagonist EPPTB. VTA neuron activity was also reduced by ulotaront: inhibitory effects in VTA were attenuated by the TAAR1 antagonist EPPTB but not the 5-HT1A antagonist WAY-100635. It seems that the inhibitory effects of ulotaront on the activity of DRN neurons were mediated via the activation of serotonin 5-HT1A receptors but that in the VTA neurons they were at least partially dependent on TAAR1 activation [17]. Analysis of extracellular single-unit activities of the DRN neurons of anesthetized rats corroborated the findings gained via whole-cell patch-clamp recordings in isolated mouse brain slices. At a dose of 5 mg/kg (i/v), ulotaront completely suppressed neuron firing, and this inhibition was fully reversed by the serotonin 5-HT1A antagonist WAY-100635, indicating that the inhibitory effects of ulotaront on DRN neurons are mediated exclusively through serotonin 5-HT1A receptors [17]. To directly evaluate the action of ulotaront on serotonin 5-HT1A receptors in brain tissue in vitro, autoradiography in rat brain slices was performed. Serotonin 5-HT1A agonist 8-OH-DPAT radioligand binding in the absence and presence of ulotaront was quantified. Ulotaront displaced 8-OH-DPAT in a concentration-dependent manner, and the highest receptor binding was observed in the septum and throughout the cortex [17]. To assess ulotaront occupancy at D2R, in vivo autoradiography experiments with the radioligand D2R antagonist raclopride in Sprague Dawley rats were carried out. Ulotaront did not produce significant occupancy at D2R in the brain at plasma concentrations 200-fold greater than those that were behaviorally effective, and no significant interaction of the drug with D2R was shown [17]. Furthermore, PET imaging of fallypride radiotracers in anesthetized baboons was conducted to determine D2R occupancy in primates. Ulotaront, even at very high concentrations, showed very low D2R occupancy levels (less than 10%) in brain regions. The lack of direct D2R interaction appears to extend to primates as well [17]. Taken together, these data indicate that ulotaront can act predominantly via the activation of TAAR1 and serotonin 5-HT1A receptors without a significant effect on D2R and serotonin 5-HT2A receptors.

3. In Vivo Behavioral Studies

3.1. Antipsychotic Action: Positive Symptoms

Some of the most widely accepted pathogenetic hypotheses of schizophrenia are increased dopaminergic and decreased glutamatergic transmission [56][57]. Drugs acting through an increase in dopamine or a decrease in glutamate signaling are usually applied for modeling schizophrenia endophenotypes in rodents and for testing potential drugs in these models. Positive symptoms are usually modeled in tests involving the locomotor hyperactivity of mice and rats following administration of the dopaminergic stimulant amphetamine or the glutamate NMDA receptor antagonist phencyclidine (PCP) [58]. Ulotaront showed good efficacy in a PCP-induced hyperactivity psychosis model, which was used for modeling positive symptoms. All tested doses (0.3, 1, and 3 mg/kg, p/o) decreased the hyperlocomotion of mice in a dose-dependent manner [17]. The attenuation of PCP-induced hyperlocomotion was also observed in rats, with a minimal effective dose of 1 mg/kg, p/o. The serotonin 5-HT1A receptor antagonist WAY-100635 partially decreased the ability of ulotaront to attenuate PCP-induced hyperactivity in mice [17]. The potential role of the 5-HT1A mechanism of ulotaront in its action on PCP-induced hyperactivity was further supported recently in mice lacking TAAR1: pretreatment with the drug (10 mg/kg, p/o) diminished MK-801-induced hyperactivity independently of TAAR1 [59]. Intriguingly, ulotaront failed to mitigate locomotor hyperactivity induced by dopaminergic drugs, indicating the complex action of the agent on dopamine neurotransmission and emphasizing the non-D2R mechanism(s) involved. Thus, pretreatment with the agent (dose range: 1–10 mg/kg, p/o) did not reverse d-amphetamine-induced hyperlocomotion [59][60]. Similar data were obtained when the effect of ulotaront was evaluated in the dopamine agonist apomorphine-induced climbing test in mice [61]. At the same time, treatment with ulotaront potentiated effects of the antipsychotic drug olanzapine in this test as well as in the NMDA antagonist MK-801-induced hyperactivity test in mice [61].

3.2. Antipsychotic Action: Negative Symptoms and Cognitive Deficits

One of the commonly used negative symptom models is decreased social interaction in rodents induced by chronic PCP administration [62][63]. Ulotaront was effective against sub-chronic PCP-induced deficits in the social interaction test in rats. All tested doses of ulotaront increased social interaction time, the magnitude of the effect tending to decrease as the dose increased from 1 to 10 mg/kg [60]. Ulotaront at 10 mg/kg also ameliorated cognitive impairments caused by sub-chronic treatment with PCP in the novel object recognition test in rats [60]. Furthermore, ulotaront slightly mitigated MK-801-induced deficits in the Morris water maze test and potentiated the ameliorative effect of olanzapine in this cognitive assay [61]. Deficits in sensorimotor gating are present in patients suffering from schizophrenia, and these deficits can be modeled in rodents. Studies of drug effects in the pre-pulse inhibition (PPI) test of the acoustic startle response in rodents showed good utility in the identification of potential antipsychotic medications [64]. Ulotaront at doses of 0.3–30 mg/kg, p/o, dose-dependently increased PPI compared with the vehicle, with a minimal effective dose of 3 mg/kg [17]. These observations were supported further by an independent group [59]. The administration of ulotaront at a dose of 10 mg/kg, p/o, increased PPI and, most importantly, restored PPI disrupted by pretreatment with MK-801 in wild-type but not TAAR1-knockout mice [59]. These results indicate that ulotaront’s action on negative symptoms is directly related to its TAAR1 agonistic activity.

3.3. Common Adverse Reactions of Antipsychotics

Extrapyramidal symptoms and weight gain are among the common adverse reactions induced by antipsychotic therapy. The catalepsy bar test was carried out to assess ulotaront’s potential to cause the development of extrapyramidal symptoms; haloperidol was used as a positive control. Ulotaront, at the highest studied dose of 100 mg/kg, p/o, produced no effect in mice, indicating the low potential of the drug to induce cataleptic effects at doses much higher than efficacious doses in psychosis models in mice [17]. However, ulotaront (10 mg/kg, p/o) reduced the basal locomotor activity of mice [59]. The last effect seems to be TAAR1-dependent because the agent did not affect locomotor activity in TAAR1-knockout mice [46]. Ulotaront’s effect on animal weight was also estimated in mice. It has been demonstrated that chronic treatment with the agent (dose range: 2–3 mg/kg, p/o) was not associated with weight gain [61]. Moreover, administration of ulotaront (3 mg/kg, p/o) prevented weight gain in animals chronically treated with olanzapine [61].

3.4. Other Effects of Ulotaront

The use of second-generation antipsychotics as adjunctive agents in the therapy of depression is well known [65][66]. An analysis of ulotaront’s effects in the forced swim test (FST), a routine animal test performed to estimate the antidepressant-like activity of pharmacological agents, revealed that administration of the compound (dose range: 1–10 mg/kg, p/o) resulted in a reduction in immobility time in mice, indicating that ulotaront may have some antidepressant-like action [17]. Recently, these findings were further corroborated by another group [67]. In this study, ulotaront decreased immobility time in both the FST and its analog, the tail suspension test, as well as the potentiated effects of the antidepressant duloxetine [67]. Moreover, ulotaront (15 mg/kg, p/o, for 21 days) mitigated modeled anhedonia-like states induced by chronic mild unpredictable stress in the sucrose preference test, with no effect in non-stressed mice [67]. Ulotaront was tested in rats to determine its effect on sleep architecture. Ulotaront at doses of 1, 3, and 10 mg/kg, p/o, produced a dose-dependent decrease in rapid eye movement (REM) sleep, an increase in latency to REM sleep, and an increase in cumulative wake time. Ulotaront did not affect the cumulative non-REM time and latency to non-REM. Taken together, these results suggest that ulotaront can improve vigilance when administered during the inactive phase [17]. The development of any new psychotropic agents always raises questions about their addictive potential. In a recently published work, Synan and colleagues addressed this issue [68]. In this study, ulotaront was not able to maintain the self-administration (SA) of d-amphetamine, heroin, or cocaine, or serve as a substitute for cocaine in a drug discrimination paradigm. However, the compound can partly substitute for MDMA in drug discrimination tests, although the effect was demonstrated only for an extremely high (30 mg/kg, p/o) dose. Moreover, ulotaront (10 mg/kg, p/o) was found to be able to mitigate que- (but not prime-)induced reinstatement of cocaine SA. Intriguingly, ulotaront, as well as TAAR1 agonists in other studies ([69]; Dravolina et al., unpublished), inhibited food-reinforced behavior [68]. Importantly, ulotaront attenuated the ketamine-induced increase in the striatal dopamine synthesis capacity in mice without producing an effect in drug-naïve controls, indicating that it may modulate the presynaptic dopamine dysfunction observed in patients with schizophrenia [70]. The ability of acute ulotaront administration to regulate rat brain expression of the activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, an immediate-early gene involved in neuroplasticity, memory formation, and sustaining cognitive processes, was tested. Following ulotaront administration, Arc and c-Fos mRNA levels were significantly upregulated in the prefrontal cortex and ventral hippocampus, but not in the striatum or dorsal hippocampus. At the same time, ulotaront attenuated increased Arc expression in the prefrontal cortex following acute PCP administration. Furthermore, mRNA levels of Zif268/Egr1 (involved in several neuronal plasticity processes) and Npas4 (a neuronal transcription factor that regulates the excitatory–inhibitory balance) were also significantly upregulated by acute ulotaront treatment in the PFC but not in other brain regions [60].

4. Pharmacokinetics and Metabolism

4.1. Pharmacokinetics in Experimental Animals

The pharmacokinetics for intravenous (i/v) and per os (p/o) administration of ulotaront was preclinically assessed in male ICR mice (10 mg/kg, p/o), Sprague Dawley rats (5 and 10 mg/kg, p/o and i/v), and rhesus macaques (10 mg/kg, p/o and i/v) [17]. In mice, the Cmax for 10 mg/kg, p/o, was 2854 ± 298 ng/mL and 7972 ± 2908 ng/g in plasma and the brain, respectively; the Tmax was 30 min for plasma and 15 min for brain tissue; and the T1/2 was 0.847 h and 0.808 h in plasma and the brain, respectively. In rats, following 10 mg/kg, p/o, the Cmax was 1750 ± 369 ng/mL and 3762 ± 1324 ng/g in plasma and the brain, respectively; the Tmax values for plasma and brain tissue were equal at 15 min; and the T1/2 was 2.1 h and 2.33 h in plasma and the brain, respectively. In rats, following 5 mg/kg, i/v, and 5 mg/kg, p/o, the Cmax in plasma was 2578 ± 110 ng/mL and 1056 ± 173 ng/g; the Tmax was 0.083 and 0.42 ± 0.14 h; and the T1/2 in plasma was 1.17 ± 0.16 h and 1.24 ± 0.1 h, respectively. In monkeys, following 5 mg/kg, p/o, the Cmax in plasma was 431 ± 104 ng/mL, the Tmax was 6.00 ± 2.83 h, and the T1/2 was 3.03 h. In monkeys, following 5 mg/kg, i/v, the Cmax in plasma was 2191 ± 194 ng/mL, the Tmax was 0.083, and the T1/2 was 3.14 ± 1.26 h. The mean residence time was 5.90 h [17]. Thus, in experimental animals, ulotaront is rapidly absorbed, has a good bioavailability (~100% in rats, 92% in dogs, and 71% in monkeys), and tends to concentrate in brain tissue (brain concentration and brain AUC were approximately three times higher than in plasma). In follow-up in vitro ADME and preclinical pharmacokinetic studies, a high solubility and permeability for ulotaront has been also demonstrated [71]. In this study, ulotaront demonstrated low binding to animal and human plasma proteins, with an unbound fraction greater than 78% (in both animals and humans) [71]. Ulotaront exhibited low-to-moderate hepatic clearance in mouse, rat, monkey, and human hepatocytes [71]. Ulotaront’s hepatic clearance formation is mainly determined by CYP2D6, and both NADPH-dependent and NADPH-independent pathways seem to be involved in its metabolism [71]. The major metabolite identified in the plasma of mice, rats, rabbits, dogs, monkeys, and humans after a single dose or repeat dose of ulotaront is SEP-383103 [71].

4.2. Pharmacokinetics in Humans

The population pharmacokinetics of ulotaront in adult subjects was analyzed using pooled data from seven phase 1 studies, one phase 2 acute study, and one 6-month extension study. Pharmacokinetic parameters were evaluated in men and women aged 18 to 55 years. Data were obtained from healthy volunteers (n = 99) and patients with schizophrenia (n = 305). A total of 53.7% of the tested subjects were White, 31.4% were Black, 10.9% were Asian, and 3.9% were other/mixed race. Over 80% of the Asian subjects in the analysis were Japanese [72]. Single and multiple oral doses (5–150 mg/day) were used. According to the pharmacokinetic analysis, ulotaront is well absorbed when taken orally. Ulotaront demonstrated dose proportionality for doses ranging from 25 to 100 mg, the mean maximum concentration, the area under the concentration–time curve, and the minimum concentration. The estimated median Tmax was 2.8 h, and the median effective half-life was 7 h, leading to an accumulation ratio of 1.1 upon daily dosing. There were no major alterations in pharmacokinetic parameters after up to 12 weeks of daily dose administration. The pharmacokinetic parameters of Ulotaront were independent of sex, race, age, formulation, or the presence of schizophrenia. Only the body weight of the patients influenced ulotaront pharmacokinetics. Since CYP2D6 is involved in the metabolism of ulotaront, CYP2D6 metabolizer status could potentially affect pharmacokinetics, but due to the small sample size it is not yet possible to unequivocally answer this question. Taken together, these data indicate that ulotaront has a pharmacokinetic profile that is consistent with once-a-day dose administration [73]. The bioequivalence of tablet and capsule formulations of ulotaront was assessed, with no significant differences revealed [74]. Furthermore, no effect of food on the pharmacokinetics of the tablet form in humans was found [74].

5. Clinical studies

5.1. Schizophrenia

Phase III clinical trials are currently underway[75]. Previous studies showed efficacy of ulotaront in reduction of positive and negative symptoms of schizophrenia with minimal side effects[53][72].

5.2. Parkinson's Disease Psychosis

In one proof-of-concept study, improvements across several measures of the Scale for Assessment of Positive Symptoms—Parkinson’s Disease (SAPS-PD) were noted, without worsening of motor parkinsonism[76].

5.3. Other disorders

Safety and efficacy studies are also being conducted for major depressive disorder (NCT05593029) and generalized anxiety disorder (NCT05729373)[77][78].

One of the studies investigated the effects of different doses of the drug on patients with narcolepsy-cataplexy (NCT05015673), but ulotaront did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy[79].

Acknowledgments

We thank LLC Accellena[80], Russia, for continuous support.

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