WO2024050323A1 - Ulotaront pour le traitement adjuvant d'un trouble dépressif majeur - Google Patents

Ulotaront pour le traitement adjuvant d'un trouble dépressif majeur Download PDF

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WO2024050323A1
WO2024050323A1 PCT/US2023/073033 US2023073033W WO2024050323A1 WO 2024050323 A1 WO2024050323 A1 WO 2024050323A1 US 2023073033 W US2023073033 W US 2023073033W WO 2024050323 A1 WO2024050323 A1 WO 2024050323A1
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subject
total score
score
ulotaront
weeks
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Nina DEDIC
Robert Hayes
Justine KENT
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Sunovion Pharmaceuticals Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present disclosure relates to antidepressant therapies, to methods for augmenting antidepressant therapies, particularly antidepressant therapies that have failed to produce an adequate response, and to patient populations who benefit from such augmentation.
  • Major depressive disorder or MDD
  • MDD Major depressive disorder
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs norepinephrine reuptake inhibitors
  • bupropion and mirtazapine.
  • Ulotaront was identified during a medicinal chemistry program designed to develop structurally and mechanistically novel antipsychotics using in vivo mouse phenotypic screening in combination with comprehensive in vitro and in vivo molecular profiling. As reported by Dedic 2019, this testing revealed that ulotaront was behaviorally active. At 0.3 mg/kg, ulotaront was classified as an anxiolytic but showed a dose-dependent increase in an antipsychotic classification such that the signatures at 1 and 10 mg/kg were predominantly antipsychotic-like. Ulotaront also reportedly showed a modest antidepressant-like signal.
  • the disclosure provides a method of adjunctively treating MDD (major depressive disorder) in a human subject in need thereof who has exhibited an inadequate response to antidepressant therapy, comprising administering the antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof to the subject.
  • MDD major depressive disorder
  • the disclosure provides a method of adjunctively treating a subject suffering from treatment resistant depression comprising administering to the subject antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.
  • the 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 has experienced an inadequate response to an antidepressant therapy, and inadequate response is defined as a ⁇ 50% reduction in MADRS total score from the initiation of antidepressant therapy.
  • the disclosure relates to methods for the combined treatment of depression using ulotaront and antidepressant therapy.
  • the disclosure provides a method of treating a subject suffering from depression (for example, MDD) comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and antidepressant therapy.
  • ranges are given by specifying the lower end of a range separately from the upper end of the range, or particular numerical values are specified, it will be understood that a range can be defined by selectively combining any of the lower end variables, upper end variables, and particular numerical values that are mathematically possible.
  • a range when a range is defined as spanning from one endpoint to another, the range will be understood also to encompass a span between and excluding the two endpoints, including any and all ranges and subranges therein. The range is understood to encompass each discrete point within the range as if the same were fully set forth herein.
  • embodiments of the disclosure include treatment of various disorders, patient populations, administrations of dosage forms, at various dosages, minimization of various adverse events, and improvements in various efficacy measures, etc. Any combinations of various embodiments are within the scope of the disclosure.
  • test methodology or diagnostic instrument is performed based on the version in effect on July 1, 2022, unless otherwise stated to the contrary herein. This is true even when the methodology or instrument is defined herein based on a publication reporting an earlier version.
  • Adjunctive MDD therapy refers to the addition of an agent to an antidepressant regimen in order to improve efficacy, because the subject has experienced an inadequate response to an antidepressant regimen that has been optimized in dose and duration.
  • administering encompasses the delivery to a subject of ulotaront, or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e g., as described herein.
  • the “AIMS” (Abnormal Involuntary Movement Scale) assessment consists of 10 items describing symptoms of dyskinesia. Guy 1976. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) are observed unobtrusively while the subject is at rest; the investigator also makes global judgments on the subject’s dyskinesias (items 8 through 10). Each item is rated on a 5-point scale, with a score of zero representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress). In addition, the AIMS includes 2 yes/no questions that address the subject’s dental status.
  • the AIMS Movement Rating Score is defined as the sum of items 1 through 7 (i.e., items 1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, trunk movements).
  • an “antidepressant regimen” or “antidepressant therapy” refers to any pharmacological therapeutic regimen administered as therapy for the treatment of depression, and should be distinguished from augmentation, which is the addition of an agent - not thought to be an antidepressant itself - to an antidepressant regimen in order to improve efficacy.
  • pharmacological agents for the treatment of depression include, without limitation, SSRIs, SNRIs, bupropion and mirtazapine, and their pharmaceutically acceptable salts.
  • ‘Anxious distress” is used herein in accordance DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).
  • a subject with anxious distress must have 2 of the following 5 symptoms for the majority of a major depressive episode: 1) feeling keyed up or tense, 2) feeling unusually restless, 3) difficulty concentrating because of worry, 4) fear that something out might happen, and 5) a feeling that one might lose control of himself/herself.
  • 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).
  • an “at risk” individual is an individual who is at risk of developing a disorder to be treated. This may be shown, for example, by one or more risk factors, which are measurable parameters that correlate with development of a disorder and are known in the art.
  • risk factors which are measurable parameters that correlate with development of a disorder and are known in the art.
  • the “BARS” (Bames Akathisia Rating Scale) is a global clinical assessment of akathisia. Barnes 1989.
  • the BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the subject, subjective distress due to akathisia, and global clinical assessment of akathisia.
  • the first 3 items are rated on a 4-point scale, with a score of zero representing absence of symptoms and a score of 3 representing a severe condition.
  • the global clinical evaluation is made on a 6-point scale, with zero representing absence of symptoms and a score of 5 representing severe akathisia.
  • CGI-S Clinical Global Impression - Severity Scale
  • the “CGI-S” Clinical Global Impression - Severity Scale is a standardized, clinician- administered global rating scale that measures disease severity on a 7-point Likert scale. A higher score on the CGI-S represents a higher severity of disease.
  • the term “clinically significant” or “clinically meaningful” means an improvement in symptoms which is both statistically significant, and meaningful from a patient’s, clinician’s, or caregiver’s perspective, typically based on a static measure such as CGI-S or a retrospective evaluation of improvement such as the CGI-C, as described generally in various publications of the United States Food and Drug Administration, including FDA 2018, FDA 2019, and FDA 2020.
  • a treatment or benefit shows clinically significant efficacy in a population of patients to a degree of statistical significance.
  • CSFQ-14 is a 14-item short form questionnaire version of the CSFQ (Changes in Sexual Functioning Questionnaire) that produces an overall measure of sexual functioning as well as scores on 2 sets of subscales: a set of 5 scales corresponding to important dimensions of sexual functioning and a set of three scales corresponding to the three phases of the sexual response cycle.
  • “delaying” development of a disorder means to defer, hinder, slow, stabilize, and/or postpone development of the disorder. Delay can be of varying lengths of time, depending on the history of the disease and/or the individual being treated.
  • depression has the meaning normally ascribed to the term in the field of psychiatric medicine and can assume the definition set forth in DSM-5.
  • depression is referred to herein, it will be understood that MDD is a species of depression, and that the disclosure in all aspects is more specifically targeted at the treatment of MDD.
  • DSM-5 refers to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Terms used herein can be defined by reference to DSM-5 when necessary to give life and meaning to the term. When a person is defined in this document based on DSM-5, it will be understood that the person need not have been diagnosed using the criteria in DSM-5, but that the person would meet the criteria specified in DSM-5 if so diagnosed.
  • the “FAST” (Functional Assessment Short Test) is a 24-item questionnaire designed to assess to what extent the subject is experiencing difficulties in various aspects of functioning. The subjects rate their level of difficulty as 0 (no difficulty), 1 (mild difficulty), 2 (moderate difficulty), and 3 (severe difficulty).
  • HAM-A Halton Anxiety Rating Scale
  • SIGH-A Hamilton Anxiety Rating Scale
  • HAM-D17 (17-item Hamilton Depression Rating Scale) is another well-known instrument for evaluating a subject’s level of depression and is administered utilizing the Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D). Williams 1988.
  • SIGH-D Structured Interview Guide for the Hamilton Depression Rating Scale
  • inadequate response is defined as a ⁇ 50%, ⁇ 40%, ⁇ 30%, or ⁇ 20% reduction in MADRS total score from the initiation of therapy, and/or a CGI-C score of > 3 from the initiation of therapy.
  • inadequate response is defined as a ⁇ 50% reduction in MADRS total score from the initiation of therapy.
  • inadequate response is defined as a CGI-C score of > 3.
  • inadequate response is defined as a ⁇ 50% reduction in MADRS total score from the initiation of therapy and a CGI-C score of > 3.
  • inadequate response is defined as a ⁇ 50% improvement in symptom severity per MGH-ATRQ (Massachusetts General Hospital Antidepressant Treatment Response Questionnaire).
  • inadequate response is defined as a ⁇ 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score.
  • inadequate response is defined as a HAM-D17 total score > 14.
  • the “MADRS” (Montgomery-Asberg Depression Rating Scale) is a well-known instrument for evaluating a subject’s level of depression. Montgomery 1979.
  • the MADRS consists of 10 items, each rated from 0 to 6. A higher score on the MADRS represents a higher severity of the level of depression.
  • a “Major Depressive Episode” or “MDE” has the definition ascribed to the term in DSM-5. Thus, (i) the patient must have 5 or more depressive symptoms for > 2 weeks; (ii) the patient must have either depressed mood or loss of interest/pleasure; (iii) the symptoms must cause significant distress or impairment; and (iv) the patient has never had a manic or hypomanic episode.
  • Depressive symptoms are selected from the group consisting of: (i) depressed mood, (ii) markedly diminished interest or pleasure in most or all activities, (iii) significant weight loss (or poor appetite) or weight gain, (iv) insomnia or hypersomnia, (v) psychomotor retardation, (vi) fatigue or loss of energy, (vii) feelings of worthlessness or excessive or inappropriate guilt, (viii) diminished ability to think or concentrate, or indecisiveness, and (ix) recurrent thoughts of death (not just fear of dying), or suicidal ideation, plan, or attempt.
  • the “PGI-C” Principal Global Impression - Change Scale measures efficacy of drug treatment by rating the subject’s total change from the initiation of drug therapy whether or not it is due entirely to drug treatment, from the patient’s perspective.
  • PKI-S Patient Global Impression - Severity
  • Subjects are asked: “Please choose the response below that best describes the severity of your depression over the past week.”
  • Representative answers include nonoverlapping responses such as none, mild, moderate, and severe.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et. al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Pharmaceutically acceptable salts ofulotaront include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic 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 such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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 such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • X may be pharmaceutically undesirable anions, such as iodide, oxalate, trifluoromethanesulfonate and the like, when such salts are chemical intermediates.
  • the term “pharmaceutically acceptable excipient” includes, without limitation, any binder, fdler, adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, anti-caking agent, flavor, desiccants, plasticizers, disintegrants, lubricant, polymer matrix system, and polishing agents, which has been approved by or is otherwise acceptable to the United States Food and Drug Administration upon proper qualification for use in humans or domestic animals.
  • prevention refers to a regimen that protects against the onset of the disorder such that the clinical symptoms of the disorder do not develop. Accordingly, “prevention” relates to administration of a therapy to a subject before signs of the diseases are detectable in the subject (for example, administration of a therapy in the absence of a detectable symptom of the disorder). The subject may be an individual at risk of developing the disorder.
  • PSQI Personal Sleep Quality Index
  • the “PSQI” contains 19 self-rated questions and 5 questions rated by the bed partner or roommate (if one is available). Only self-rated questions are included in the scoring.
  • the 19 self-rated items are combined to form 7 “component” scores, each of which has a range of 0 to 3 points. In all cases, a score of “0” indicates no difficulty, while a score of “3” indicates severe difficulty.
  • the 7 component scores are then added to yield one “global” score, with a range of 0 to 21 points, “0” indicating no difficulty and “21” indicating severe difficulties in all areas.
  • Remission of MDD means that the subject no longer suffers from MDD, e.g., as defined by DSM-5.
  • remission can be defined based on a MADRS total score ⁇ 10, and > 50% reduction in MADRS total score from the initiation of therapy.
  • response refers to a clinically significant improvement in the subject’s diagnosis from the initiation of therapy.
  • response can be defined as > 50% reduction in MADRS total score from the initiation of therapy.
  • response can be defined as a CGI-C score of 1 or 2 (very much improved or much improved) from the initiation of therapy.
  • response can be defined as > 50% reduction in MADRS total score from the initiation of therapy and a CGI-C score of 1 or 2 (very much improved or much improved) from the initiation of therapy.
  • the “SAS” (Simpson Angus Scale) consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia).
  • SAS Sudson Angus Scale
  • Each item is rated on a 5-point scale, with a score of zero representing absence of symptoms, and a score of 4 representing a severe condition.
  • the SAS Total Score is the sum of the scores for all 10 items.
  • the “SF-36” (36-Item Short-form Survey) is a self-reported questionnaire with a standard recall period of 4 weeks which measures generic health-related quality of life on 2 broad domains, physical and mental composites, across 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 on a scale of 0 to 100 where lower scores on the physical component summary and mental component summary represent a lower health-related quality of life and a score of 50 references the normative data derived from surveys of representative samples of US general population.
  • the SF-36 provides a risk for depression score and the SF-6D health utility index on a scale from 0.0 (worst measured health state) to 1.0 (best measured health state).
  • the term “significantly” refers to a 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, the level of statistical significance when the term “significant,” “significantly,” or other variations of the term are used is p ⁇ 0.05.
  • a measurable result or effect is expressed or identified herein, it will be understood that the result or effect is typically evaluated based upon its statistical significance relative to a baseline such as placebo.
  • a treatment or benefit is described herein, it will be understood that the treatment or benefit typically shows efficacy in a population of patients to a degree of statistical significance.
  • SNRIs Serotonin-norepinephrine Reuptake Inhibitors
  • Pristiq® desvenlafaxine
  • duloxetine duloxetine
  • Levomilnacipran levomilnacipran
  • venlafaxine Effexor® XR
  • SSRIs Selective Serotonin Reuptake Inhibitors
  • citalopram Celexa®
  • escitalopram Lexapro®
  • fluoxetine Prozac®
  • paroxetine Paxil®, Pexeva®
  • sertraline Zoloft®
  • subject or “patient” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) 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.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.
  • the term “therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to accomplish such treatment of the disorder.
  • the effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated.
  • the effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint).
  • An effective amount may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, including but not limited to therapeutic benefit.
  • treatment is administered after one or more symptoms have developed, for example, acute exacerbation of symptoms.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • agents When treatment with two separate agents is described herein, it will be understood that the agents will be administered concomitantly, based on concurrently running dosing regimens, which may differ in dosing frequency or time of administration.
  • the two agents do not necessarily have to be administered at the same time for the administration to be concomitant.
  • concomitant administration may include one agent that is administered three times per day and one agent that is administered once a day.
  • Therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated; it also includes the eradication and/or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • treatment includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder); (b) slowing or arresting the development of one or more symptoms associated with the disorder (for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder); and/or (c) relieving the disorder (for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life.)
  • Treatment resistant depression or “treatment failure” have the same clinical criteria and will assume the U.S. FDA regulatory definition of the term unless otherwise specified herein, i.e., a lack of clinically meaningful improvement ( ⁇ 25% in MADRS total score) in the current episode of depression after treatment with at least 2 different antidepressant agents prescribed in adequate dosages for an adequate duration (at least 6 weeks).
  • the term can be defined as having ⁇ 25% improvement in MADRS total score to 2 or 3 prior antidepressants despite adequate dosage and duration as documented on the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (ATRQ).
  • Ulotaront as referred to 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:
  • ulotaront standing alone, includes the free form of ulotaront and also includes its pharmaceutically acceptable salts, hydrates, solvates, amorphous and crystalline forms.
  • free form or any other form or salt is specifically intended, it will be stated as such expressly.
  • Ulotaront can be used in the methods described herein as the free base (free form) or in the form of a pharmaceutically acceptable salt.
  • a hydrochloric acid (HC1) salt of ulotaront is used in the methods described herein.
  • Ulotaront, or a pharmaceutically acceptable salt thereof, including its HC1 crystalline forms can be obtained according to the production methods described in PCT Patent Publication No. WO2011/069063 (U.S. Patent No. 8,710,245, issued April 29, 2014) or PCT Patent Publication No. WO2019/161238, which are incorporated herein by reference in entirety and for all purposes, or a method analogous thereto.
  • compositions and dosage forms comprising ulotaront, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Compositions and dosage forms provided herein may further comprise one or more additional active ingredients.
  • Ulotaront, or a pharmaceutically acceptable salt thereof may be administered as part of a pharmaceutical composition as described herein. Discussion
  • the disclosure provides a method of adjunctively treating MDD (major depressive disorder) in a human subject in need thereof who has exhibited an inadequate response to antidepressant therapy, for example, after at least 8 weeks of antidepressant therapy, comprising administering the antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof to the subject.
  • MDD major depressive disorder
  • the disclosure provides a method of adjunctively treating a subject suffering from treatment resistant depression comprising administering to the subject antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.
  • the 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 has experienced an inadequate response to an antidepressant therapy, and inadequate response is defined as a ⁇ 50% reduction in MADRS total score from the initiation of therapy.
  • the method is adjunctive to an antidepressant regimen comprising antidepressant therapy, in a subject who has exhibited an inadequate response to the antidepressant therapy, e.g., after at least eight weeks of the antidepressant therapy.
  • inadequate response is further defined as a CGI-C score of > 3 from the initiation of therapy.
  • the disclosure provides a method of treating a subject suffering from depression (for example, MDD) comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and antidepressant therapy.
  • a subject suffering from depression for example, MDD
  • administering comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and antidepressant therapy.
  • the antidepressant therapy comprises an SSRI (Selective Serotonin Reuptake Inhibitor) or an SNRI (Serotonin-norepinephrine Reuptake Inhibitor).
  • antidepressant therapies comprise 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 a SNRI selected from duloxetine 30 to 60 mg/day and venlafaxine 37.5 to 225 mg/day.
  • the foregoing therapies are generally considered to be “adequate therapies” when tailored to a particular subject. In any of the embodiments of the current disclosure, the subject has experienced an inadequate response or treatment failure to the antidepressant therapies mentioned in this paragraph.
  • any of the embodiments of the current disclosure can further be defined by the subject to be treated.
  • the subject is suffering from a major depressive episode (MDE), e.g., as defined by DSM-5.
  • MDE major depressive episode
  • the MDE can be of varying lengths, including > 4 weeks, > 8 weeks, or > 26 weeks in duration. In some embodiments, the MDE is > 8 weeks in duration and ⁇ 52 weeks in duration.
  • 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 and confirmable by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
  • MGH-ATRQ Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
  • the subject is characterized by an inadequate response to at least 1 and no more than 3 adequate antidepressant therapies (ADTs) during the current MDE.
  • ADTs antidepressant therapies
  • the antidepressant therapy comprises an SSRI or SNRI, or one of the therapies aforementioned in this document.
  • the subject is characterized by his or her degree of depression prior to the ADT.
  • the subject has a 17-item Hamilton Depression Rating Scale (HAM-D17) total score > 18, but optionally > 14, > 16, > 20, or > 22 prior to the ADT.
  • HAM-D17 17-item Hamilton Depression Rating Scale
  • the subject treated, prior to ADT will satisfy all three of the foregoing requirements for MDE status of at least 8 weeks, inadequate response to an earlier course of antidepressant therapy, and a HAM-D17 total score of > 18.
  • the subject has an inadequate response after at least 8 weeks of antidepressant therapy, defined as: (a) a ⁇ 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score; or (b) a HAM-D17 total score > 14; or (c) a CGLC (Clinical Global Impression - Change) Scale score of > 3; or (d) a ⁇ 50% reduction in MADRS (Montgomery Asberg Depression Rating Scale) total score; or (e) a combination of any two or more of (a) - (d).
  • the methods of the current disclosure can also be defined based on the dose of ulotaront administered.
  • the therapeutically effective amount comprises from 10 to 150 mg, from 15 to 125 mg, from 25 to 100 mg, from 25 to 75 mg, or from 50 to 100 mg of ulotaront or a pharmaceutically acceptable salt thereof, based on the weight of the free form of ulotaront.
  • the therapeutically effective amount comprises 50 or 75 mg of ulotaront or a pharmaceutically acceptable salt thereof, based on the weight of the free form of ulotaront.
  • 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 the free form of ulotaront.
  • the therapeutically effective amount of ulotaront is administered once daily for a period of at least six weeks.
  • any of the methods of the current disclosure can produce remission of the depression, including remission of the depression wherein the depression is defined according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).
  • any of the methods of the disclosure can further produce a mean change in the subject’s Montgomery-Asberg Depression Rating Scale.
  • the methods can reduce the MADRS total score greater than antidepressant therapy alone by > 1, > 2, > 3, > 4, or > 5 points.
  • the treatment improves the subject’s MADRS total score.
  • the treatment improves the subject’s CGI-S score of > 2, > 3, or > 4 points.
  • the treatment produces a clinically significant improvement in the subject’s MADRS total score and CGI-S score.
  • the method improves the subject’s FAST (Functional Assessment Short Test) score.
  • FAST Full Assessment Short Test
  • PGI-S Patient Global Impression - Severity
  • the method improves the subject’s SF-36 (36-Item Short form Survey) score. [0085] In further embodiments, the method improves the subject’s HAM-A (Hamilton Anxiety Rating Scale) total score.
  • the method improves the subject’s HAM D17 (17-item Hamilton Depression Rating Scale) total score.
  • the method produces a CGI-C (Clinical Global Impression - Change) score of 1 or 2 (very much improved or much improved).
  • the method reduces the subject’s MADRS total score by > 50%.
  • the method reduces the subject’s MADRS total score to ⁇ 10.
  • the method reduces the subject’s MADRS total score to ⁇ 10 and reduces the subject’s MADRS total score by > 50%.
  • the method also can be defined based on its period of administration, typically improving the subject’s depression symptoms at least until the end of the period.
  • any of the embodiments of the disclosure can be practiced by administering the ulotaront or pharmaceutically acceptable salt and improving the subject’s depression symptoms for a therapeutically effective period of time of 6 weeks or more, 8 weeks or more, 12 weeks or more, 18 weeks or more, 26 weeks or more, or 52 weeks or more.
  • the improvement is represented, e.g., by a reduction in the subject’s MADRS score (i.e., a > 25% reduction, > 40%reduction, or > 50% reduction), a resulting MADRS total score of ⁇ 14, ⁇ 12, ⁇ 10, or ⁇ 8, or a combination of score reduction and absolute total score, for example, a ⁇ 50% reduction and a total score ⁇ 10.
  • MADRS score i.e., a > 25% reduction, > 40%reduction, or > 50% reduction
  • a resulting MADRS total score of ⁇ 14, ⁇ 12, ⁇ 10, or ⁇ 8, or a combination of score reduction and absolute total score, for example, a ⁇ 50% reduction and a total score ⁇ 10.
  • the improvement is represented by a > 50% reduction in the subject’s MADRS score a resulting MADRS total score of ⁇ 10, and is observed for a therapeutically effective period of time of at least 26 weeks.
  • the methods of the disclosure can also be defined based on their excellent side effect profile.
  • the method results in no clinically significant worsening of the subject’s: (a) abnormal involuntary movements as measured by the AIMS (Abnormal Involuntary Movement Scale); or (b) akathisia, e.g., as measured by the BARS (Barnes Akathisia Rating Scale); or (c) sexual functioning, e.g., as measured by the CSFQ-14 (Changes in Sexual Functioning Questionnaire, Short Form); or (d) suicidality, e.g., as measured by the C SSRS (Columbia-Suicide Severity Rating Scale); or (e) Parkinsonism, e.g., as measured by the SAS (Simpson Angus Scale); or (f) sleep quality, e.g., as measured by the PSQI (Pittsburgh Sleep Quality Index); or (g) any combination of two or more of (a)
  • the methods are optionally further monitored for the emergence of any potential side-effects.
  • the methods further comprise monitoring for CNS (central nervous system) stimulation including agitation, restlessness, insomnia, depression including lethargy, somnolence, and shallow breathing, impaired muscle coordination, effects on heart rate, and change in pupil size.
  • CNS central nervous system
  • Embodiment AA A method of adjunctively treating MDD (major depressive disorder) in a human subject in need thereof who has exhibited an inadequate response to antidepressant therapy, comprising administering the antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof to the subject.
  • Embodiment AB A method of adjunctively treating a human subject suffering from treatment resistant depression comprising administering to the subject antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof.
  • Embodiment 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 experienced an inadequate response to an antidepressant therapy, and inadequate response is defined as a ⁇ 50% reduction in MADRS total score from the initiation of antidepressant therapy.
  • Embodiment 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 experienced an inadequate response to an antidepressant therapy, and inadequate response is defined as a ⁇ 50% reduction in MADRS total score from the initiation of antidepressant therapy, and a CGI-C score of > 3 from the initiation of therapy.
  • Embodiment AG The method of embodiment AE or AF, wherein the method is adjunctive to an antidepressant regimen comprising antidepressant therapy in a human subject in need thereof who has exhibited an inadequate response to the antidepressant therapy.
  • Embodiment AH The method of any of embodiments AA-AG, wherein the antidepressant therapy comprises an SSRI (Selective Serotonin Reuptake Inhibitor) or an SNRI (Serotoninnorepinephrine Reuptake Inhibitor).
  • SSRI Selective Serotonin Reuptake Inhibitor
  • SNRI Serotoninnorepinephrine Reuptake Inhibitor
  • the antidepressant therapy comprises an SSRI selected from escital opram 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.
  • Embodiment AK The method of any of embodiments AA, AD, AH, and Al, wherein inadequate response is defined as a CGI-C score of > 3 from the initiation of therapy.
  • Embodiment AL The method of any of embodiments AA and AD-AI, wherein the inadequate response is defined as: (a) (i) a ⁇ 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score or (ii) a HAM-D17 total score > 14; and (b) a CGI-C (Clinical Global Impression - Change) Scale score of > 3; and (c) a ⁇ 50% reduction in MADRS (Montgomery Asberg Depression Rating Scale) total score.
  • MADRS Monitoring Asberg Depression Rating Scale
  • Embodiment AM The method of any of embodiments AA and AD-AI wherein the inadequate response is defined as: (a) a ⁇ 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score; and (b) a HAM-D17 total score > 14; and (c) a CGI-C (Clinical Global Impression - Change) Scale score of > 3; and (d) a ⁇ 50% reduction in MADRS (Montgomery Asberg Depression Rating Scale) total score.
  • MADRS Monitoring Asberg Depression Rating Scale
  • Embodiment AN The method of any of embodiments AA and AD- AM, wherein the subject has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score > 18 prior to antidepressant therapy, and inadequate response is defined, after at least 8 weeks of antidepressant therapy, as: (a) a ⁇ 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score, or (b) a HAM-D17 total score > 14; or (c) a CGI-C (Clinical Global Impression - Change) Scale score of > 3; or (d) a ⁇ 50% reduction in MADRS (Montgomery Asberg Depression Rating Scale) total score; or (e) a combination of (a) - (d).
  • Embodiment AO The method of any of embodiments AA and AD- AM, wherein the subject has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score > 18 prior to antidepressant therapy, and inadequate response is defined, after at least 8 weeks of antidepressant therapy, as: (a) a ⁇ 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score; and (b) a HAM-D17 total score > 14; and (c) a CGI-C (Clinical Global Impression - Change) Scale score of > 3; and (d) a ⁇ 50% reduction in MADRS (Montgomery Asberg Depression Rating Scale) total score.
  • MADRS Monitoring Asberg Depression Rating Scale
  • Emodiment BB The method of any of embodiments AA-BA, 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.
  • MADRS Monitoring Asberg Depression Rating Scale
  • CGI-S Chronic Global Impression - Severity
  • Emodiment BG The method of any of embodiments AA-BF, wherein the method improves the subject’s HAM D17 (17-item Hamilton Depression Rating Scale) total score.
  • Emodiment BL The method of any of embodiments AA-BK, wherein the method results in no clinically significant worsening of the subject’s: abnormal involuntary movements as measured by the AIMS (Abnormal Involuntary Movement Scale); or akathisia as measured by the BARS (Barnes Akathisia Rating Scale); or sexual functioning as measured by the CSFQ-14 (Changes in Sexual Functioning Questionnaire, Short Form); or suicidality as measured by the C SSRS (Columbia-Suicide Severity Rating Scale); or Parkinsonism as measured by the SAS (Simpson Angus Scale); or sleep quality as measured by the PSQI (Pittsburgh Sleep Quality Index); or any combination thereof.
  • AIMS Abnormal Involuntary Movement Scale
  • BARS Barnes Akathisia Rating Scale
  • CSFQ-14 Choanges in Sexual Functioning Questionnaire, Short Form
  • C SSRS Coldia-Suicide Severity Rating Scale
  • Parkinsonism
  • Embodiment BO A method of 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 antidepressant therapy.
  • a subject suffering from depression e.g., MDD
  • administering comprising administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and antidepressant therapy.
  • Embodiment BP The method of embodiment BO, wherein the antidepressant therapy comprises a therapeutically effective amount of an SSRI (Selective Serotonin Reuptake Inhibitor) or an SNRI (Serotonin-norepinephrine Reuptake Inhibitor).
  • SSRI Selective Serotonin Reuptake Inhibitor
  • SNRI Serotonin-norepinephrine Reuptake Inhibitor
  • 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 a SNRI selected from duloxetine (e.g., 30 to 60 mg/day) and venlafaxine (e.g., 37.5 to 225 mg/day).
  • 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
  • sertraline e.g., 50 to 200 mg/day
  • a SNRI selected from duloxetine e.g., 30 to 60 mg/day
  • venlafaxine e.g., 37.5 to 225 mg/day
  • Emodiment BR The method of any of embodiments AA-BQ, wherein the patient has a HAM- D17 (17-item Hamilton Depression Rating Scale) total score > 14, > 16, or > 18 prior to ulotaront therapy.
  • Embodiment BS The method of any of embodiments AA-BR, wherein the patient has a MADRS (Montgomery -Asberg Depression Rating Scale) total score > 20, > 22, > 24, > 26, >28, > 30, > 32, or > 34 prior to ulotaront therapy.
  • MADRS Monitoring -Asberg Depression Rating Scale
  • Embodiment BU The method of any of embodiments AA, and AD-BS, wherein the patient does not have treatment resistant depression.
  • Ulotaront was evaluated in the mouse forced swim test (FST). In this test, mice are placed in a small tank of water from which they cannot escape, and their behavior is monitored. Acute administration of all major classes of marketed antidepressants decreases the duration of immobility in this test.
  • Ulotaront treatment significantly reduced immobility duration at doses of 1, 3, and 10 mg/kg with the maximal effect achieved at the 1 mg/kg dose level.
  • the results demonstrate that ulotaront shows antidepressant-like effects in the mouse FST, however this effect is strain specific. Varying sensitivity to established antidepressant drugs has also been reported across different mouse strains (Lucki 2001; David 2003).
  • Ulotaront was evaluated in the rat learned helplessness model which assesses loss of behavioral control over aversive situations and is responsive to antidepressant treatment (Willner 2015).
  • rats are first exposed to inescapable foot shock to induce a helpless state which is then expressed by a subsequent failure to learn to avoid escapable foot shocks (active avoidance).
  • All rats were tested in a 2-compartment active avoidance chamber where delivery of foot shock was signaled by a light cue.
  • the test session began with 5 min of free exploration after which 30 stimulus-shock trials were delivered during a 15 min period. Each trial lasted 30 seconds with an initial 24 second rest period, followed by a 6 second light cue presentation with foot shock delivered during the last 3 seconds. Crossing to the opposite compartment during the first 3 seconds of light cue presentation avoided the shock and was considered an active avoidance. Failure to avoid full delivery of the foot shock (i.e., failing to cross during 3 second shock presentation) was considered an escape failure. Crossings to the opposite compartment of the shuttle box during the 24 second rest period were recorded as inter-trial interval (ITI) crossings.
  • ITI inter-trial interval
  • Escape failures and ITI crossings were analyzed by two way repeated measures ANOVA with treatment as a main factor and test session (i.e., day) as the repeated measure. Significant ANOVA results were followed by Dunnetf s post- hoc analysis to examine the effect of treatment at each test session compared to vehicle-treated, helpless rats.
  • Example 4 A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Flexible Doses of Ulotaront as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder
  • the trial population will include subjects 18 to 65 years of age, inclusive, at the time of informed consent with a primary diagnosis of MDD, and in a current major depressive episode (MDE), as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM- 5) criteria and confirmed by the MGH-ATRQ.
  • MDE major depressive episode
  • the current MDE must be > 8 weeks in duration. Additionally, subjects must have a reported history for the current MDE of an inadequate response to at least 1 and no more than 3 adequate ADTs. Subjects must also have a 17-item Hamilton Depression Rating Scale (HAM-D17) total score > 18 at the screening and baseline visits.
  • HAM-D17 17-item Hamilton Depression Rating Scale
  • a primary objective of the study is to compare the efficacy of ulotaront (50 to 75 mg/day) to placebo as adjunctive therapy to an assigned open-label ADT in subjects with MDD who demonstrate an inadequate response to a prospective 8-week trial of the same assigned open label ADT.
  • Primary efficacy will be evaluated by change from the end of Phase A (Week 8 visit) to the end of Phase B (Week 14 visit) in the MADRS total score.
  • Efficacy will also be evaluated, inter alia, by change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in the CGI S.

Abstract

L'invention concerne des thérapies antidépressives, des méthodes pour renforcer des thérapies antidépressives, en particulier des thérapies antidépressives qui ont échoué à produire une réponse adéquate, et des populations de patients qui bénéficient d'un tel renforcement.
PCT/US2023/073033 2022-08-30 2023-08-29 Ulotaront pour le traitement adjuvant d'un trouble dépressif majeur WO2024050323A1 (fr)

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