ULOTARONT for adjuvant treatment of major depression

Abstract

The present invention provides antidepressant therapies, methods of enhancing antidepressant therapies, in particular antidepressant therapies that fail to produce sufficient response, and patient populations that benefit from such enhancement.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. USSN 63 / 373,909, filed on August 30, 2022, the entire contents of which are hereby incorporated by reference as if fully set forth herein. Technical Field

[0003] The present disclosure relates to antidepressant therapies, methods of enhancing antidepressant therapies, particularly antidepressant therapies that have failed to produce an adequate response, and patient populations that would benefit from such enhancement. Background Art

[0004] Major depressive disorder (MDD) is a common and disabling disorder that affects up to 15% of people over their lifetime. Connolly 2011. The introduction of newer generation antidepressants has greatly improved outcomes for these patients, but still only about 50-60% of patients respond to first-line treatment, and only 35-40% achieve symptom remission in an initial 8-week trial. Connolly 2011. Drugs recommended as first-line antidepressants include, in particular, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), bupropion, and mirtazapine.

[0005] Although there are many guidelines to help treat major depression, recommendations for the treatment of depression that is inadequately responsive to antidepressants, including refractory depression, are more limited. Professional guidelines include the American Psychiatric Association's practice guideline for the treatment of patients with major depression, the 2009 Malhi Clinical Practice Recommendations for Depression, the Canadian Network for Mood and Anxiety Treatments (CANMAT), and the Clinical Guidelines for the Management of Major Depressive Disorder in Adults. These guidelines include several recommendations after failure of an initial antidepressant trial, including the addition of psychotherapy, lithium augmentation, second-generation antipsychotic (SGA) augmentation, triiodothyronine augmentation, and switching to a different antidepressant. While lithium and thyroid hormone have been shown to augment failed treatment, this has only been demonstrated when used in combination with tricyclic antidepressants (TCAs), and the trials supporting this use were conducted in patients who were less refractory to treatment than those typically treated with TCAs today. Connolly 2011. Of all the strategies for augmenting the efficacy of newer generation antidepressants, Connolly 2011 reported that quetiapine and aripiprazole have the most evidence support, although the cost-effectiveness and long-term benefits of these strategies have not yet been established. See also Marcus 2008. The development of adjunctive therapies is complicated by the fact that the effects of combination therapy observed in preclinical efficacy trials in psychiatry often do not translate to clinical trial results, as reported in the literature. DeMartinis 2019.

[0006] Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity, currently in Phase 3 clinical trials for the treatment of schizophrenia, with the following chemical structure:

[0007]

[0008] It has a novel mechanism of action (MOA) compared to antipsychotics, as it is not an antagonist at dopamine D2 or serotonin 5-HT2A receptors. Dedic 2019. Ulotaront demonstrated efficacy in treating exacerbations of schizophrenia in a large, randomized, double-blind, placebo-controlled clinical trial and continued to improve in a 6-month open-label extension study, as reported in US 2020 / 0179336A1 (June 11, 2020). Nonclinical studies suggest that agonism of TAAR1 and 5-HT1A receptors is one of the mechanisms of action of ulotaront. Dedic 2019.

[0009] Ulotaront was discovered in a medicinal chemistry program designed to develop structurally and mechanistically novel antipsychotics using in vivo phenotypic screening in mice combined with comprehensive in vitro and in vivo molecular analysis. This testing showed that ulotaront was behaviorally active, as reported in Dedic 2019. At the 0.3mg / kg dose, ulotaront was classified as an anxiolytic, but the antipsychotic classification showed a dose-dependent increase so that the characteristics at the 1 and 10mg / kg doses were primarily antipsychotic-like. Ulotaront also reportedly showed modest antidepressant-like signals.

[0010] What is needed are therapies that augment conventional antidepressant therapy, which is inadequately responsive to major depressive disorder and treatment-resistant depression, and criteria for identifying patients who respond to such therapies. SUMMARY OF THE INVENTION

[0012] As reported in the Examples herein, ulotaront was surprisingly found to have antidepressant behavioral activity in a rat model, a disorder that many traditional antidepressants fail to treat. Thus, in one embodiment, the present disclosure provides a method of adjunctive treatment of MDD (major depressive disorder) in a human subject who has demonstrated an inadequate response to antidepressant therapy, comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

[0013] In another embodiment, the present disclosure provides a method of adjunctive treatment of a subject with treatment-resistant depression comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

[0014] Other methods of treating depression are based on patient characteristics. Thus, in another embodiment, the present disclosure provides a method of treating a subject suffering from depression, comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the subject exhibits an inadequate response to antidepressant therapy, an inadequate response being defined as a decrease in the MADRS total score of <50% from the start of the antidepressant therapy.

[0015] In other aspects, the present disclosure relates to methods for treating depression using ulotaront in combination with an antidepressant therapy. Thus, in another embodiment, the present disclosure provides a method for treating a subject suffering from depression (e.g., MDD), comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and an antidepressant therapy.

[0016] 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 practicing the present disclosure. The advantages of the present disclosure will be realized and obtained by the elements and combinations specifically pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory and do not limit the claimed present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0018] All published documents cited herein are incorporated by reference in their entirety.

[0019] Terminology used

[0020] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0021] Unless otherwise indicated, the term "includes" (or any variation 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.

[0022] In this specification and the claims that follow, the word "comprise" and variations such as "comprising" and "comprises" mean "including but not limited to", and are not intended to exclude, for example, other additives, components, 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 a plurality, or "consisting of" or "consisting essentially of" a plurality or a combination of a plurality or a plurality of components, steps or conditions.

[0023] When a range is given by specifying the lower limit of the range and the upper limit of the range separately, or when specifying a specific numerical value, it should be understood that the range can be defined by selectively combining any lower limit variable, upper limit variable and specific numerical value that is mathematically possible. Similarly, when a range is defined as spanning from one endpoint to another, it should be understood that the range also covers the span between the two endpoints and does not include the two endpoints, including any and all ranges and sub-ranges therein. It should be understood that the range covers each discrete point within the range, just as if they were fully set forth in this article.

[0024] The present disclosure describes various embodiments. After reading the present disclosure, those skilled in the art will readily recognize that the various embodiments can be combined in any variation. For example, the embodiments of the present disclosure include various obstacles for treatment, patient populations, dosage forms for administration at various doses, minimizing various adverse events, and improving various efficacy measurements, etc. Any combination of the various embodiments is within the scope of the present disclosure.

[0025] When this document refers to published test methods and diagnostic tools, it should be understood that the test method or diagnostic tool is based on the version that is effective July 1, 2022, unless otherwise stated in this document. This is the case even if the method or tool in this document is based on the definition of a publication reporting an earlier version.

[0026] Unless defined otherwise, 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 belongs.

[0027] definition

[0028] Adjunctive MDD therapy refers to the addition of a medication to an antidepressant regimen to improve efficacy because the subject has had an inadequate response to the antidepressant regimen that has been optimized for dose and duration of treatment.

[0029] 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).

[0030] The “AIMS” (Abnormal Involuntary Movement Scale) assessment consists of 10 items that describe symptoms of movement disorders. Guy 1976. While the subject is at rest, facial and oral movements (items 1 to 4), limb movements (items 5 and 6), and trunk movements (item 7) are observed unobtrusively; the researcher also makes an overall judgment of the subject's movement disorder (items 8 to 10). Each item is scored on a 5-point scale, with 0 indicating no symptoms (unconscious for item 10) and 4 indicating severe condition (conscious, severe distress for item 10). In addition, AIMS includes 2 yes / no questions to answer about the subject's dental condition. The AIMS Movement Rating Scale score is defined as the sum of items 1 to 7 (i.e., items 1 to 4, facial and oral movements; items 5 and 6, limb movements; item 7, trunk movements).

[0031] An "antidepressant regimen" or "antidepressant therapy" refers to any drug regimen administered as a therapy for the treatment of depression and should be distinguished from augmentation therapy, which is the addition of a drug (not itself considered an antidepressant) to an antidepressant regimen to improve efficacy. Examples of drugs used to treat depression include, but are not limited to, SSRIs, SNRIs, bupropion, and mirtazapine, and pharmaceutically acceptable salts thereof.

[0032] As used herein, "anxious distress" is consistent with DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Therefore, a subject with anxious distress must have 2 of the following 5 symptoms of most major depressive episodes: 1) feeling nervous or on edge, 2) feeling unusually uneasy, 3) having trouble concentrating because of worry, 4) fear that something terrible will happen, and 5) feeling that one may lose control of oneself. 0 or 1 symptom = no anxious distress, 2 symptoms = mild anxious distress, 3 symptoms = moderate anxious distress, 4-5 symptoms = moderate to severe anxious distress (psychomotor agitation must be present).

[0033] As used herein, an "at risk" individual is an individual who is at risk of developing the disorder to be treated. This can be indicated, for example, by one or more risk factors, which are measurable parameters associated with the development of the disorder and are known in the art. When a method is said to treat a disorder without causing or inducing an adverse event, it is understood that the method can be implemented in a patient who is at risk of an adverse event.

[0034] "BARS" (Barnes Akathisia Rating Scale) is a comprehensive clinical assessment of akathisia. Barnes 1989. BARS consists of 4 items related to akathisia: the objective observation of akathisia by the investigator, the subjective discomfort of the subject, the subjective distress caused by akathisia, and a comprehensive clinical assessment of akathisia. The first 3 items are scored on a 4-point scale, where 0 represents no symptoms and 3 represents severe conditions. The comprehensive clinical assessment is performed on a 6-point scale, where 0 represents no symptoms and 5 represents severe akathisia.

[0035] The "CGI-C" (Clinical Global Impression-Change) scale measures the effectiveness of drug treatment by assessing the overall change in the subject since starting drug therapy (regardless of whether the change is entirely attributable to drug therapy). Response options include: 1 = very improved, 2 = very improved, 3 = slightly improved, 4 = no change, 5 = slightly worse, 6 = much worse, 7 = very worse.

[0036] The "CGI-S" (Clinical Global Impression-Severity) scale is a standardized, clinician-administered, global rating scale that uses a 7-point Likert scale to measure the severity of the disorder. Higher CGI-S scores represent greater severity of the disorder. To make this assessment, the rater or researcher answers the following question: "Given your overall clinical experience with this particular population, how sick is the patient at this time?" Answer options include: 1 = normal, not sick at all; 2 = borderline psychotic; 3 = mildly sick; 4 = moderately sick; 5 = markedly sick; 6 = severely sick; 7 = the sickest patient.

[0037] As used herein, the term "clinically significant" or "clinically meaningful" refers to an improvement in symptoms that is both statistically significant and meaningful from the perspective of the patient, clinician, or caregiver, typically based on a static measure (e.g., CGI-S) or a retrospective improvement assessment (e.g., 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 is understood that, in one embodiment, a treatment or benefit demonstrates a clinically significant efficacy to a statistically significant degree in a patient population.

[0038] The “CSFQ-14” is a 14-item short-form version of the CSFQ (Changing Sexual Function Questionnaire) that produces an overall measure of sexual function as well as scores on 2 sets of scales: a set of 5 scales corresponding to important dimensions of sexual function and a set of 3 scales corresponding to the three phases of the sexual response cycle. Keller 2006.

[0039] As used herein, "delaying" the development of a disorder means postponing, hindering, slowing, stabilizing and / or delaying the development of the disorder. The length of time for the delay can vary, depending on the history of the disease and / or the individual being treated.

[0040] "Depression" has the meaning commonly given to the term in the field of psychiatry, and the definition set forth in DSM-5 may be adopted. When depression is mentioned herein, it should be understood that MDD is a type of depression, and the present disclosure is more specifically directed to the treatment of MDD in all aspects.

[0041] "DSM-5" means the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Terms used herein are defined with reference to DSM-5 where necessary to give life and meaning to the term. When a person is defined herein in accordance with DSM-5, it is understood that the person does not necessarily have to have been diagnosed using the criteria in DSM-5, but if so diagnosed, the person meets the criteria set forth in DSM-5.

[0042] The "FAST" (Functional Assessment Short Test) is a 24-item questionnaire designed to assess the degree of difficulty that subjects experience in various aspects of functioning. Subjects rate their own difficulty as 0 (no difficulty), 1 (mild difficulty), 2 (moderate difficulty), and 3 (severe difficulty).

[0043] The "HAM-A" (Hamilton Anxiety Rating Scale) assesses a patient's anxiety symptoms and, in one embodiment, is conducted using the Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A). Williams 2008.

[0044] "HAM-D 17 The 17-item Hamilton Depression Rating Scale is another well-known tool for assessing the degree of depression in subjects and is conducted using the Structured Interview Guide for Hamilton Depression Rating Scale (SIGH-D). Williams 1988.

[0045] Unless otherwise specified, "inadequate response" refers to no clinically significant improvement in the subject's depressive symptoms since the start of therapy. Inadequate response is always based on an antidepressant therapy that is sufficient or therapeutically effective in an acceptable time period. In some embodiments, inadequate response is defined as a decrease in the total score of MADRS <50%, <40%, <30% or <20% since the start of therapy, and / or a CGI-C score of ≥3 since the start of therapy. In one embodiment, inadequate response is defined as a decrease in the total score of MADRS <50% since the start of therapy. In another embodiment, inadequate response is defined as a decrease in the total score of MADRS <50% and a CGI-C score of ≥3 since the start of therapy. In another embodiment, inadequate response is defined as a decrease in the total score of MADRS <50% and a CGI-C score of ≥3 since the start of therapy. In one embodiment, inadequate response is defined as an improvement in the severity of symptoms <50% according to MGH-ATRQ (Massachusetts General Hospital Antidepressant Therapy Response Questionnaire). In another embodiment, inadequate response is defined as a decrease in the total score of HAM-D17 (17 Hamilton Depression Rating Scale) <50%. In another embodiment, inadequate response is defined as a total score of HAM-D17 ≥14.

[0046] The “MADRS” (Montgomery-Asberg Depression Rating Scale) is a well-known tool for assessing the degree of depression in subjects. Montgomery 1979. MADRS consists of 10 items, each of which is scored from 0 to 6. A higher MADRS score represents a more severe depression.

[0047] The definition of a “major depressive episode” or “MDE” is consistent with that in DSM-5. Thus, (i) patients must have 5 or more depressive symptoms for ≥ 2 weeks; (ii) patients must have depressed mood or loss of interest / pleasure; (iii) symptoms must cause significant distress or impairment; and (iv) patients have never had a manic or hypomanic episode. Depressive symptoms are selected from the group consisting of: (i) depressed mood, (ii) marked decrease in interest or pleasure in most or all activities, (iii) marked weight loss (or loss of appetite) or weight gain, (iv) insomnia or hypersomnia, (v) psychomotor retardation, (vi) fatigue or lack of energy, (vii) feelings of worthlessness or excessive or inappropriate guilt, (viii) decreased ability to think or concentrate, or indecisiveness, and (ix) recurrent thoughts of death (not just fear of death) or suicidal ideation, plans, or attempts.

[0048] The "PGI-C" (Patient Global Impression-Change) scale measures the efficacy of drug treatment by evaluating the subject's overall change since starting drug therapy from the patient's perspective (regardless of whether this change is entirely attributable to drug treatment).

[0049] The "PGI-S" (Patient Global Impression-Severity) is a single-item report of the severity of a subject's symptoms. Subjects are asked: "Please select the answer below that best describes the severity of your depression over the past week." Representative answers include non-overlapping answers such as none, mild, moderate, and severe.

[0050] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0051] The term "pharmaceutically acceptable salt" as used herein refers to those salts which are suitable for use in contact with the tissues of humans and lower animals, without causing excessive toxicity, irritation, allergic reaction, etc., and which have a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of ulotaront include salts derived from suitable inorganic and organic acids and bases.

[0052] Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Although pharmaceutically acceptable counterions are often used in the preparation of pharmaceutical preparations, other anions (X) are also possible as synthetic intermediates. Thus, when these salts are chemical intermediates, X may be a pharmaceutically undesirable anion, such as iodide, oxalate, triflate, etc.

[0053] The term "pharmaceutically acceptable excipient" as used herein 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 has been approved or otherwise accepted by the U.S. Food and Drug Administration and is appropriately qualified for use in humans or livestock.

[0054] As used herein, "prevention" or "preventing" refers to a regimen that prevents the onset of a disorder so that clinical symptoms of the disorder do not develop. Thus, "prevention" involves treating a subject before signs of the disorder are detected in the subject (e.g., treating in the absence of detectable symptoms of the disorder). A subject may be an individual at risk for developing the disorder.

[0055] The "PSQI" (Pittsburgh Sleep Quality Index) consists of 19 self-rated questions and 5 questions rated by the bed partner or roommate (if any). Only the self-rated questions are scored. The 19 self-rated items are combined into 7 "sub-item" scores, each ranging from 0 to 3 points. In all cases, a score of "0" indicates no difficulty and a score of "3" indicates severe difficulty. The 7 sub-item scores are then added together to create a "total score" ranging from 0 to 21 points, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas.

[0056] Unless otherwise indicated, "remission" of MDD means that the subject no longer suffers from MDD, e.g., as defined in DSM-5. Alternatively, in other embodiments, remission can be defined based on a MADRS total score of ≤ 10 and a decrease in the MADRS total score of ≥ 50% since the start of therapy.

[0057] Unless otherwise indicated, a "response" after treatment refers to a clinically significant improvement in the subject's diagnosis since the start of therapy. Alternatively, a response can be defined as a decrease of ≥50% in the total MADRS score since the start of therapy. Alternatively, a response can be defined as a CGI-C score of 1 or 2 (very significantly improved or significantly improved) since the start of therapy. Alternatively, a response can be defined as a decrease of ≥50% in the total MADRS score since the start of therapy and a CGI-C score of 1 or 2 (very significantly improved or significantly improved).

[0058] The "SAS" (Simpson Angus Scale) consists of a list of 10 symptoms of Parkinson's disease (gait, arm drop, shoulder tremor, elbow stiffness, wrist stiffness, head rotation, glabellar tapping, tremor, salivation, and akathisia). Simpson 1970. Each item is scored on a 5-point scale, with 0 indicating no symptoms and 4 indicating severe disease. The total SAS score is the sum of the scores for all 10 items.

[0059] The "SF-36" (Short Form Survey 36) is a self-report questionnaire with a standardized recall period of 4 weeks that measures general health-related quality of life in 2 broad domains (physical and mental composite) and covers 8 health domain scales: physical functioning, pain, role physical, general health, vitality / fatigue, social functioning, role emotional, and mental health. The SF-36 uses norm-based scoring to generate scores ranging from 0 to 100, where lower scores on the physical component summary and the mental component summary represent lower health-related quality of life and 50 is referenced to normative data derived from a survey of a representative sample of the U.S. general population. In addition to the composite score and individual health domain scores, the SF-36 also provides a depression risk score and the SF-6D Health Utility Index, which ranges from 0.0 (worst measured health) to 1.0 (best measured health).

[0060] As used herein, the term "significant" refers to a statistically significant level. The statistically significant level can be p<0.1, p<0.05, p<0.01, p<0.005, or p<0.001. Unless otherwise stated, when the term "significant," "significantly," or other variants of the term are used, the statistically significant level is p<0.05. When a measurable result or effect is expressed or identified herein, it is understood that the result or effect is typically evaluated based on its statistical significance relative to a baseline (e.g., placebo). Similarly, when treatment or benefit is described herein, it is understood that treatment or benefit typically demonstrates a statistically significant effect in a patient population.

[0061] "SNRIs" (serotonin-norepinephrine reuptake inhibitors) include, but are not limited to, desvenlafaxine Duloxetine Levomilnacipran and venlafaxine and pharmaceutically acceptable salts thereof.

[0062] "SSRI" (Selective Serotonin Reuptake Inhibitors) include but are not limited to Citalopram Escitalopram Fluoxetine Paroxetine and sertraline and pharmaceutically acceptable salts thereof.

[0063] As used herein, "subjects" or "patients" contemplated for administration 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 adults, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds, such as chickens, ducks, geese, quail, and / or turkeys.

[0064] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount effective to cause a desired biological or medical response, including an amount of a compound sufficient to complete the treatment of a disorder when the compound is administered to a subject to treat the disorder. The effective amount will vary depending on the disorder and its severity, as well as the age, weight, etc. of the subject to be treated. The effective amount can be one or more doses (e.g., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint). An effective amount can be considered to be administered in an effective amount if the desired or beneficial result can be achieved or has been achieved in combination with one or more other agents. Due to the combined, additive or synergistic effects of the compounds, the appropriate dose of any co-administered compound may optionally be reduced.

[0065] The terms "treatment" and "treating" as used herein refer to reversing, alleviating, delaying the onset of a disorder or condition or one or more of its symptoms or inhibiting its progression, including but not limited to therapeutic benefits. In some embodiments, treatment is performed after the onset of one or more symptoms (e.g., acute exacerbation of symptoms). In some embodiments, treatment can be performed in the absence of symptoms. For example, the subject can be treated before the onset of symptoms (e.g., according to a history of symptoms and / or according to genetic or other predisposing factors). Treatment can also be continued after the symptoms subside, for example to prevent or delay their recurrence.

[0066] When treatment with two different drugs is described herein, it is understood that the drugs will be administered simultaneously according to a concurrent dosing regimen that may differ in the frequency or timing of administration. Two drugs do not necessarily have to be administered at the same time to be considered concurrent administration. For example, concurrent administration may include one drug being administered three times per day and one drug being administered once per day.

[0067] A therapeutic benefit includes eradication and / or amelioration of the underlying disorder being treated; it also includes eradication and / or amelioration of one or more symptoms associated with the underlying disorder such that improvement is observed in the subject, notwithstanding that the subject may still be suffering from the underlying disorder.

[0068] In some embodiments, "treating" includes one or more of the following: (a) inhibiting the disorder (e.g., reducing one or more symptoms caused by the disorder, and / or lessening the extent of the disorder); (b) slowing or arresting 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., causing clinical regression of symptoms, improving the disorder, delaying the progression of the disorder, and / or improving the quality of life.)

[0069] "Treatment-resistant depression" or "treatment failure" has the same clinical criteria and will adopt the US FDA regulatory definition of this term unless otherwise specified in this article, which is the lack of clinically meaningful improvement (MADRS total score ≤ 25%) in the current depressive episode after treatment with at least 2 different antidepressants at adequate doses for an adequate period of time (at least 6 weeks). Alternatively, the term can be defined as an improvement of ≤ 25% in the MADRS total score over 2 or 3 prior antidepressants despite adequate doses and duration, as documented by the Massachusetts General Hospital Antidepressant Therapy Response Questionnaire (ATRQ).

[0070] The "Ulotaront" referred to herein for use in the disclosed methods 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:

[0071]

[0072] Unless otherwise indicated, or unless the context requires otherwise, for purposes of the present disclosure, the term "ulotaront" alone includes the free form of ulotaront, as well as its pharmaceutically acceptable salts, hydrates, solvates, amorphous and crystalline forms. When the free form or any other form or salt is intended, this will be clearly indicated.

[0073] Ulotaront can be used in the methods described herein in the form of a free base (free form) or a pharmaceutically acceptable salt. In some embodiments, the hydrochloric acid (HCl) salt of ulotaront is used in the methods described herein. Ulotaront or its pharmaceutically acceptable salt (including its HCl crystalline form) can be obtained according to the production method described in PCT Patent Publication No. WO2011 / 069063 (U.S. Patent No. 8,710,245, authorized on April 29, 2014) or PCT Patent Publication No. WO2019 / 161238, which are incorporated herein by reference in their entirety and for all purposes, or obtained according to methods similar thereto.

[0074] Also provided herein are pharmaceutical compositions and dosage forms comprising ulotaront or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The compositions and dosage forms provided herein may also comprise one or more other active ingredients. Ulotaront or a pharmaceutically acceptable salt thereof may be administered as part of a pharmaceutical composition described herein.

[0075] discuss

[0076] In one embodiment, the present disclosure provides a method of adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof who has demonstrated an inadequate response to antidepressant therapy (e.g., after at least 8 weeks of antidepressant therapy), comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

[0077] In another embodiment, the present disclosure provides a method of adjunctive treatment of a subject with treatment-resistant depression comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

[0078] In another embodiment, the disclosure provides a method for treating a subject with depression, comprising administering a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has an insufficient response to antidepressant therapy, and insufficient response is defined as a decrease in the total MADRS score of <50% since the start of therapy. In one embodiment, the method assists an antidepressant regimen including antidepressant therapy for subjects who show insufficient response to antidepressant therapy (e.g., after at least eight weeks of antidepressant therapy). In another embodiment, insufficient response is further defined as a CGI-C score of ≥3 since the start of therapy.

[0079] In another embodiment, the present disclosure provides a method of treating a subject suffering from depression (eg, MDD) comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and an antidepressant therapy.

[0080] In any embodiment of the present disclosure, the antidepressant therapy comprises an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin-norepinephrine reuptake inhibitor). In some embodiments, the antidepressant therapy comprises an SSRI selected from escitalopram 10 to 20 mg / day, fluoxetine 20 to 60 mg / day, paroxetine 25 to 62.5 mg / day, or sertraline 50 to 200 mg / day; or an SNRI selected from duloxetine 30 to 60 mg / day and venlafaxine 37.5 to 225 mg / day. The above therapies are generally considered "adequate therapies" when tailored to a particular subject. In any embodiment of the present disclosure, the subject exhibits an inadequate response or treatment failure to the antidepressant therapy mentioned in this paragraph.

[0081] Any embodiment currently disclosed may be further defined by the subject to be treated. Therefore, in one embodiment, the subject suffers from a major depressive episode (MDE), for example, as defined by DSM-5. MDE can have different lengths, including a duration of ≥4 weeks, ≥8 weeks, or ≥26 weeks. In some embodiments, the MDE duration is ≥8 weeks and the duration is ≤52 weeks. In another embodiment, the subject is in a current major depressive episode (MDE), as defined by the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria and can be confirmed by the Massachusetts General Hospital Antidepressant Therapy Response Questionnaire (MGH-ATRQ).

[0082] In another embodiment, the subject is characterized by an inadequate response to at least 1 and no more than 3 adequate antidepressant therapies (ADT) during the current MDE. In some embodiments, the antidepressant therapy comprises an SSRI or SNRI, or one of the therapies mentioned herein.

[0083] In other embodiments, the subject is characterized by his or her level of depression prior to ADT. Thus, in another embodiment, the subject has a 17-item Hamilton Depression Rating Scale (HAM-D17) total score of ≥18 prior to ADT, but optionally ≥14, ≥16, ≥20, or ≥22.

[0084] In a further embodiment, treated subjects will meet all three of the above requirements prior to ADT: MDE status for at least 8 weeks, inadequate response to prior antidepressant therapy, and HAM-D17 total score ≥18.

[0085] In other embodiments, the subject has an inadequate response after at least 8 weeks of antidepressant therapy, defined as: (a) a decrease in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of <50%; or (b) a HAM-D17 total score ≥14; or (c) a CGI-C (Clinical Global Impression-Change) scale score ≥3; or (d) a decrease in the MADRS (Montgomery Asberg Depression Rating Scale) total score of <50%; or (e) a combination of any two or more of (a)-(d).

[0086] Other embodiments are defined according to the patient's treatment response measured by MADRS. Thus, in one embodiment, an inadequate response is defined as a decrease in the MADRS total score of ≤25%. In another embodiment, an inadequate response is defined as a decrease in the MADRS total score of <50% and >25%.

[0087] Still other embodiments are particularly applicable to subjects suffering from anxiety-related distress and based on the subject's level of anxiety. Thus, any of the methods disclosed herein can be practiced in patients suffering from anxiety-related distress (as defined in DSM 5).

[0088] The methods of the present disclosure can also be defined according to the dose of ulotaront administered. Thus, in one embodiment, the therapeutically effective amount comprises 10 to 150 mg, 15 to 125 mg, 25 to 100 mg, 25 to 75 mg, or 50 to 100 mg of ulotaront or a pharmaceutically acceptable salt thereof, based on the weight of ulotaront in free form. In another embodiment, the therapeutically effective amount comprises 50 or 75 mg of ulotaront or a pharmaceutically acceptable salt thereof, based on the weight of ulotaront in free form. In a further embodiment, the therapeutically effective amount comprises 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of ulotaront or a pharmaceutically acceptable salt thereof, based on the weight of ulotaront in free form.

[0089] In any of these embodiments, the therapeutically effective amount of ulotaront is administered once daily for a period of at least six weeks.

[0090] The methods of the present disclosure can be further defined based on their effects on the disease. Thus, any method of the present disclosure can produce relief from depression, including relief from depression, wherein depression is defined according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).

[0091] Any method disclosed herein can further produce the average change of the Montgomery-Asberg Depression Rating Scale of the experimenter.In various embodiments, these methods can make the MADRS total score drop more than ≥1, ≥2, ≥3, ≥4 or ≥5 points more than the antidepressant therapy alone.In other embodiments, the treatment improves the MADRS total score of the experimenter.In other embodiments, the treatment improves the CGI-S score of the experimenter by ≥2, ≥3 or ≥4 points.In further embodiments, the treatment makes the MADRS total score and CGI-S score of the experimenter produce clinically significant improvement.

[0092] Other embodiments may be defined based on alternative endpoints.Thus, in various embodiments, the method improves a subject's FAST (Functional Assessment Short Test) score.

[0093] In a further embodiment, the method improves the subject's PGI-S (Patient Global Impression-Severity) score.

[0094] In other embodiments, the method improves the subject's SF-36 (36-Item Brief Survey) score.

[0095] In a further embodiment, the method improves the subject's HAM-A (Hamilton Anxiety Rating Scale) total score.

[0096] In a further embodiment, the method improves the subject's HAM D17 (17-item Hamilton Depression Rating Scale) total score.

[0097] In other embodiments, the method produces a CGI-C (Clinical Global Impression - Change) score of 1 or 2 (Very Improved or Much Improved).

[0098] In further embodiments, the method reduces the subject's MADRS total score by ≥ 50%.

[0099] In a further embodiment, the method reduces the subject's MADRS total score to ≤10.

[0100] In another embodiment, the method reduces the subject's MADRS total score to ≤ 10 and reduces the subject's MADRS total score by ≥ 50%.

[0101] The method can also be defined according to its administration time, usually improving the depressive symptoms of the subject at least before the end of this time. Therefore, any embodiment of the present disclosure can be practiced by applying ulotaront or a pharmaceutically acceptable salt and improving the depressive symptoms of the subject within the effective treatment time, and the effective treatment time is 6 weeks or longer, 8 weeks or longer, 12 weeks or longer, 18 weeks or longer, 26 weeks or longer or 52 weeks or longer. Improvement is such as a decline in the MADRS score of the subject (i.e., a decline of ≥25%, a decline of ≥40% or a decline of ≥50%), a MADRS total score of ≤14, ≤12, ≤10 or ≤8, or a combination of a decline in the score and an absolute total score, such as a decline of ≤50% and a total score of ≤10.

[0102] In another embodiment, the improvement is demonstrated by a decrease in the subject's MADRS score of ≥50%, resulting in a MADRS total score of ≤10, and the treatment effect is observed for at least 26 weeks.

[0103] The method of the present disclosure can also be defined according to its excellent side effect profile. Therefore, in various embodiments, the method does not cause clinically significant deterioration in the following aspects of the subject: (a) abnormal involuntary movement, such as measured by AIMS (abnormal involuntary movement scale); or (b) akathisia, for example, as measured by BARS (Barnes akathisia rating scale); or (c) sexual function, for example, as measured by CSFQ-14 (Sexual Function Change Questionnaire, Short Form); or (d) suicidal tendency, for example, as measured by C SSRS (Columbia Suicide Severity Rating Scale); or (e) Parkinson's disease, for example, as measured by SAS (Simpson Angus Scale); or (f) sleep quality, for example, as measured by PSQI (Pittsburgh Sleep Quality Index); or (g) any combination of two or more of (a)-(f).

[0104] Although these methods have an excellent side effect profile, any potential side effects are optionally monitored for occurrence. In some embodiments, these methods further include monitoring for CNS (central nervous system) stimulation, including agitation, restlessness, insomnia, depression (including lethargy, somnolence, and shallow breathing), impaired muscle coordination, affected heart rate, and changes in pupil size.

[0105] Certain aspects of the present disclosure may be defined based on the following embodiments AA to BW:

[0106] [Embodiment AA] A method for adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof who has demonstrated an inadequate response to antidepressant therapy, comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

[0107] [Embodiments AB] A method of adjunctive treatment of a human subject suffering from treatment-resistant depression, comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

[0108] [Embodiment AC] The method of Embodiment AB, wherein refractory depression is defined as failure to respond to more than one antidepressant therapy.

[0109] [Embodiment AD] The method of Embodiment AA, wherein an inadequate response is defined as a <50% decrease in depressive symptom severity after at least 8 weeks of antidepressant therapy, as assessed by the Massachusetts General Hospital Antidepressant Therapy Response Questionnaire (MGH-ATRQ).

[0110] [Embodiments AE] A method of treating a human subject suffering from depression, comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the subject has an inadequate response to antidepressant therapy, an inadequate response being defined as a decrease in MADRS total score of <50% since initiation of antidepressant therapy.

[0111] [Embodiments AF] A method of treating a human subject suffering from depression, comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof, wherein the subject has had an inadequate response to antidepressant therapy, an inadequate response being defined as a <50% decrease in MADRS total score since initiation of antidepressant therapy and a CGI-C score ≥3 since initiation of treatment.

[0112] [Embodiment AG] The method of Embodiment AE or AF, wherein the method is adjunctive to an antidepressant regimen comprising antidepressant therapy for a human subject in need thereof who has demonstrated an inadequate response to antidepressant therapy.

[0113] [Embodiment AH] The method of any one of Embodiments AA-AG, wherein the antidepressant therapy comprises an SSRI (selective serotonin reuptake inhibitor) or a SNRI (serotonin-norepinephrine reuptake inhibitor).

[0114] [Embodiment AI] The method of any one of Embodiments AA-AG, wherein the antidepressant therapy comprises an SSRI selected from escitalopram 10 to 20 mg / day, fluoxetine 20 to 60 mg / day, paroxetine 25 to 62.5 mg / day, and sertraline 50 to 200 mg / day; or an SNRI selected from duloxetine 30 to 60 mg / day and venlafaxine 37.5 to 225 mg / day.

[0115] [Embodiment AJ] The method of any one of Embodiments AA, AD, AH, and AI, wherein an inadequate response is defined as a decrease in MADRS total score of <50% since the start of therapy.

[0116] [Embodiment AK] The method of any one of Embodiments AA, AD, AH, and AI, wherein an inadequate response is defined as a CGI-C score of ≥ 3 since the start of therapy.

[0117] [Embodiment AL] The method of any of Embodiments AA and AD-AI, wherein an inadequate response is defined as: (a) (i) a decrease in the total score of HAM-D17 (17-item Hamilton Depression Rating Scale) of <50% or (ii) a total score of HAM-D17 ≥14; and (b) a CGI-C (Clinical Global Impression-Change) scale score of ≥3; and (c) a decrease in the total score of MADRS (Montgomery Asberg Depression Rating Scale) of <50%.

[0118] [Implementation Option AM] The method of any one of Implementation Options AA and AD-AI, wherein an inadequate response is defined as: (a) a decrease in the total score of HAM-D17 (17-item Hamilton Depression Rating Scale) of <50%; and (b) a total score of HAM-D17 ≥14; and (c) a CGI-C (Clinical Global Impression-Change) scale score of ≥3; and (d) a decrease in the total score of MADRS (Montgomery Asberg Depression Rating Scale) of <50%.

[0119] [Embodiment AN] The method of any one of Embodiments AA and AD-AM, wherein the subject has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score ≥ 18 before antidepressant therapy, and an inadequate response is defined as, after at least 8 weeks of antidepressant therapy: (a) a decrease in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of <50%; or (b) a HAM-D17 total score of ≥14; or (c) a CGI-C (Clinical Global Impression-Change) scale score of ≥3; or (d) a decrease in the MADRS (Montgomery Asberg Depression Rating Scale) total score of <50%; or (e) a combination of (a)-(d).

[0120] [Embodiment AO] The method of any one of Embodiments AA and AD-AM, wherein the subject has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score ≥ 18 before antidepressant therapy, and an inadequate response is defined as, after at least 8 weeks of antidepressant therapy: (a) a decrease in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of <50%; and (b) a HAM-D17 total score of ≥14; and (c) a CGI-C (Clinical Global Impression-Change) scale score of ≥3; and (d) a decrease in the MADRS (Montgomery Asberg Depression Rating Scale) total score of <50%.

[0121] [Embodiment AP] The method of any one of Embodiments AA-AO, wherein the subject is in a current major depressive episode (MDE) as defined by DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria.

[0122] [Implementation AQ] The method of any one of implementations AA-AO, wherein the subject is in a current major depressive episode (MDE), as defined by DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria, lasting ≥ 8 weeks.

[0123] [Embodiment AR] The method of any of Embodiments AA-AQ, comprising administering ulotaront or a pharmaceutically acceptable salt thereof and improving the subject's depressive symptoms for a therapeutically effective period of time, wherein the therapeutically effective period is 6 weeks or longer, 8 weeks or longer, 12 weeks or longer, 26 weeks or longer, or 52 weeks or longer.

[0124] [Embodiment AS] The method of any one of Embodiments AA-AR, wherein the therapeutically effective amount comprises 25 to 100 mg of ulotaront or a pharmaceutically acceptable salt thereof based on the weight of ulotaront in free form.

[0125] [Embodiment AT] The method of any one of Embodiments AA-AR, wherein the therapeutically effective amount comprises 50 or 75 mg ulotaront or a pharmaceutically acceptable salt thereof based on the weight of ulotaront in free form.

[0126] [Embodiment AU] The method of any of Embodiments AA and AD-AT, wherein the subject has demonstrated an inadequate response after at least eight weeks of antidepressant therapy.

[0127] [Embodiment AV] The method of any one of Embodiments AA-AU, comprising administering ulotaront or a pharmaceutically acceptable salt thereof for a period of at least six weeks.

[0128] [Embodiment AW] The method of any one of Embodiments AA-AV, wherein the method increases the subject's Montgomery-Asberg Depression Rating Scale total score by ≥1, ≥2, ≥3, or ≥4 points compared to antidepressant therapy alone.

[0129] [Embodiment AX] The method of any one of Embodiments AA-AW, wherein the method results in relief of depression.

[0130] [Embodiment AY] The method of any one of Embodiments AA-AW, wherein the method produces remission of depression as defined in DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).

[0131] [Embodiments AZ] The method of any one of Embodiments AA-AY, wherein the method improves the subject's MADRS (Montgomery Asberg Depression Rating Scale) total score.

[0132] [Embodiment BA] The method of any one of Embodiments AA-AZ, wherein the method improves the subject's CGI-S (Clinical Global Impression-Severity) score by ≥2, ≥3, or ≥4 points.

[0133] [Embodiment BB] The method of any one of Embodiments AA-BA, wherein the method produces clinically significant improvements in the subject's MADRS (Montgomery Asberg Depression Rating Scale) total score and CGI-S (Clinical Global Impression-Severity) score.

[0134] [Embodiment BC] The method of any one of Embodiments AA-BB, wherein the method improves the subject's FAST (Functional Assessment Short Test) score or PGI-S (Patient Global Impression-Severity) score.

[0135] [Embodiment BD] The method of any one of Embodiments AA-BC, wherein the subject suffers from anxiety-related distress as defined in DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).

[0136] [Embodiment BE] The method of any one of Embodiments AA-BD, wherein the method improves the subject's SF-36 (36-item Brief Survey) score.

[0137] [Embodiments BF] The method of any one of Embodiments AA-BE, wherein the method improves the subject's HAM-A (Hamilton Anxiety Rating Scale) total score.

[0138] [Embodiment BG] The method of any one of Embodiments AA-BF, wherein the method improves the subject's HAMD17 (17-item Hamilton Depression Rating Scale) total score.

[0139] [Embodiment BH] The method of any one of Embodiments AA-BG, wherein the method produces a CGI-C (Clinical Global Impression - Change) score of 1 or 2 (very improved or much improved).

[0140] [Embodiment BI] A method as described in any of embodiments AA-BH, wherein the method reduces the subject's MADRS total score by ≥50%.

[0141] [Embodiment BJ] The method of any one of embodiments AA-BI, wherein the method reduces the subject's total MADRS score to ≤10.

[0142] [Embodiment BK] The method of any one of Embodiments AA-BJ, wherein the method reduces the subject's MADRS total score to ≤ 10 and reduces the subject's MADRS total score by ≥ 50%.

[0143] [Embodiment BL] The method of any one of Embodiments AA-BK, wherein the method does not result in a clinically significant deterioration in the subject's abnormal involuntary movements as measured by AIMS (Abnormal Involuntary Movement Scale); or akathisia as measured by BARS (Barnes Akathisia Rating Scale); or sexual function as measured by CSFQ-14 (Sexual Function Change Questionnaire, Short Form); or suicidal tendencies as measured by C SSRS (Columbia Suicide Severity Rating Scale); or Parkinson's disease as measured by SAS (Simpson Angus Scale); or sleep quality as measured by PSQI (Pittsburgh Sleep Quality Index); or any combination thereof.

[0144] [Embodiment BM] The method of any one of Embodiments AA-BK, wherein the method does not result in clinically significant sedation, symptoms of metabolic syndrome (e.g., weight gain, diabetes, hyperlipidemia), or movement disorders.

[0145] [Embodiment BN] The method of any one of Embodiments AA-BL further comprises monitoring CNS (central nervous system) stimulation, including agitation, restlessness, insomnia, depression (including drowsiness, narcolepsy and shallow breathing), impaired muscle coordination, affected heart rate and changes in pupil size.

[0146] [Embodiment BO] A method of treating a subject suffering from depression (eg, MDD) comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and an antidepressant therapy.

[0147] [Embodiment BP] The method of Embodiment BO, wherein the antidepressant therapy comprises a therapeutically effective amount of an SSRI (selective serotonin reuptake inhibitor) or a SNRI (serotonin-norepinephrine reuptake inhibitor).

[0148] [Embodiment BQ] The method of Embodiment BO, wherein the antidepressant therapy comprises an SSRI selected from escitalopram (e.g., 10 to 20 mg / day), fluoxetine (e.g., 20 to 60 mg / day), paroxetine (e.g., 25 to 62.5 mg / day), or sertraline (e.g., 50 to 200 mg / day); or an SNRI selected from duloxetine (e.g., 30 to 60 mg / day) and venlafaxine (e.g., 37.5 to 225 mg / day).

[0149] [Embodiment BR] The method of any one of Embodiments AA-BQ, wherein the patient has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score of ≥14, ≥16, or ≥18 before ulotaront treatment.

[0150] [Implementation BS] The method of any one of implementations AA-BR, wherein the patient has a total score of MADRS (Montgomery-Asberg Depression Rating Scale) ≥20, ≥22, ≥24, ≥26, ≥28, ≥30, ≥32 or ≥34 before ulotaront treatment.

[0151] [Embodiment BT] The method of any one of Embodiments AA, and AD-BS, wherein inadequate response is defined as treatment failure.

[0152] [Embodiment BU] The method of any of Embodiments AA and AD-BS, wherein the patient does not suffer from treatment-resistant depression.

[0153] [Embodiment BV] The method of any one of Embodiments AA and AD-BS, wherein an inadequate response is defined as a decrease in the MADRS total score of ≤ 25%.

[0154] [Embodiments B-W] The method of any one of Embodiments AA and AD-BS, wherein an inadequate response is defined as a decrease in the MADRS total score of <50% and >25%. Example

[0155] In the following examples, we have tried to ensure accuracy of the numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be taken into account. The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to perform and evaluate the methods claimed herein, and are intended to be exemplary of the disclosure only and are not intended to limit the scope of what the inventors consider their disclosure.

[0156] Example 1. Effect of Ulotaront combined with antidepressants in the forced swim test in mice

[0157] Ulotaront was evaluated in the mouse forced swim test (FST), in which mice are placed in a small water tank from which they cannot escape, and their behavior is monitored. Acute administration of all major classes of commercially available antidepressants shortens immobility time in this test.

[0158] These specific FST studies were conducted in male Swiss mice (5-6 weeks old, n=10 per group) and included mice coadministered with imipramine, fluoxetine, paroxetine, venlafaxine, or citalopram. A single dose of ulotaront (0.3, 1, 3, or 10 mg / kg, po) did not significantly alter immobility time nor enhance the antidepressant activity of imipramine, fluoxetine, paroxetine, venlafaxine, or citalopram following single-dose coadministration.

[0159] These results contrast with the FST results of male BalbC / J mice reported by Dedic 2019. Male BalbC / J mice (6 weeks old, n=8 per group) received a single dose of vehicle (po), ulotaront (0.3, 1, 3 or 10 mg / kg, po) or sertraline (20 mg / kg, ip) as a positive control. Ulotaront treatment significantly shortened the immobility time at doses of 1, 3 and 10 mg / kg, reaching the maximum effect at the 1 mg / kg dose level. The results showed that ulotaront exhibited antidepressant-like effects in the mouse FST, but this effect was strain-specific. It has been reported that different mouse strains also have different sensitivities to known antidepressant drugs (Lucki 2001; David 2003).

[0160] Example 2. Effect of Ulotaront in the Rat Forced Swim Test

[0161] The antidepressant-like effects of ulotaront were also examined in the rat FST test using two different dosing regimens. In both procedures, rats were pre-trained for 15 minutes of swimming (day 0) before a 5-minute FST performed 24 hours later (day 1).

[0162] In the first study, adult male Wistar rats (206-260 g; n = 12 per group) received the designated treatments three times, 24 hours (i.e., immediately pre-swim), 4 hours, and 1 hour before testing. Treatment groups were as follows: vehicle (po), ulotaront (0.3, 1, 3, or 10 mg / kg po), or imipramine (64 mg / kg, po) as a positive control. An observer blinded to treatment conditions recorded the immobility time during the 5-min test, and the results were analyzed by one-way ANOVA with Dunnett's post hoc comparisons. Ulotaront significantly reduced the immobility time at a dose of 3 mg / kg (po) compared to the vehicle-treated control group.

[0163] In the second study, adult male Sprague-Dawley rats (190-234 g, n = 10 per group) were dosed only once, pre-swimming, 24 hours before testing. This dosing regimen has been used to show antidepressant-like effects of acute ketamine treatment, while other drug classes (e.g., SSRIs and tricyclics) are generally ineffective (Ardalan 2017; Cryan 2005; Koike 2014). Rats were treated with vehicle (po), ulotaront (0.3, 1, 3, or 10 mg / kg, po), or ketamine (10 mg / kg, ip) as a positive control. During the 5-min test period, behavior was quantified using a time sampling technique, in which the actual behavior observed, i.e., immobility, climbing, or swimming, was recorded every 5 seconds for a total of 60 observations. Results were analyzed by one-way ANOVA with Dunnett post hoc comparisons.

[0164] Ulotaront significantly decreased immobility frequency at all doses tested (Table 1). The magnitude of the effect was similar to that seen in rats treated with ketamine and was associated with a significant increase in swimming behavior.

[0165] Table 1

[0166]

[0167]

[0168] a p<0.05 compared with vehicle (one-way ANOVA with Dunnett's post hoc test)

[0169] Example 3: Effect of Ulotaront in the Rat Learned Helplessness Model

[0170] Ulotaront has been evaluated in a rat model of learned helplessness, which assesses loss of behavioral control over an aversive situation and responds to antidepressant therapy (Willner 2015). In this model, rats first receive an inescapable foot shock to induce a state of helplessness and subsequently display an inability to learn to escape an escapable foot shock (active avoidance). Treatment with established antidepressants (usually in a subchronic regimen) reduces the number of escape failures in helpless rats.

[0171] Adult male Wistar rats (186-262 g; n = 16-17 per group) were randomly assigned to 6 different groups. On day 1, animals in 5 groups were exposed to an inevitable foot shock every 15 seconds for 1 hour through an electrified stainless steel grid floor to induce helplessness. The remaining group did not receive the inevitable shock and served as a non-helpless control group. Approximately 6 hours after the induction of helplessness on day 1, rats were given oral (po) vehicle, the tricyclic antidepressant imipramine (32 mg / kg) or ulotaront (1, 3 or 10 mg / kg). Treatment continued on days 2-5, with all subjects receiving the test drug or vehicle twice a day (morning and afternoon). Active avoidance was tested 60 minutes after the morning dosing on days 3, 4 and 5. All rats were tested in a 2-chamber active avoidance chamber, in which the foot shock signal was issued by a light cue. The test session began with 5 minutes of free exploration, followed by 30 stimulus-shock trials in 15 minutes. Each trial lasted 30 s, with an initial 24 s rest period, followed by a 6 s presentation of the light cue, and a final 3 s delivery of the foot shock. Crossing to the opposite compartment within the first 3 s of the light cue avoided the shock and was considered active avoidance. Failure to completely avoid the foot shock (i.e., failure to cross during the 3 s shock period) was considered an escape failure. Crossing the opposite compartment of the shuttle box during the 24 s rest period was recorded as an inter-trial interval (ITI) crossing. Escape failures and ITI crossings were analyzed by two-way repeated measures ANOVA with treatment as the main factor and testing time (i.e., day) as the repeated measure. Significant ANOVA results were followed by Dunnett's post hoc analysis, comparing to helpless rats receiving vehicle treatment to examine the effect of treatment during each test period.

[0172] Ulotaront dose-dependently reduced the number of escape failures in helpless rats, with significant effects observed at 10 mg / kg orally on test days 4 and 5. A significant reduction in the number of escape failures was also observed in rats treated with imipramine (Table 2).

[0173] Table 2

[0174]

[0175] a p<0.05 vs. helpless / vehicle

[0176] Analysis of ITI passage on test days 3, 4, and 5 showed that ITI passage in non-helpless rats was not significantly different from that in the helpless control group (Table 3). Treatment with 10 mg / kg ulotaront significantly increased ITI passage on day 5 compared with the helpless, vehicle-treated control group, but had no effect on ITI passage on days 3 and 4. This suggests that the interpretation of the antidepressant-like effects of ulotaront on day 4 is not confounded by effects on locomotor activity.

[0177] Table 3

[0178]

[0179] a p<0.05 vs. helpless / vehicle

[0180] The results showed that ulotaront exhibited antidepressant-like activity in the rat learned helplessness model.

[0181] Example 4: Phase 2 / 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Flexible Dosing Ulotaront as Adjunctive Therapy in Adult Patients with Major Depressive Disorder

[0182] This is a Phase 2 / 3, multicenter, randomized, double-blind, placebo-controlled, flexible-dose trial designed to evaluate the safety and efficacy of ulotaront (50 to 75 mg / day) as adjunctive therapy to assigned open-label antidepressant therapy (ADT) in patients with MDD who have demonstrated an inadequate response to a prospective 8-week trial of the same assigned open-label ADT.

[0183] The trial population will include subjects aged 18 to 65 years at the time of informed consent, with a primary diagnosis of MDD and in a current major depressive episode (MDE) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the MGH-ATRQ. The current MDE must last ≥ 8 weeks. In addition, subjects must report a history of current MDE that is inadequately responded to at least 1 and no more than 3 adequate ADTs. Subjects will have a score of 1 on the 17-item Hamilton Depression Rating Scale (HAM-D) at screening and baseline visits. 17 )The total score must also be ≥18.

[0184] The primary objective of this study is to compare the efficacy of ulotaront (50 to 75 mg / day) versus placebo as an adjunct to assigned open-label ADT in subjects with MDD who have demonstrated an inadequate response to a prospective 8-week trial of the same assigned open-label ADT. Primary efficacy will be assessed by the change in MADRS total score from the end of period A (week 8 visit) to the end of period B (week 14 visit). Efficacy will also be assessed by the change in CGIS from the end of period A (week 8 visit) to the end of period B (week 14 visit), among others.

[0185] References

[0186] American Psychiatric Association practice guideline for treatment of patients with major depressive disorder,third edition[online].Available fromURL:http: / / www.psy chiatryonline.com / pracGuide / pracGuideTopic_7.aspx[Accessed2022Jul 17].

[0187] Ardalan M, Rafati AH, Nyengaard JR, Wegener G. Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. Br J Pharmacol 2017;174:483–492.

[0188] Barnes TR.A rating scale for drug-induced akathisia.Br JPsychiatry.1989;154:672 676.

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[0211] In this application, various publications are cited. The disclosures of these publications are hereby incorporated by reference into this application to more fully describe the prior art to which the present disclosure relates. It will be clear to those skilled in the art that various modifications and variations may be made to the present disclosure without departing from the scope or spirit of the present disclosure. Other embodiments of the present disclosure will be clearly understood by those skilled in the art from the practice of the specification and disclosure disclosed herein. The specification and examples are to be regarded as exemplary only, and the true scope and spirit of the present disclosure are indicated by the following claims.

Claims

1. A method of adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof who has demonstrated an inadequate response to an antidepressant therapy, comprising administering to the subject said antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein an inadequate response is defined as a <50% decrease in depressive symptom severity after at least 8 weeks of antidepressant therapy, as assessed by the Massachusetts General Hospital Antidepressant Therapy Response Questionnaire (MGH-ATRQ).

3. The method of claim 1, wherein the antidepressant therapy comprises an SSRI (selective serotonin reuptake inhibitor) or a SNRI (serotonin-norepinephrine reuptake inhibitor).

4. The method of claim 1, wherein the antidepressant therapy comprises: a) an SSRI selected from escitalopram 10 to 20 mg / day, fluoxetine 20 to 60 mg / day, paroxetine 25 to 62.5 mg / day, and sertraline 50 to 200 mg / day; or b) a SNRI selected from duloxetine 30 to 60 mg / day and venlafaxine 37.5 to 225 mg / day.

5. The method of claim 1, wherein: a) Subjects suffered from major depressive episode (MDE); b) the subject has a history of current MDE that has been inadequately responsive to at least 1 and no more than 3 adequate antidepressant therapies (ADT); and c) The subjects' 17-item Hamilton Depression Rating Scale (HAM-D 17 )Total score ≥18.

6. The method of claim 1, wherein an inadequate response is defined as, after at least 8 weeks of antidepressant therapy: a) (i) HAM-D17 (17-item Hamilton Depression Rating Scale) total score decreased by <50%; or (ii) HAM-D17 total score ≥14; b) CGI-C (Clinical Global Impression-Change) scale score ≥ 3; and c) MADRS decrease <50%.

7. The method of claim 1, wherein an inadequate response is defined as, after at least 8 weeks of antidepressant therapy: a) The total score of HAM-D17 (17-item Hamilton Depression Rating Scale) decreased by <50%; b) HAM-D17 total score ≥14; c) CGI-C (Clinical Global Impression-Change) scale score ≥ 3; and d) MADRS total score decreased by <50%.

8. The method of any one of claims 1-7, wherein an inadequate response is defined as a reduction in the MADRS total score of <50% and >25%.

9. The method of claim 1, wherein the subject suffers from anxiety-related distress.

10. The method of claim 1, comprising administering ulotaront or a pharmaceutically acceptable salt thereof and improving the subject's depressive symptoms for a therapeutically effective period of time, wherein the therapeutically effective period is 6 weeks or more, 8 weeks or more, 12 weeks or more, 26 weeks or more, or 52 weeks or more.

11. The method of claim 1, wherein the therapeutically effective amount comprises 25 to 100 mg of ulotaront or a pharmaceutically acceptable salt thereof based on the weight of ulotaront in free form.

12. The method of claim 1, wherein the therapeutically effective amount comprises 50 or 75 mg of ulotaront or a pharmaceutically acceptable salt thereof based on the weight of ulotaront in free form.

13. The method of claim 1, wherein the subject has demonstrated an inadequate response after at least eight weeks of antidepressant therapy.

14. The method of claim 1, comprising administering ulotaront or a pharmaceutically acceptable salt thereof for a period of at least six weeks.

15. The method of claim 1, wherein the method produces relief from depression.

16. The method of claim 1, wherein the method produces relief from depression as defined by DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).

17. The method of claim 1, wherein the method improves the subject's MADRS total score.

18. The method of claim 1, wherein the method reduces the subject's MADRS total score by ≥ 1, ≥ 2, ≥ 3, or ≥ 4 points more than antidepressant therapy alone.

19. The method of claim 1, wherein the method improves the subject's CGI-S (Clinical Global Impression - Severity) score by ≥2, ≥3, or ≥4 points.

20. The method of claim 1, wherein the method produces a clinically significant improvement in the subject's MADRS (Montgomery Asberg Depression Rating Scale) total score and CGI-S (Clinical Global Impression-Severity) score.

21. The method of claim 1, wherein the method improves the subject's FAST (Functional Assessment Short Test) score.

22. The method of claim 1, wherein the method improves the subject's PGI-S (Patient Global Impression-Severity) score.

23. The method of claim 1, wherein the method improves the subject's SF-36 (36-item Brief Survey) score.

24. The method of claim 1, wherein the method improves the subject's HAM-A (Hamilton Anxiety Rating Scale) total score.

25. The method of claim 1, wherein the method improves the subject's HAM-D17 (17-item Hamilton Depression Rating Scale) total score.

26. The method of claim 1, wherein the method produces a CGI-C (Clinical Global Impression - Change) score of 1 or 2 (Very Improved or Much Improved).

27. The method of claim 1, wherein the method reduces the subject's MADRS total score by ≥ 50%.

28. The method of claim 1, wherein the method reduces the subject's MADRS total score to ≤ 10.

29. The method of claim 1, wherein the method reduces the subject's MADRS total score to ≤ 10 and reduces the subject's MADRS total score by ≥ 50%.

30. The method of claim 1, wherein the method does not result in a clinically significant worsening of: a) abnormal involuntary movements measured by AIMS (Abnormal Involuntary Movement Scale); b) akathisia, as measured by BARS (Barnes Akathisia Rating Scale); c) sexual function measured by CSFQ-14 (Changes in Sexual Function Questionnaire, short form); d) suicidal tendencies measured by C-SSRS (Columbia-Suicide Severity Rating Scale); e) Parkinson's disease measured by SAS (Simpson Angus Scale); f) sleep quality as measured by the PSQI (Pittsburgh Sleep Quality Index); or g) Any combination of two or more of (a) to (f).

31. The method of claim 1, wherein the method does not result in clinically significant sedation, symptoms of metabolic syndrome selected from weight gain, diabetes and hyperlipidemia, or movement disorders.

32. The method of claim 1, further comprising monitoring for signs of: i) CNS (central nervous system) stimulation, including agitation, restlessness and / or insomnia; ii) depression, including sleepiness, drowsiness and / or shallow breathing; or iii) Impaired muscle coordination, affected heart rate and / or changes in pupil size.

33. The method of claim 1, wherein an inadequate response is defined as a decrease in the MADRS total score of ≤ 25%.

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