Ulotarone for treating anxiety and related conditions

Abstract

Neuropsychiatric treatments, including methods, regimens and interventions for the treatment of anxiety and related symptoms based on ulotarone administration.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority of U.S. Provisional Application 63 / 381,327, filed on October 28, 2022, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] The present disclosure relates to pharmacological neuropsychiatric treatments, as well as methods, regimens, and interventions for treating anxiety and related disorders based on the administration of ulotaront. Background art

[0004] Generalized anxiety disorder (GAD) (a common and often - recurrent disorder) is associated with significant medical and psychiatric morbidity and mortality, functional impairment, and healthcare costs. Recent surveys have shown that in the adult population of the United States, the 12 - month prevalence of GAD is 2.9%, and the lifetime prevalence is 6.2% (Kessler 2012). In global surveys, the 12 - month prevalence of GAD is 1.8%, and the lifetime prevalence is 3.7%, and both the prevalence and functional impact are higher in high - income countries compared to low - income countries (Ruscio 2017). Generally, anxiety disorders are important contributing factors to decreased work performance and increased utilization of healthcare resources, imposing a substantial economic impact (Wittchen 2002; DuPont 1996; Greenberg 1999). GAD in particular has a significant impact and economic burden on individuals and society (Pollack 2009).

[0005] Pharmacological therapies for GAD typically consist of antidepressants (e.g., selective serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI)), benzodiazepines, and other agents used as augmentation when needed (Garakani 2020). SSRIs and SNRIs have generally had modest success in controlling GAD symptoms, but they have a substantial number of side effects, which are important limiting factors for medication therapy adherence and ultimate treatment outcomes (Kong 2020; Garakani 2020). Although benzodiazepines have shown immediate and robust efficacy against GAD symptoms (Gomez 2018; Garakani 2020), their potential for abuse and dependence limits their use to relatively short intervals in most treatment guidelines (Balon 2020). These factors, combined with GAD being a chronic disorder, result in a large number of patients who do not respond to or are intolerant of first-line treatments (Bandelow 2008 Goodwin 2002; Altamura 2008; Allgulander 2002; Baldwin 2005). Related to this, the remission rate of GAD is low (Yonkers 1996), and the probability of relapse 3 years after remission is 27 - 39% (Yonkers 2000).

[0006] For these reasons, there is a large unmet need for new agents for treating GAD that relieve symptoms, improve response and remission rates, but do not carry the burden of side effect profiles associated with existing neuropsychiatric medications and do not have the abuse and dependence propensities of benzodiazepines and other neuropsychiatric drugs. SUMMARY OF THE INVENTION

[0007] In one embodiment, the present disclosure provides a method of treating an anxiety disorder in a non-schizophrenic human subject in need thereof, the human subject being at most mildly depressed, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to placebo.

[0008] In another embodiment, the present disclosure provides a method of treating an anxiety disorder in a human subject in need thereof, the human subject having a total HAM-A score ≥20, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to placebo.

[0009] Another embodiment provides a method for treating an anxiety disorder in a human subject in need thereof, wherein the human subject has a total HAM-A score ≥ 20, a HAM-A anxiety mood score ≥ 2 and a HAM-A tension score ≥ 2, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to a placebo.

[0010] Another embodiment provides a method for treating tension in a human subject who also has a neuropsychiatric disorder, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to a placebo.

[0011] Additional advantages of the present disclosure are set forth in part in the following description, and in part will be apparent from the description, or may be learned by practice of the present disclosure. The advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed present disclosure. Detailed Description

[0012] All published documents cited herein are hereby incorporated by reference in their entirety.

[0013] Use of Terms

[0014] As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0015] Unless otherwise noted, the word "includes" (or any variant thereof, such as "include", "including", etc.) is intended to be open-ended. For example, "A includes 1, 2, and 3" means that A includes but is not limited to 1, 2, and 3.

[0016] As used in this specification and in the claims that follow, the word "comprise" and variations of the word, such as "comprising" and "comprises", mean "including but not limited to" and are not intended to exclude, for example, other additives, ingredients, integers or steps. When an element is described as comprising a plurality of components, steps or conditions, it should be understood that the element may also be described as comprising any combination of such plurality of components, steps or conditions, or "consisting of" or "consisting essentially of": a plurality of components, steps or conditions or a combination of components, steps or conditions.

[0017] When a range is given by separately specifying a lower end and an upper end of the range, or a particular numerical value is specified, it should be understood that the range can be defined by selectively combining any mathematically possible lower end variable, upper end variable, and particular numerical value. When a range is expressed as extending from one endpoint to another endpoint, it should be understood that both endpoints are included within the range. However, it should also be understood that the from / to range also includes embodiments in which the range is defined as being between two specified endpoints, and the term "between" can replace the from / to language to omit the endpoints from the range.

[0018] The present disclosure describes various embodiments. Those skilled in the art will readily recognize that the various embodiments can be combined in any variation. For example, embodiments of the present disclosure include treating various disorders, patient populations, dosage forms administered, various doses, minimization of various adverse events, and improvement of various efficacy measurements, etc. Any combination of the various embodiments is within the scope of the present disclosure.

[0019] When a published test method and diagnostic tool are referred to herein, it should be understood that the test method or diagnostic tool is based on the version effective as of October 1, 2022, unless otherwise stated to the contrary herein. This is true even when the method or tool is defined herein based on a publication reporting an earlier version.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0021] Definitions

[0022] As used herein, "administering" or "administration" of ulotaront or a pharmaceutically acceptable salt thereof includes delivering ulotaront or a pharmaceutically acceptable salt thereof or a prodrug or other pharmaceutically acceptable derivative thereof to a subject using any suitable formulation or route of administration (e.g., as described herein).

[0023] The term "atypical antidepressant" refers to antidepressants that do not conform to the conventional classification of antidepressants (e.g., SSRI, SSNI, tricyclic, and MOAI). Examples include bupropion (Wellbutrin®), vilazodone (Viibryd®), vortioxetine (Trintellix®), nefazodone, NASSA (norepinephrine and specific serotonergic antidepressants, such as mirtazapine (Remeron®)), SARI (serotonin antagonist and reuptake inhibitor, such as trazodone (Molipaxin®)), and NARI (norepinephrine reuptake inhibitor, such as reboxetine).

[0024] The "CGI-C" (Clinical Global Impression - Change) scale measures the efficacy of pharmacotherapy by rating the total change in the subject since the start of pharmacotherapy (regardless of whether this change is entirely attributable to pharmacotherapy). Response options include: 1 = Very much improved, 2 = Much improved, 3 = Minimal improvement, 4 = Slight improvement, 5 = Slight worsening, 6 = Much worsening, 7 = Very much worsening.

[0025] The "CGI-S" (Clinical Global Impression - Severity) scale is a standardized, clinician-administered global rating scale that measures the severity of a disease on a 7-point Likert scale. The higher the CGI-S score, the higher the severity of the disease. For this assessment, the rater or investigator answers the following question: "Considering your overall clinical experience with this specific group, how ill is the patient at this time with respect to their mental illness?" Response options include: 1 = Normal, not ill at all; 2 = Borderline mental illness; 3 = Mild illness; 4 = Moderate illness; 5 = Marked illness; 6 = Severe illness; and 7 = Among the most severely ill patients.

[0026] As used herein, a "clinically significant" or "clinically meaningful" improvement can refer to an improvement that is statistically significant and meaningful from the perspective of the patient, clinician, or caregiver, typically based on a static measurement (such as CGI-S) or a retrospective assessment of improvement (such as CGI-C), as generally described in various publications of the U.S. Food and Drug Administration (including FDA 2018, FDA 2019, and FDA 2020). When a treatment or benefit is described herein, it should be understood that the treatment or benefit preferably shows clinically significant efficacy to a statistically significant degree in a patient population.

[0027] "Cyclic antidepressants" include tricyclics and tetracyclics and generally act by blocking the reuptake of the neurotransmitters serotonin and norepinephrine, increasing the levels of these two neurotransmitters in the brain. Examples include amitriptyline, amoxapine, desipramine (Norpramin®), doxepin, imipramine (Tofranil®), nortriptyline (Pamelor®), protriptyline, trimipramine, and maprotiline.

[0028] As used herein, "delaying" the development of a disorder refers to postponing, hindering, slowing, stabilizing, and / or retarding the development of the disorder. The delay can have different time lengths, depending on the disease history and / or the individual being treated.

[0029] "DSM-5" refers to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Terms used in this document may be defined with reference to DSM-5 as necessary to give life and meaning to the term. When a person is defined based on DSM-5 in this document, it should be understood that the person does not need to have been diagnosed using the criteria in DSM-5, but rather the person who meets the criteria specified in DSM-5 is so diagnosed.

[0030] The Hamilton Anxiety Rating Scale (HAM-A) is a clinician-administered rating scale developed to quantify the severity of anxiety symptomatology. It consists of 14 items, each defined by a series of symptoms. Each item is rated on a 5-point scale (0 - 4), with higher scores indicating greater severity. (Hamilton 1959).

[0031] Healthcare resource utilization (HCRU) is a quantification or description of the use of services by people for the purpose of preventing and treating health problems, promoting the maintenance of health and well-being, or obtaining information about their personal health status and prognosis. HCRU includes questions regarding the number of physician office visits, emergency room (ER) visits, hospitalizations, and length of hospitalization for any reason and for GAD-related care during the past 1-month period.

[0032] "MAOI" refers to antidepressant drugs of the monoamine oxidase inhibitor class. Examples include isocarboxazid (Marplan®), phenelzine (Nardil®), selegiline (Emsam®), and tranylcypromine (Parnate®).

[0033] The Medication Satisfaction Questionnaire (MSQ) is a single-item, subject-rated, rater-administered questionnaire that asks subjects to rate their satisfaction with their medication using a 7-point Likert-type scale. Subjects are asked the following question: "Overall, how satisfied are you with your current GAD medication?" Subjects select 1 out of 7 potential responses (from (1) very dissatisfied to (7) very satisfied) based on their level of satisfaction.

[0034] The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated assessment of the depressive level of a subject. The measure contains 10 items that measure obvious and reported sadness, inner tension, decreased sleep and appetite, difficulty concentrating, fatigue, anhedonia, pessimistic thoughts, and suicidal thoughts. Each item is scored on a scale from 0 to 6, with higher scores indicating an increase in depressive symptoms. (Montgomery 1979).

[0035] "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S. M. Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19. The pharmaceutically acceptable salts of ulotaront include those derived from suitable inorganic and organic acids and bases.

[0037] Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed when the amino group reacts with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods such as ion exchange that are used in the art. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Although pharmaceutically acceptable counterions are preferred for the preparation of pharmaceutical formulations, other anions (X) are also fully acceptable as synthetic intermediates. Thus, when these salts are chemical intermediates, X may be an anion that is not pharmaceutically desirable, such as iodide, oxalate, trifluoromethanesulfonate, etc.

[0038] As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any binder, filler, adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, anti-caking agent, flavoring agent, desiccant, plasticizer, disintegrant, lubricant, polymer matrix system, and polishing agent that have been approved by or otherwise accepted by the U.S. Food and Drug Administration for use in humans or livestock in appropriate qualifications.

[0039] As used herein, "prevention" or "preventing" refers to a regimen for preventing the onset of a disorder such that the clinical symptoms of the disorder do not develop. Thus, "prevention" involves administering a therapy to a subject before signs of the disease are detectable in the subject (e.g., treating in the absence of detectable disease symptoms). The subject may be an individual at risk of developing the disorder.

[0040] Sheehan Disability Scale (SDS) The SDS is a clinician-administered scale / composed of three items to measure the degree to which three major areas of a subject's life are impaired by psychiatric or medical symptoms. This anchored visual analogue scale uses spatiovisual, numerical, and verbal descriptive anchors simultaneously to assess disability in three domains: work, social life, and home life. The subject rates the degree to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on an 11-point visual analogue scale ranging from 0 to 10. The points on the scale have verbal descriptors, as well as numerical scores that provide a more precise level of the verbal descriptor. The three items can be added together to form a single-dimensional measure of overall functional impairment, ranging from 0 (unimpaired) to 30 (highly impaired).

[0041] The term "selection" refers to the act of choosing from numbers or groups by fitness or preference. In the context of the present disclosure, ulotaront is selected from a group of generally recognized neuropsychiatric drugs for the treatment of any of the neuropsychiatric conditions described herein.

[0042] The 36-Item Short-Form Questionnaire ("SF-36") is a self-reported questionnaire with a standard recall period of 4 weeks that measures 2 broad domains (physical and mental composite), across 8 health domain scales of general health-related quality of life: physical function, pain, role physical, general health, vitality / fatigue, social function, role emotional, and mental health. The SF-36 uses norm-based scoring to generate scores on a scale of 1 to 100, where lower scores for the physical component summary and mental component summary represent lower health-related quality of life, and a score of 50 refers to norm data derived from a survey of a representative sample of the general population in the United States.

[0043] As used herein, the term "significantly" refers to the level of statistical significance. The level of statistical significance can be p < 0.1, p < 0.05, p < 0.01, p < 0.005, or p < 0.001. Unless otherwise specified, when the terms "significant", "significantly", or other variants of the term are used, the level of statistical significance is p < 0.05. When measurable results or effects are expressed or identified herein, it should be understood that the results or effects are preferably evaluated based on their statistical significance relative to a baseline (e.g., placebo). In a similar manner, when a treatment or benefit is described herein, it should be understood that the treatment or benefit preferably demonstrates efficacy to a statistically significant degree in a patient population.

[0044] "SNRI" (serotonin-norepinephrine reuptake inhibitor) includes but is not limited to desvenlafaxine (Pristiq ), duloxetine (Cymbalta ), levomilnacipran (Fetzima ), and venlafaxine (Effexor XR) and pharmaceutically acceptable salts thereof.

[0045] "SSRI" (selective serotonin reuptake inhibitor) includes but is not limited to citalopram (Celexa ), escitalopram (Lexapro ), fluoxetine (Prozac ), paroxetine (Paxil , Pexeva ), and sertraline (Zoloft ) and pharmaceutically acceptable salts thereof.

[0046] The Structured Clinical Interview for DSM-5 Axis I Disorders - Clinical Trial Version (SCID-5-CT) is a modified version of the SCID developed for use in clinical trials. This is a semi-structured interview aimed at making DSM-5 diagnoses (First 2015).

[0047] As used herein, "subjects" or "patients" to whom administration is contemplated include but are not limited to humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged or elderly individuals)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals, such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds, such as chickens, ducks, geese, quails, and / or turkeys.

[0048] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including, when administered to a subject for treating a disorder, an amount of a compound sufficient to effect treatment of such disorder. The effective amount will vary depending on the disorder and its severity, and on the age, weight, etc. of the subject to be treated. The effective amount may be one or more doses (e.g., a single dose or multiple doses may be required to reach the desired treatment endpoint). An effective amount is considered to be administered in an effective amount if a desired or beneficial result can be achieved or realized in combination with one or more other agents. Due to the combined action (additive or synergistic) of the compounds, the appropriate dose of any co-administered compound may optionally be reduced.

[0049] As used herein, the terms "treatment", "treat", and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, including, but not limited to, therapeutic benefit. In some embodiments, treatment is administered after the appearance of one or more symptoms (e.g., symptoms of an acute exacerbation). In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a subject prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, e.g., to prevent or delay their recurrence.

[0050] Therapeutic benefit includes eradicating and / or ameliorating the underlying disorder being treated; it also includes eradicating and / or ameliorating one or more symptoms associated with the underlying disorder such that an improvement is observed in the subject, although the subject may still be afflicted with the underlying disorder.

[0051] In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting a disorder (e.g., reducing one or more symptoms caused by the disorder, and / or alleviating the degree of the disorder); (b) slowing or preventing the development of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or delaying the worsening or progression of the disorder); and / or (c) alleviating the disorder (e.g., resulting in the resolution of clinical symptoms, improving the disorder, delaying the progression of the disorder, and / or improving quality of life).

[0052] "Ulotaront" (also known as SEP-363856, SEP-856) as mentioned herein for use in the methods of the present disclosure has the chemical name (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (which may be abbreviated as "(S)-TPMA"). Ulotaront has the following structure:

[0053]

[0054] Unless otherwise indicated or unless the context otherwise requires, for the purposes of this disclosure, the term “ulotaront” standing alone includes the free form of ulotaront and also includes its pharmaceutically acceptable salts, hydrates, solvates, amorphous, and crystalline forms. When the free form is intended or specifically any other form or salt is intended, this will be stated explicitly.

[0055] Ulotaront can be used in the methods described herein as the free base or in the form of a pharmaceutically acceptable salt. In a preferred embodiment, the hydrochloride (HCl) salt of ulotaront is used in the methods described herein. Ulotaront or its pharmaceutically acceptable salts (including its HCl crystalline form) can be obtained according to the production methods described in PCT Patent Publication No. WO2011 / 069063 (U.S. Patent No. 8,710,245 issued on April 29, 2014) or PCT Patent Publication No. WO2019 / 161238 or methods similar thereto, and these patents are incorporated herein by reference in their entirety and for all purposes.

[0056] Also provided herein are pharmaceutical compositions and dosage forms that comprise ulotaront or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients. The compositions and dosage forms provided herein may further comprise one or more additional active ingredients. Ulotaront or its pharmaceutically acceptable salt can be administered as part of a pharmaceutical composition as described herein.

[0057] Discussion

[0058] In one embodiment, the present disclosure provides a method of treating an anxiety disorder in a non-schizophrenic human subject in need thereof, the human subject being at most mildly depressed, the method comprising administering to the subject a therapeutically effective amount of ulotaront or its pharmaceutically acceptable salt, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to placebo.

[0059] In another embodiment, the present disclosure provides a method of treating an anxiety disorder in a human subject in need thereof, the subject having a total HAM-A score ≥20, the method comprising administering to the subject a therapeutically effective amount of ulotaront or its pharmaceutically acceptable salt, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to placebo.

[0060] Another embodiment provides a method of treating an anxiety disorder in a human subject in need thereof, wherein the human subject has a total HAM-A score ≥20, an HAM-A anxiety mood score ≥2, and an HAM-A tension score ≥2, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to placebo.

[0061] Another embodiment provides a method of treating tension in a human subject who also has a neuropsychiatric disorder, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to placebo.

[0062] In various embodiments, the treatment achieves different degrees of results. Thus, in some embodiments, the treatment results in a clinically significant decrease in the total HAM-A score of the subject compared to placebo. In some embodiments, the treatment also results in a clinically significant decrease in the CGI-S score of the subject compared to placebo. In some embodiments, the treatment results in a clinically significant decrease in both the total HAM-A score and the CGI-S score of the subject compared to placebo. In a further embodiment, at eight weeks after the start of administration, the treatment results in a clinically significant decrease in both the total HAM-A score and the CGI-S score of the subject compared to placebo. In a still further embodiment, at four weeks and eight weeks after the start of administration, the treatment results in a clinically significant decrease in both the total HAM-A score and the CGI-S score of the subject compared to placebo.

[0063] Other embodiments are defined based on the numerical benefits achieved by the method. Thus, in some embodiments, the treatment reduces the total HAM-A score of the subject to ≤12, ≤11, ≤10, ≤9, ≤8, ≤7, or ≤6. In some embodiments, the treatment reduces the total HAM-A score of the subject by ≥40%, ≥50%, or ≥60%. In some embodiments, the treatment reduces the CGI-S score of the subject by ≥1, ≥2, or ≥3.

[0064] When it is alleged that the treatment has produced a clinically significant treatment effect, it should be understood that in other embodiments, it can also be said that the treatment results in a decrease of ≥2 in the CGI-S score of the subject. When it is alleged that the treatment has produced a clinically significant treatment effect, it should be understood that in other embodiments, it can also be said that the treatment results in a decrease of ≥50% in the CGI-S score of the subject.

[0065] Given the unique behavioral characteristics of ulotaront (as reported in Dedic 2019), the human clinical results reported in PCT patent publication number WO2020 / 118032, and the novel mechanism of action and receptor binding characteristics of ulotaront, it is expected that ulotaront treats neuropsychiatric disorders with a high degree of safety and efficacy. Accordingly, in one embodiment, ulotaront is administered to a patient who also has a neuropsychiatric disorder selected from psychosis, depression, pain, cognition, mood disorder, and anxiety disorder.

[0066] In another embodiment, the neuropsychiatric disorder includes schizophrenia, schizophrenic spectrum disorder, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizotypal personality disorder, schizoid personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, excitatory psychosis, organic or NOS psychosis, movement disorder, mood disorder, anxiety, affective disorder (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar affective disorder, e.g., bipolar depressive disorder, manic disorder, seasonal affective disorder), pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), cognitive disorder, and movement disorder.

[0067] In one embodiment, the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety disorder. In another embodiment, the neuropsychiatric disorder is schizophrenia. In another embodiment, the neuropsychiatric disorder is bipolar depression (specifically MDD as defined by DSM-5, and more specifically AMDD). In still another embodiment, the neuropsychiatric disorder is anxiety disorder (e.g., generalized anxiety disorder (GAD) as defined by DSM-5). In one embodiment, the neuropsychiatric disorder is an anxiety disorder.

[0068] In some embodiments, the treatment includes alleviating tension or anxiety disorder. In some embodiments, the treatment includes a complete response to tension or anxiety disorder. In other embodiments, the treatment includes alleviating tension or anxiety disorder and a complete response to tension or anxiety disorder.

[0069] In one embodiment, the subject is treatment naïve.

[0070] In one embodiment, the subject has failed to respond adequately to prior buspirone or antidepressant therapy.

[0071] In one embodiment, the subject has not tolerated previous buspirone or antidepressant therapy adequately.

[0072] As exemplary antidepressant therapies, SSRI, SNRI, cyclic antidepressants, atypical antidepressants, and MAOI may be mentioned, although any molecule showing an antidepressant mechanism of action is intended to be covered.

[0073] Anxiety disorders treated by the methods of the present disclosure include but are not limited to generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder. In one embodiment, the anxiety disorder is generalized anxiety disorder (GAD).

[0074] The methods of the present disclosure can also be used to treat tension when used to treat anxiety disorders. Thus, when the patient also has tension, the method can further include treating the tension. In one embodiment, the patient has tension and the method includes treating the tension to a clinically significant degree.

[0075] In a similar manner, the methods of the present disclosure can also be used to treat anxiety disorders when used to treat tension. Thus, when the patient also has an anxiety disorder, the method can further include treating the anxiety disorder.

[0076] In one embodiment, the methods of the present disclosure are used to treat non-schizophrenic patients. In other embodiments, the methods are used to treat patients with at most mild depression.

[0077] When scores are provided (including but not limited to HAM-A, MADRS, CGI-S, etc.), unless otherwise stated, the scores are determined at the start of therapy. For example, "A method of treating an anxiety disorder in a human subject in need, wherein the subject has a total HAM-A score ≥20..." means that the subject's total HAM-A score is ≥20 at the start of therapy.

[0078] The methods of the present disclosure can also be practiced based on the subject's HAM-A score. In some embodiments, the subject has a total HAM-A score ≥20. In some embodiments, the subject has a total HAM-A score ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35.

[0079] In some embodiments, the subject has a HAM-A anxiety mood score ≥2. In some embodiments, the subject has a HAM-A anxiety mood score ≥2, ≥4, or =4.

[0080] In some embodiments, the HAM-A tension score of the subject is ≥2. In some embodiments, the HAM-A tension score of the subject is ≥2, ≥3 or =4.

[0081] In other embodiments, the total HAM-A score of the subject is ≥20, the HAM-A anxiety mood score is ≥2 and the HAM-A tension score is ≥2.

[0082] The methods of the present disclosure may also be practiced based on the MADRS score of the subject. In some embodiments, the total MADRS score of the subject is ≤22. In some embodiments, the total MADRS score of the subject is ≤22, ≤20, ≤18, ≤16, ≤14, ≤12 or ≤10. When the term "mild depression" is used herein, it should be understood that when using the MADRS scoring system, a MADRS score in the range of 7 to 19 generally indicates "mild depression". However, for the purposes of the present disclosure, the term mild depression includes patients with a MADRS score ≤22. Thus, a subject with at most "mild depression" may alternatively be defined as having a total MADRS score ≤22, ≤19, ≤16, ≤14, ≤12, ≤10 or ≤8. Alternatively, the subject may be described based on a non-depressed MADRS score (i.e., <7) or a mild depression MADRS score (i.e., from 7 to 22 or from 7 to 19).

[0083] In some embodiments, the MADRS inner tension score of the subject is ≥2, ≥3, ≥4, ≥5 or =6.

[0084] The methods of the present disclosure may also be implemented based on the CGI-S score of the subject. In some embodiments, the CGI-S of the subject is ≥4. In some embodiments, the CGI-S score of the subject is ≥4, and the treatment reduces the CGI-S score of the subject by ≥2 points. In some embodiments, the CGI-S score of the subject is ≥4, and the treatment reduces the CGI-S score to ≤3.

[0085] The anxiety disorders of the present disclosure may be characterized based on one or a combination of sensations or symptoms. In one embodiment, the anxiety disorder includes one or a combination of sensations or symptoms selected from anxiety mood, tension, fear, insomnia, intellectual, depressive mood, somatic (muscle), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, urogenital symptoms, autonomic symptoms, and anxiety behavior.

[0086] In one embodiment, the anxiety disorder includes one or more anxiety feelings or symptoms selected from the following: worry, worst-case expectation, fear of expectation, and irritability. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A anxiety emotion score is ≥2, ≥3, or =4.

[0087] In one embodiment, the anxiety disorder includes one or more tension feelings or symptoms selected from the following: feeling tense, easy fatigability, startle reaction, being easily moved to tears, trembling, feeling restless, and inability to relax. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A tension score is ≥2, ≥3, or =4.

[0088] In one embodiment, the anxiety disorder includes one or more fears selected from the following: fear of darkness, fear of strangers, fear of being alone, fear of animals, fear of traffic, and fear of crowds. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A fear score is ≥2, ≥3, or =4.

[0089] In one embodiment, the anxiety disorder includes one or more insomnia feelings or symptoms selected from the following: difficulty falling asleep, fragmented sleep, unsatisfactory sleep, fatigue upon waking, dreaming, nightmares, and night terrors. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A insomnia score is ≥2, ≥3, or =4.

[0090] In one embodiment, the anxiety disorder includes one or more intellect-related feelings or symptoms selected from the following: difficulty concentrating and poor memory. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A intellect-related score is ≥2, ≥3, or =4.

[0091] In one embodiment, the anxiety disorder includes one or more depressive mood feelings or symptoms selected from the following: loss of interest, lack of pleasure in hobbies, depression, early awakening, and diurnal swing. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A depressive mood score is ≥2, ≥3, or =4.

[0092] In one embodiment, the anxiety disorder includes one or more somatic (muscular) feelings or symptoms selected from the following: pain and distress, tremors, stiffness, myoclonic jerks, teeth grinding, voice instability, and increased muscle tone. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A somatic (muscular) score is ≥2, ≥3, or =4.

[0093] In one embodiment, the anxiety disorder includes one or more somatic (sensory) feelings or symptoms selected from the following: tinnitus, blurred vision, hot flushes and cold flushes, weakness, and tingling sensations. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A somatic (sensory) score is ≥2, ≥3, or =4.

[0094] In one embodiment, the anxiety disorder includes one or more cardiovascular symptoms selected from the following: tachycardia, palpitations, chest pain, throbbing of blood vessels, feeling of fainting, and heart beats out of rhythm. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A cardiovascular score is ≥2, ≥3, or =4.

[0095] In one embodiment, the anxiety disorder includes one or more respiratory symptoms selected from the following: chest pressure or constriction, sense of suffocation, sighing, and dyspnea. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A respiratory score is ≥2, ≥3, or =4.

[0096] In one embodiment, the anxiety disorder includes one or more gastrointestinal symptoms selected from the following: dysphagia, wind abdominal pain, burning sensation, abdominal fullness, nausea, vomiting, borborygmus, diarrhea, weight loss, and constipation. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A gastrointestinal score is ≥2, ≥3, or =4.

[0097] In one embodiment, the anxiety disorder includes one or more urogenital symptoms selected from the following: frequent urination, urgency, amenorrhea, menorrhagia, development of frigidity, premature ejaculation, loss of libido, and impotence. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A urogenital score is ≥2, ≥3, or =4.

[0098] In one embodiment, the anxiety disorder includes one or more autonomic symptoms selected from the following: dry mouth, flushing, pallor, sweating easily, dizziness, tension headache, and piloerection. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A autonomic score is ≥2, ≥3, or =4.

[0099] In one embodiment, the anxiety disorder includes one or more anxiety behaviors selected from the following: restlessness, fidgeting or pacing, hand tremors, frowning, tense facial expression, sighing or rapid breathing, pale face, or swallowing. In another embodiment, the total HAM-A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM-A interview behavior score is ≥2, ≥3, or =4.

[0100] The therapeutically effective amount of ulotaront can be alternatively described as 10 - 150 mg / day or 25 - 150 mg / day or 25 - 100 mg / day or 50 - 125 mg / day or 50 - 100 mg / day or 50 - 75 mg / day, administered orally. Alternatively, the therapeutically effective amount can be described as 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, or 150 mg / day, administered orally. In any embodiment of the present disclosure, the therapeutically effective amount can be administered once daily in the fed or fasted state. Ulotaront can also be administered as the hydrochloride salt.

[0101] Preferred aspects of the present disclosure can be defined based on the following embodiments AA to CM:

[0102] [Embodiment AA] A method for treating an anxiety disorder in a non-schizophrenic human subject in need thereof, the human subject being at most mildly depressed, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to a placebo.

[0103] [Embodiment AB] A method for treating an anxiety disorder in a human subject in need thereof, the human subject having a total HAM-A score ≥ 20, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to a placebo.

[0104] [Embodiment AC] A method for treating an anxiety disorder in a human subject in need thereof, the human subject having a total HAM-A score ≥ 20, a HAM-A anxiety mood score ≥ 2, and a HAM-A tension score ≥ 2, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a decrease in the total HAM-A score of the subject compared to a placebo.

[0105] [Embodiment AD] The method of any one of embodiments AA-AC, wherein the treatment results in a clinically significant decrease in the total HAM-A score of the subject compared to a placebo.

[0106] [Embodiment AE] The method of any one of embodiments AA-AC, wherein the treatment also results in a clinically significant decrease in the CGI-S score of the subject compared to a placebo.

[0107] [Embodiment AF] The method of any one of embodiments AA-AC, wherein at eight weeks after the start of administration, the treatment results in a clinically significant decrease in the total HAM-A score and the CGI-S score of the subject compared to a placebo.

[0108] [Embodiment AG] The method of any one of embodiments AA-AC, wherein at four weeks and eight weeks after the start of administration, the treatment results in a clinically significant decrease in the total HAM-A score and the CGI-S score of the subject compared to a placebo.

[0109] [Embodiment AH] The method of any one of embodiments AA-AG, wherein the treatment reduces the total HAM-A score of the subject to ≤ 7.

[0110] [Embodiment AI] The method of any one of embodiments AA - AH, wherein the treatment reduces the total HAM - A score of the subject by ≥ 50%.

[0111] [Embodiment AJ] The method of any one of embodiments AA - AI, wherein the treatment reduces the CGI - S score of the subject by ≥ 1 or ≥ 2.

[0112] [Embodiment AK] The method of any one of embodiments AA - AI, wherein the treatment reduces the CGI - S score of the subject to ≤ 3.

[0113] [Embodiment AL] The method of any one of embodiments AA - AI, wherein the treatment reduces the CGI - S score of the subject to ≤ 2.

[0114] [Embodiment AM] The method of any one of embodiments AB - AL, wherein the subject is non - schizophrenic.

[0115] [Embodiment AN] The method of any one of embodiments AB - AL, wherein the subject has at most mild depression.

[0116] [Embodiment AO] The method of any one of embodiments AA or AD - AL, wherein the total HAM - A score of the subject is ≥ 20.

[0117] [Embodiment AP] The method of any one of embodiments AA or AB or embodiments AD - AL, wherein the HAM - A anxiety mood score of the subject is ≥ 2.

[0118] [Embodiment AQ] The method of any one of embodiments AA or AB or embodiments AD - AL, wherein the HAM - A tension score of the subject is ≥ 2.

[0119] [Embodiment AR] The method of any one of embodiments AA or AB or embodiments AD - AL, wherein the total HAM - A score of the subject is ≥ 20, the HAM - A anxiety mood score is ≥ 2, and the HAM - A tension score is ≥ 2.

[0120] [Embodiment AS] The method of any one of embodiments AA - AR, wherein the total MADRS score of the subject is ≤ 22.

[0121] [Embodiment AT] The method of any one of embodiments AA - AS, wherein the MADRS inner tension score of the subject is ≥ 2, ≥ 3, ≥ 4, ≥ 5, or = 6.

[0122] [Embodiment AU] The method of any one of embodiments AA - AT, wherein the CGI - S score of the subject is ≥ 4.

[0123] [Embodiment AV] The method of any one of embodiments AA - AU, wherein the anxiety disorder includes one or a combination of feelings or symptoms selected from anxious mood, tension, fear, insomnia, intellectual - related, depressive mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and anxious behavior.

[0124] [Embodiment AW] The method of any one of embodiments AA - AV, wherein the anxiety disorder includes one or more anxious mood feelings or symptoms selected from worry, worst - case expectation, fear of expectation, and irritability.

[0125] [Embodiment AX] The method of any one of embodiments AA - AW, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM - A anxious mood score is ≥2, ≥3, or = 4.

[0126] [Embodiment AY] The method of any one of embodiments AA - AX, wherein the anxiety disorder includes one or more tension feelings or symptoms selected from the feeling of tension, easy fatigability, startle reaction, easy to be moved to tears, trembling, uneasy feeling, and inability to relax.

[0127] [Embodiment AZ] The method of any one of embodiments AA - AY, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM - A tension score is ≥2, ≥3, or = 4.

[0128] [Embodiment BA] The method of any one of embodiments AA - AZ, wherein the anxiety disorder includes one or more fears selected from fear of darkness, fear of strangers, fear of being alone, fear of animals, fear of traffic, and fear of crowds.

[0129] [Embodiment BB] The method of any one of embodiments AA - BA, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5, or ≥35, and the HAM - A fear score is ≥2, ≥3, or = 4.

[0130] [Embodiment BC] The method of any one of embodiments AA - BB, wherein the anxiety disorder includes one or more insomnia feelings or symptoms selected from difficulty falling asleep, interrupted sleep, unsatisfactory sleep, and fatigue when waking up, dreaming, nightmares, and night terrors.

[0131] [Embodiment BD] The method according to any one of Embodiments AA - BC, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A insomnia score is ≥2, ≥3 or = 4.

[0132] [Embodiment BE] The method according to any one of Embodiments AA - BD, wherein the anxiety disorder includes one or more intellectual - related feelings or symptoms selected from the following: difficulty in concentrating and poor memory.

[0133] [Embodiment BF] The method according to any one of Embodiments AA - BE, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A intellectual - related score is ≥2, ≥3 or = 4.

[0134] [Embodiment BG] The method according to any one of Embodiments AA - BF, wherein the anxiety disorder includes one or more depressive - mood feelings or symptoms selected from the following: loss of interest, lack of pleasure in hobbies, depression, early awakening, and diurnal mood swings.

[0135] [Embodiment BH] The method according to any one of Embodiments AA - BG, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A depressive - mood score is ≥2, ≥3 or = 4.

[0136] [Embodiment BI] The method according to any one of Embodiments AA - BH, wherein the anxiety disorder includes one or more somatic (muscular) feelings or symptoms selected from the following: pain and distress, twitching, stiffness, myoclonic jerks, teeth grinding, voice instability, and increased muscle tone.

[0137] [Embodiment BJ] The method according to any one of Embodiments AA - BI, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A somatic (muscular) score is ≥2, ≥3 or = 4.

[0138] [Embodiment BK] The method according to any one of Embodiments AA - BJ, wherein the anxiety disorder includes one or more somatic (sensory) feelings or symptoms selected from the following: tinnitus, blurred vision, hot flushes and cold flushes, weakness, and tingling sensations.

[0139] [Embodiment BL] The method of any one of Embodiments AA - BK, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A somatic (sensory) score is ≥2, ≥3 or = 4.

[0140] [Embodiment BM] The method of any one of Embodiments AA - BL, wherein the anxiety disorder includes one or more cardiovascular symptoms selected from the following: tachycardia, palpitations, chest pain, vascular throbbing, sense of fainting, and heart beats out of rhythm.

[0141] [Embodiment BN] The method of any one of Embodiments AA - BM, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A cardiovascular score is ≥2, ≥3 or = 4.

[0142] [Embodiment BO] The method of any one of Embodiments AA - BN, wherein the anxiety disorder includes one or more respiratory symptoms selected from the following: chest constriction or contraction, sense of suffocation, sighing, and dyspnea.

[0143] [Embodiment BP] The method of any one of Embodiments AA - BO, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A respiratory score is ≥2, ≥3 or = 4.

[0144] [Embodiment BQ] The method of any one of Embodiments AA - BP, wherein the anxiety disorder includes one or more gastrointestinal symptoms selected from the following: dysphagia, flatulence with abdominal pain, burning sensation, abdominal fullness, nausea, vomiting, borborygmus, diarrhea, weight loss, and constipation.

[0145] [Embodiment BR] The method of any one of Embodiments AA - BQ, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A gastrointestinal score is ≥2, ≥3 or = 4.

[0146] [Embodiment BS] The method of any one of Embodiments AA - BR, wherein the anxiety disorder includes one or more urogenital symptoms selected from the following: frequent urination, urgency of urination, amenorrhea, menorrhagia, development of frigidity, premature ejaculation, loss of libido, and impotence.

[0147] [Embodiment BT] The method of any one of Embodiments AA - BS, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A urogenital score is ≥2, ≥3 or = 4.

[0148] [Embodiment BU] The method of any one of Embodiments AA - BT, wherein the anxiety disorder includes one or more autonomic symptoms selected from the following: dry mouth, flushing, pallor, sweating easily, dizziness, tension headache, and piloerection.

[0149] [Embodiment BV] The method of any one of Embodiments AA - BU, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A autonomic score is ≥2, ≥3 or = 4.

[0150] [Embodiment BW] The method of any one of Embodiments AA - BV, wherein the anxiety disorder includes one or more anxiety behaviors selected from the following: restlessness, fidgeting or pacing, hand tremors, frowning, tense facial expression, sighing or rapid breathing, facial pallor, or swallowing.

[0151] [Embodiment BX] The method of any one of Embodiments AA - BW, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A interview behavior score is ≥2, ≥3 or = 4.

[0152] [Embodiment BY] The method of any one of Embodiments AA - BX, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35.

[0153] [Embodiment BZ] The method of any one of Embodiments AA - BY, wherein the HAM - A anxiety mood score of the subject is ≥2, ≥3 or = 4.

[0154] [Embodiment CA] The method of any one of Embodiments AA - BZ, wherein the HAM - A tension score of the subject is ≥2, ≥3 or = 4.

[0155] [Embodiment CB] The method of any one of Embodiments AA - CA, wherein the total MADRS score of the subject is ≤22, ≤20, ≤18, ≤16, ≤14, ≤12 or ≤10.

[0156] [Embodiment CC] The method of any one of Embodiments AA - CB, wherein the subject is untreated.

[0157] [Embodiment CD] A method according to any one of embodiments AA - CB, wherein the subject has failed to respond adequately to a previous treatment with buspirone or an antidepressant.

[0158] [Embodiment CE] A method according to any one of embodiments AA - CB, wherein the subject has failed to tolerate adequately a previous treatment with buspirone or an antidepressant.

[0159] [Embodiment CF] A method according to embodiment CD or CE, wherein the antidepressant treatment is selected from SSRI, SNRI, cyclic antidepressants, atypical antidepressants, and MAOI.

[0160] [Embodiment CG] A method according to any one of embodiments AA - CF, wherein the treatment comprises alleviating an anxiety disorder.

[0161] [Embodiment CH] A method according to any one of embodiments AA - CF, wherein the treatment comprises a complete response to an anxiety disorder.

[0162] [Embodiment CI] A method according to any one of embodiments AA - CH, wherein the anxiety disorder is selected from generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive - compulsive disorder (OCD), post - traumatic stress disorder (PTSD), and panic disorder.

[0163] [Embodiment CJ] A method according to any one of embodiments AA - CI, wherein the anxiety disorder is generalized anxiety disorder (GAD).

[0164] [Embodiment CK] A method according to any one of embodiments AA - CJ, wherein the therapeutically effective amount is 10 - 150 mg / day, 25 - 150 mg / day, 25 - 100 mg / day, 50 - 125 mg / day, 50 - 100 mg / day, or 50 - 75 mg / day, administered orally.

[0165] [Embodiment CL] A method according to any one of embodiments AA - CK, wherein the therapeutically effective amount is 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, or 150 mg / day, administered orally.

[0166] [Embodiment CM] A method according to any one of embodiments AA - CL, wherein the therapeutically effective amount is administered once daily, in the fed or fasted state.

[0167] [Embodiment CN] A method according to any one of embodiments AA - CM, wherein ulotaront is administered as the hydrochloride salt.

[0168] Examples

[0169] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be taken into account. The following examples are presented to provide a complete disclosure and description to those skilled in the art of how the methods claimed herein are performed and evaluated, and are intended to be purely illustrative of the present disclosure and not intended to limit the scope that the inventors regard as their disclosure.

[0170] Example 1. Effects of SEP-363856 on marble burying and locomotor activity in mice

[0171] SEP-363856 was evaluated in the mouse marble burying test, which is sensitive to several anxiolytic and antidepressant drugs (Nicolas 2006). Male Swiss mice (5 weeks old, n = 10 / group) received a single administration of vehicle (po), SEP 363856 (0.3, 1, 3, or 10 mg / kg, po), or clobazam (8 mg / kg, ip) as a positive control. Thirty minutes later, the mice were individually placed in a transparent plastic cage with 5 cm of sawdust on the floor and 25 marbles grouped in the center of the cage. The number of marbles covered (covered 2 / 3 or more) with sawdust was counted at the end of the 30 min test. Two days later, the general locomotor activity of the same animals was evaluated in an activity meter test. Thirty minutes after drug administration, the mice were placed in an automated activity meter device, and the number of crossings during a 5-minute period was recorded for 30 minutes. Chlorpromazine (4 mg / kg, i.p.) was included as a positive assay control. The SEP-363856 results of the marble burying test were analyzed by the Kruskal-Wallis test, followed by the Mann-Whitney U test to determine group effects. Locomotor activity was analyzed by one-way ANOVA, followed by Dunnett's post hoc inference analysis. The effects of clobazam in the marble burying and activity meter tests were examined by the Mann-Whitney U test and unpaired Student's t test, respectively.

[0172] Compared to vehicle-treated controls, SEP-363856 significantly reduced the number of marbles buried at the levels of 0.3, 3, and 10 mg / kg, po (Table 1). In the activity meter test, a moderate but significant reduction in the number of crossings was observed only at the highest dose (10 mg / kg, po) (Table 2). The results suggest that at dose levels ≤ 3 mg / kg, the anxiolytic-like effects of SEP-363856 in the marble burying test are unlikely to be attributable to locomotor confounding.

[0173] Table 1. Effects of SEP-363856 in the mouse marble burying test

[0174]

[0175] Compared with the vehicle, a p < 0.05, b p = 0.06

[0176] Table 2. Effect of SEP-363856 in the mouse locomotor activity test

[0177]

[0178] Compared with the vehicle, a p < 0.05

[0179] Example 2. A Phase 2 / 3, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose, multicenter study to evaluate the efficacy and safety of SEP-363856 in the treatment of adults with generalized anxiety disorder

[0180] This is a multicenter, randomized, double-blind, parallel-group, flexible-dose, outpatient study to evaluate the efficacy and safety of flexible-dose SEP-363856 (50 - 75 mg / day) versus placebo in patients with GAD over an 8-week treatment period. The study is expected to randomize approximately 434 subjects in a 1:1 ratio into 2 treatment groups (SEP-363856 [50 - 75 mg / day] or placebo). The study drug is taken at approximately the same time every night before bedtime and may be taken with or without food.

[0181] The study consists of 3 phases: screening / washout (up to 21 days), treatment (8 weeks), and follow-up (7 days after the last study drug administration for subjects who discontinued prior to Week 8 visit [Visit 7] or for subjects who completed the study).

[0182] During the screening / washout period (up to 21 days), subjects will be evaluated at the screening visit (Visit 1) to determine their eligibility for the study. During the screening / washout period, subjects taper off all psychotropic medications (except permitted concomitant medications) in a manner consistent with the label recommendations and routine medical practice and discontinue completely at least 3 days or 5 half-lives (whichever is longer) prior to randomization.

[0183] During the treatment period (8 weeks), at baseline (Day 1), subjects who have successfully completed the previous drug washout and meet the eligibility criteria will be randomly assigned in a 1:1 ratio to one of two treatment arms via a randomization and trial supply management (RTSM) system: SEP-363856 (50 - 75 mg / day) or placebo. Administration of the study drug begins on the evening of the baseline visit. Treatment continues once daily, at bedtime in the evening, for the remainder of the 8-week treatment period.

[0184] All subjects received 25 mg / day or a matching placebo for the first three days of the treatment period and started receiving 50 mg / day or a matching placebo on Day 4. All subjects started receiving 75 mg / day or a matching placebo on Day 8. The researchers could require a dose reduction at any time after Week 1 (Visit 3) for reasons of safety or tolerability as judged by the researchers. Subjects who could not tolerate the study drug after a dose reduction (blinded sham dose reduction or actual dose reduction) would discontinue the study.

[0185] At the end of the treatment period, subjects had an End of Treatment (EOT) visit at Week 8 (Visit 7). Subjects who discontinued the study early or completed the study had to complete the follow-up within 7 days (±2 days) after the last dose of the study drug. During the 1-week follow-up period, subjects should not start a new treatment unless due to the occurrence of an adverse event or as required by the researcher's judgment for the safety of the subject. After the follow-up period was completed, treatment could be started based on the judgment of the researcher or the subject's primary care physician.

[0186] Primary efficacy objective: To evaluate the efficacy of flexible-dose SEP-363856 (50–75 mg / day) compared with placebo in patients with GAD, as measured by the total score on the Hamilton Anxiety Rating Scale (HAM-A).

[0187] Secondary efficacy objective: To evaluate the efficacy of flexible-dose SEP-363856 (50–75 mg / day) compared with placebo in patients with GAD, as measured by the Clinical Global Impression-Severity (CGI-S) score.

[0188] Other efficacy objectives: (i) To evaluate the efficacy of flexible-dose SEP-363856 (50–75 mg / day) compared with placebo in patients with GAD, as measured by the proportion of subjects meeting the HAM-A response criteria (≥50% improvement relative to baseline score), the proportion of subjects meeting the HAM-A remission criteria (total score ≤7 points), and the Montgomery-Åsberg Depression Rating Scale (MADRS); (ii) To evaluate the effect of flexible-dose SEP-363856 (50–75 mg / day) on health-related quality of life and work productivity, as measured by the following: 36-Item Short Form Questionnaire (SF-36), Sheehan Disability Scale (SDS), and Healthcare Resource Utilization (HCRU); (iii) To evaluate medication satisfaction, as measured by the Medication Satisfaction Questionnaire (MSQ).

[0189] Primary endpoint: Change in the total HAM-A score at the endpoint (Week 8) relative to baseline.

[0190] Secondary efficacy endpoint: Change in CGI-S score at endpoint (Week 8) relative to baseline.

[0191] Other efficacy endpoints: (i) Changes relative to baseline in the following: total MADRS score at Weeks 4 and 8, total SDS score at Weeks 4 and 8, SF-36 physical component score, mental component score, and subscales at Week 8; (ii) Change in MSQ score at Week 8 relative to screening; (iii) HAM-A response rate, defined as the proportion of subjects with a ≥50% improvement in total HAM-A score relative to baseline at each scheduled visit and endpoint (Week 8); (iv) HAM-A remission rate, defined as the proportion of subjects with a total HAM-A score ≤7 at each scheduled visit and endpoint (Week 8); (v) HCRU at baseline and Week 8.

[0192] Subject selection inclusion criteria: To be eligible for participation, subjects must meet all of the following selection inclusion criteria: (i) At the time of consent, male or female subjects aged between 18 and 65 years (inclusive); (ii) Subjects meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for GAD, as determined by clinical interview (using DSM-5 as a reference and confirmed using the Structured Clinical Interview for DSM-5 Clinical Trials Version (SCID-5CT)) (subjects may have DSM-5-based comorbid diagnoses of panic disorder, social anxiety disorder, or specific phobia, provided that these symptoms are secondary to GAD and not the primary focus of treatment); (iii) At screening and baseline, in the clinician-administered HAM-A, subjects must have a total HAM-A score ≥20, and both the score for Item 1 (Anxious mood) and Item 2 (Tension) of the HAM-A ≥2; (iv) At screening and baseline, subjects must have a total MADRS score ≤22; (v) At screening and baseline, subjects must have a CGI-S score ≥4.

[0193] References

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[0200] Throughout this application, various publications are cited. The disclosures of these publications are hereby incorporated by reference in their entirety into this application so as to more fully describe the prior art relevant to the present disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the present disclosure. By considering the specification and practicing the disclosure herein, other embodiments of the present disclosure will be apparent to those skilled in the art. The specification and examples are only to be considered as exemplary, and the true scope and spirit of the present disclosure are indicated by the following claims.

Claims

1. A method for treating an anxiety disorder in a non-schizophrenic human subject in need thereof, the human subject being at most mildly depressed, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to a placebo.

2. A method for treating an anxiety disorder in a human subject in need thereof, the human subject having a total HAM-A score ≥ 20, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to a placebo.

3. A method for treating an anxiety disorder in a human subject in need thereof, the human subject having a total HAM-A score ≥ 20, a HAM-A anxiety mood score ≥ 2, and a HAM-A tension score ≥ 2, the method comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in the total HAM-A score of the subject compared to a placebo.

4. The method according to any one of claims 1-3, wherein the treatment results in a clinically significant reduction in the total HAM-A score of the subject compared to a placebo.

5. The method according to any one of claims 1-3, wherein the treatment also results in a clinically significant reduction in the CGI-S score of the subject compared to a placebo.

6. The method according to any one of claims 1-3, wherein eight weeks after the start of the administration, the treatment results in a clinically significant reduction in the total HAM-A score and the CGI-S score of the subject compared to a placebo.

7. The method according to any one of claims 1-3, wherein four weeks and eight weeks after the start of the administration, the treatment results in a clinically significant reduction in the total HAM-A score and the CGI-S score of the subject compared to a placebo.

8. The method according to any one of claims 1-3, wherein the treatment reduces the total HAM-A score of the subject to ≤ 7.

9. The method according to any one of claims 1-3, wherein the treatment reduces the total HAM-A score of the subject by ≥ 50%.

10. The method according to any one of claims 1-3, wherein the treatment reduces the CGI-S score of the subject by ≥ 1 or ≥ 2.

11. The method according to any one of claims 1-3, wherein the treatment reduces the CGI-S score of the subject to ≤ 3.

12. The method according to any one of claims 1-3, wherein the treatment reduces the CGI-S score of the subject to ≤ 2.

13. The method according to any one of claims 2-3, wherein the subject is non-schizophrenic.

14. The method according to any one of claims 2-12, wherein the subject is at most mildly depressed.

15. The method according to claim 1, wherein the subject has a total HAM-A score ≥ 20.

16. The method according to claim 1 or 2, wherein the HAM-A anxiety score of the subject ≥ 2.

17. The method according to claim 1 or 2, wherein the HAM-A tension score of the subject ≥ 2.

18. The method according to claim 1 or 2, wherein the total HAM-A score of the subject ≥ 20, the HAM-A anxiety score ≥ 2 and the HAM-A tension score ≥ 2.

19. The method according to any one of claims 1-3, wherein the total MADRS score of the subject ≤ 22.

20. The method according to any one of claims 1-3, wherein the inner tension score of the subject's MADRS ≥ 2, ≥ 3, ≥ 4, ≥ 5 or = 6.

21. The method according to any one of claims 1-3, wherein the CGI-S score of the subject ≥ 4.

22. The method according to any one of claims 1-3, wherein the anxiety disorder includes one or a combination of the following feelings or symptoms selected from: anxiety, tension, fear, insomnia, intelligence-related, depressive mood, somatic (muscle), somatic (sensation), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, urogenital symptoms, autonomic symptoms, and anxiety behavior.

23. The method according to any one of claims 1-3, wherein the anxiety disorder includes one or more anxiety feelings or symptoms selected from: worry, worst expectation, fear expectation, and irritability.

24. The method according to any one of claims 1-3, wherein the total HAM-A score of the subject ≥ 20, ≥ 22.5, ≥ 25, ≥ 27.5, ≥ 30, ≥ 32.5 or ≥ 35, and the HAM-A anxiety score ≥ 2, ≥ 3 or = 4.

25. The method according to any one of claims 1-3, wherein the anxiety disorder includes one or more tension feelings or symptoms selected from: feeling of tension, easy fatigability, startle reaction, easy to cry, tremble, uneasy feeling, and inability to relax.

26. The method according to any one of claims 1-3, wherein the total HAM-A score of the subject ≥ 20, ≥ 22.5, ≥ 25, ≥ 27.5, ≥ 30, ≥ 32.5 or ≥ 35, and the HAM-A tension score ≥ 2, ≥ 3 or = 4.

27. The method according to any one of claims 1-3, wherein the anxiety disorder includes one or more of the following fears: fear of darkness, fear of strangers, fear of being alone, fear of animals, fear of traffic, and fear of crowds.

28. The method according to any one of claims 1-3, wherein the total HAM-A score of the subject ≥ 20, ≥ 22.5, ≥ 25, ≥ 27.5, ≥ 30, ≥ 32.5 or ≥ 35, and the HAM-A fear score ≥ 2, ≥ 3 or = 4.

29. The method according to any one of claims 1-3, wherein the anxiety disorder includes one or more insomnia feelings or symptoms selected from: difficulty falling asleep, interrupted sleep, unsatisfactory sleep, waking up tired, dreaming, having nightmares, and night terrors.

30. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A insomnia score is ≥2, ≥3 or = 4.

31. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more intellectual - related feelings or symptoms selected from the following: difficulty in concentrating and poor memory.

32. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A intellectual - related score is ≥2, ≥3 or = 4.

33. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more depressive - mood feelings or symptoms selected from the following: loss of interest, lack of pleasure in hobbies, depression, early awakening, and diurnal mood swings.

34. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A depressive - mood score is ≥2, ≥3 or = 4.

35. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more somatic (muscular) feelings or symptoms selected from the following: pain and distress, twitching, stiffness, myoclonic jerks, teeth grinding, voice instability, and increased muscle tone.

36. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A somatic (muscular) score is ≥2, ≥3 or = 4.

37. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more somatic (sensory) feelings or symptoms selected from the following: tinnitus, blurred vision, hot flushes and cold flushes, weakness, and tingling sensations.

38. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A somatic (sensory) score is ≥2, ≥3 or = 4.

39. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more cardiovascular symptoms selected from the following: tachycardia, palpitations, chest pain, throbbing of blood vessels, feeling of fainting, and missed heartbeats.

40. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A cardiovascular score is ≥2, ≥3 or = 4.

41. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more respiratory symptoms selected from the following: chest pressure or constriction, feeling of suffocation, sighing, and dyspnea.

42. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A respiratory score is ≥2, ≥3 or = 4.

43. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more gastrointestinal symptoms selected from the following: dysphagia, flatulence with abdominal pain, burning sensation, abdominal fullness, nausea, vomiting, borborygmus, diarrhea, weight loss, and constipation.

44. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A gastrointestinal score is ≥2, ≥3 or = 4.

45. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more urogenital symptoms selected from the following: frequent urination, urgency of urination, amenorrhea, menorrhagia, development of frigidity, premature ejaculation, loss of libido, and impotence.

46. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A urogenital score is ≥2, ≥3 or = 4.

47. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more autonomic symptoms selected from the following: dry mouth, flushing, pallor, sweating easily, dizziness, tension headache, and piloerection.

48. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A autonomic score is ≥2, ≥3 or = 4.

49. The method according to any one of claims 1 - 3, wherein the anxiety disorder includes one or more anxiety behaviors selected from the following: restlessness, fidgeting or pacing, hand tremors, frowning, tense facial expression, sighing or rapid breathing, facial pallor, or swallowing.

50. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35, and the HAM - A interview behavior score is ≥2, ≥3 or = 4.

51. The method according to any one of claims 1 - 3, wherein the total HAM - A score of the subject is ≥20, ≥22.5, ≥25, ≥27.5, ≥30, ≥32.5 or ≥35.

52. The method according to any one of claims 1 - 3, wherein the HAM - A anxiety mood score of the subject is ≥2, ≥3 or = 4.

53. The method according to any one of claims 1 - 3, wherein the HAM - A tension score of the subject is ≥2, ≥3 or = 4.

54. The method according to any one of claims 1 - 3, wherein the total MADRS score of the subject is ≤22, ≤20, ≤18, ≤16, ≤14, ≤12 or ≤10.

55. The method according to any one of claims 1 - 3, wherein the subject is untreated.

56. The method according to any one of claims 1 - 3, wherein the subject has failed to respond adequately to a previous buspirone or antidepressant therapy.

57. The method according to any one of claims 1 - 3, wherein the subject has failed to tolerate a previous buspirone or antidepressant therapy adequately.

58. The method according to claim 56, wherein the antidepressant therapy is selected from SSRI, SNRI, cyclic antidepressants, atypical antidepressants, and MAOI.

59. The method according to any one of claims 1 - 3, wherein the treatment comprises alleviating the anxiety disorder.

60. The method according to any one of claims 1 - 3, wherein the treatment comprises a complete response to the anxiety disorder.

61. The method according to any one of claims 1 - 3, wherein the anxiety disorder is selected from generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive - compulsive disorder (OCD), post - traumatic stress disorder (PTSD), and panic disorder.

62. The method according to any one of claims 1 - 3, wherein the anxiety disorder is generalized anxiety disorder (GAD).

63. The method according to any one of claims 1 - 3, wherein the therapeutically effective amount is 10 - 150 mg / day, 25 - 150 mg / day, 25 - 100 mg / day, 50 - 125 mg / day, 50 - 100 mg / day, or 50 - 75 mg / day, administered orally.

64. The method according to any one of claims 1 - 3, wherein the therapeutically effective amount is 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, or 150 mg / day, administered orally.

65. The method according to any one of claims 1 - 3, wherein the therapeutically effective amount is administered once daily, either with food or on an empty stomach.

66. The method according to any one of claims 1 - 3, wherein ulotaront is administered as the hydrochloride salt.

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