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WO2024201274A1 - Eskétamine destinée à être utilisée dans le traitement de la dépression - Google Patents

Eskétamine destinée à être utilisée dans le traitement de la dépression Download PDF

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Publication number
WO2024201274A1
WO2024201274A1 PCT/IB2024/052847 IB2024052847W WO2024201274A1 WO 2024201274 A1 WO2024201274 A1 WO 2024201274A1 IB 2024052847 W IB2024052847 W IB 2024052847W WO 2024201274 A1 WO2024201274 A1 WO 2024201274A1
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Prior art keywords
treatment
patient
weeks
antidepressant
induction
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Siobhan Mulhern HAUGHEY
Ito Tetsuro
Benoit RIVE
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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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
    • A61K31/13—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • the present invention is directed to methods and dosing regimens for the treatment of treatment resistant depression in a patient that has had 2 or more, or preferably 3 or more, prior treatment failures and is experiencing inadequate symptom relief from the combination of an antidepressant and adjunctive treatment with quetiapine comprising ceasing to administering quetiapine and administering esketamine, preferably intranasal esketamine, in conjunction with the antidepressant or preferably esketamine, preferably intranasal esketamine, and a newly initiated antidepressant, preferably a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor, preferably for a total treatment period of at least 32 weeks.
  • Major Depressive Disorder is defined as the presence of one of more major depressive episodes that are not better accounted for psychotic disorder or bipolar disorder.
  • a major depressive episode is characterized by meeting five or more of the following criteria during the same 2 week period which represent a change in functioning and include at least depressed/sad mood or loss of interest and pleasure, indifference or apathy, or irritability and is usually associated with a change in a number of neurovegetative functions, including sleep patterns, appetite and body weight, motor agitation or retardation, fatigue, impairment in concentration and decision making, feelings of shame or guilt, and thoughts of death or dying (Harrison's Principles of Internal Medicine, 2000).
  • Symptoms of a depressive episode include depressed mood; markedly diminished interest or pleasure in all, or almost all, activities most of the day; weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day; insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt nearly every day; diminished ability to think or concentrate, or indecisiveness, nearly every day; recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. Further, the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, American Psychiatric Association, 1994)
  • AAOI mono-amine oxidase inhibitors
  • TCA tricyclic antidepressants
  • SSRI serotonin specific reuptake inhibitors
  • SNRI serotonin noradrenergic reuptake inhibitors
  • NRI noradrenaline reuptake inhibitor
  • "natural products” such as Kava- Kava, St. John's Wort
  • dietary supplement such as s-adenosylmethionine
  • drugs used in the treatment of depression include, but are not limited to imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, chlomipramine, fluoxetine, citalopram, sertraline, paroxetine, tianeptine, nefazadone, venlafaxine, desvenlafaxine, duloxetine, reboxetine, mirtazapine, phenelzine, tranylcypromine, and/or moclobemide.
  • these agents including, but not limited to, serotonin reuptake inhibitors are also used when depression and anxiety co-exist, such as in anxious depression.
  • treatment of treatment-resistant depression includes augmentation strategies including treatment with pharmacological agents such as, antipsychotics (such as quetiapine, aripiprazole, olanzapine, risperidone, and the like), lithium, carbamazepine, and triiodothyronine, and the like; adjunctive electroconvulsive therapy; adjunctive transcranial magnetic stimulation; etc.
  • pharmacological agents such as, antipsychotics (such as quetiapine, aripiprazole, olanzapine, risperidone, and the like), lithium, carbamazepine, and triiodothyronine, and the like; adjunctive electroconvulsive therapy; adjunctive transcranial magnetic stimulation; etc.
  • Treatment resistant depression is defined by the European Medicines Agency as non-response to >2 consecutive treatments in the current depressive episode (of an adequate dosage for an adequate duration). Patients with TRD experience low rates of remission and high rates of relapse. In fact, the greater the number of treatment failure a patient suffers the more resistant they are to adequately responding to subsequent treatment. Patients >3 prior treatment failure are particularly difficult to adequately treat with standard adjunctive therapies. [0007] There remains a need to provide an effective alternative treatment for depression, more particularly treatment resistant depression patients with >2 or >3 prior treatment failures (or PTFs) wherein patients do not find adequate relief from standard adjunctive therapy such as quetiapine, because of the inherent difficulty in treating these patient population.
  • PTFs prior treatment failures
  • the present invention is directed to a method for the treatment of treatment resistant depression in a patient that has had >2 or >3 prior treatment failures and is experiencing inadequate symptom relief from the combination of an antidepressant and adjunctive treatment with quetiapine comprising: ceasing to administer quetiapine and administering conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone or administering conjunctively with a new a therapeutically effective amount of a new antidepressant wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone is administered in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and the new
  • FIG. 1 illustrates the study disposition of a 32 week comparison between patients who were treated with either esketamine plus a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor and patients who were treated with quetiapine plus a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor.
  • Full analysis set (included all randomized patients).
  • the study included an 8-week acute phase followed by a 24-week maintenance phase. Patients who terminated the trial before Day 64 were considered to have discontinued the study by Week 8. Percentages were based on the number of patients in the indicated population.
  • FIG. 2 illustrates primary and secondary endpoints of the study measured at week eight and week 32. In this figure, Percentages were based on the number of patients in the full analysis set (included all randomized patients).
  • Remission was defined as a MADRS total score of ⁇ 10 and no treatment or study discontinuation before Week 8.
  • a Missing data for patients continuing study treatment were imputed using LOCF; patients who discontinued were imputed as non-responders;
  • Treatment groups were compared using a Cochran-Mantel-Haenszel chi-square test, adjusted for age group (18-64 years; >65 years) and total number of treatment failures (2; >3);
  • Week-32 endpoint is defined as a participant achieving remission at Week 8 and having no relapse within the consecutive 24 weeks and completed both the treatment and the trial.
  • FIG. 3 illustrates response and remission rates over time, from week one to week 32.
  • Full analysis set includes all randomised patients; data were missing for 1 patient in the quetiapine XR+SSRI/SNRI at Baseline. Percentages are based on the number of patients at each timepoint, using LOCF for missing data.
  • Remission was defined as a MADRS total score of ⁇ 10;
  • b Response was defined as >50% improvement in MADRS total score from baseline or MADRS total score ⁇ 10. Tested at a two-sided 0.05 significance level without adjustment for multiple testing. **p ⁇ 0.01; ***p ⁇ 0.001.
  • LOCF last observation carried forward
  • MADRS Montgomery-Asberg Depression Rating Scale
  • NS nasal spray
  • SNRI serotonin norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • XR extended release.
  • FIG. 4 illustrates the ESCAPE-TRD study design.
  • AD antidepressant
  • CGI-C Clinical Global Impression - Change
  • MADRS Montgomery-Asberg Depression Rating Scale
  • MDD major depressive disorder
  • NS nasal spray
  • Q4W every 4 weeks
  • SNRI serotonin norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • TRD treatment resistant depression
  • XR extended release.
  • FIG. 5 illustrates the change in MADRS score over time from week one to week 32.
  • Full analysis set (included all randomized patients).
  • LS Means and SE were based on a repeated measures mixed effects ANCOVA model with treatment, age group, number of treatment failures, time, time by treatment and Baseline value as covariates. It was modelled with an unstructured covariance structure.
  • ANCOVA analysis of covariance
  • LS least squares
  • MADRS Montgomery-Asberg Depression Rating Scale
  • NS nasal spray
  • OC observed case
  • SE standard error
  • SNRI serotonin norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • XR extended release.
  • FIG 6. is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant.
  • FIG. 7 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 2.
  • FIG. 8 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 3 or more.
  • FIG. 9 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower or MADRS score reduction by 50% for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant.
  • FIG. 10 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower or MADRS score reduction by 50% for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 2.
  • FIG. 11 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower or MADRS score reduction by 50% for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 3 or more.
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methyl
  • the treatment with the antidepressant that was administered with quetiapine is continued; that is, "the antidepressant” administered in conjunction with (S)-2-(2- chlorophenyl)-2-(methylamino)cyclohexanone is the same antidepressant as previously used in the combination with adjunctive treatment with quetiapine.
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same prior major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-
  • the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone to the patient in an amount in the range of from about 28 mg to about 84 mg, during a period of about four weeks, at a frequency of twice per week.
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same prior major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chloropheny
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the or one or more prior same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally
  • the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2
  • Suicide also known as completed suicide, is the "act of taking one's own life". Attempted suicide or non-fatal suicidal behavior is self-injury with the desire to end one's life that does not result in death. Suicidal ideation is the medical term for thoughts about or an unusual preoccupation with suicide, or thoughts of ending one's life or not wanting to live anymore but not necessarily taking any active efforts to do so.
  • Scales used in the evaluation of suicidal ideation include Beck Scale for Suicide Ideation (BSS), Columbia Suicide Severity Rating Scale (C-SSRS), Suicidal Ideation and Behavioral Assessment Tool (SIBAT) and The Kessler Psychological Distress Scale (K10, which test does not measure suicidal ideation directly, but there may be value in its administration as an early identifier of suicidal ideation. High scores of psychological distress are also, in some cases associated with suicidal ideation.
  • suicidal ideation There are also several psychiatric disorders that appear to be comorbid with suicidal ideation or considerably increase the risk of suicidal ideation.
  • the following disorders have been shown to be the strongest predictors of suicidal ideation/disorders in which risk is increased to the greatest extent: major depressive disorder (MDD), dysthymia, bipolar disorder.
  • MDD major depressive disorder
  • the main treatments for suicidality and/or suicidal ideation include: hospitalization, outpatient treatment, and medication. Hospitalization allows the patient to be in a secure, supervised environment to prevent their suicidal ideation from turning into suicide attempts. In most cases, individuals have the freedom to choose which treatment they see fit for themselves.
  • the maintenance of the antidepressant response in a patient may be determine by for example, a clinician, physician, psychiatrist, psychologist, or other suitable medical professional. Additionally, maintenance of the antidepressant response may be established by for example, an absence of relapse of the depression (or one or more symptoms of the depression), an absence of the need for additional or alternate treatment(s) for the depression, an absence of the worsening of the depression, an absence of the need for hospitalization for a suicidal attempt or to prevent suicide, or, when evaluated by MADRS score, by maintenance of a MADRS score less than about 22 and/or the absence of a MADRS score above 22 for any continuous two week period.
  • depression shall be defined to include major depressive disorder and treatment resistant depression.
  • the depression is treatment resistant depression.
  • the present invention is directed to methods and dosing regimens for the treatment of depression in suicidal patients.
  • depression in suicidal patients shall include any type of depression as herein defined, when diagnosed in a patient that also exhibits at least one symptom of suicidality, for example suicidal ideations and/or behaviors (e.g. intent, planning, etc.).
  • depression in suicidal patients includes, but is not limited to, major depressive disorder in suicidal patients, unipolar depression in suicidal patients, treatment resistant depression in suicidal patients, depression with anxious distress in suicidal patients, bipolar depression in suicidal patients and dysthymia in suicidal patients.
  • the "depression in suicidal patients” is selected from the group consisting of major depressive disorder in suicidal patients, unipolar depression in suicidal patients and treatment resistant depression in suicidal patients. More preferably, the "depression in suicidal patients” is treatment resistant depression in suicidal patients.
  • treatment-refractory or treatment-resistant depression and the abbreviation "TRD” shall be defined as a major depressive disorder that does not respond to a least two antidepressant regimens or treatments.
  • anti-antidepressant shall mean any pharmaceutical agent which can be used to treat depression. Suitable examples include, but are not limited to mono-amine oxidase inhibitors such as phenelzine, tranylcypromine, moclobemide, and the like; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, chlomipramine, amoxapine, and the like; tetracyclics such as maprotiline, and the like; non-cyclics such as nomifensine, and the like; triazolopyridines such as trazodone, and the like; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, escitolapram, fluvoxamine, and the like; serotonin receptor antagonists such as
  • the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline.
  • Therapeutically effective dosage levels and dosage regimens for antidepressants for example, mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitor, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones and other pharmaceutical agents disclosed herein
  • antidepressants for example, mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitor, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones and other pharmaceutical agents disclosed herein
  • antidepressants for example, mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors,
  • therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http://www.pdrel.com) or other sources.
  • antipsychotic includes, but is not limited to:
  • phenothiazines e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin
  • thioxanthenes e.g., thiothixene, flupentixol
  • butyrophenones e.g., haloperidol
  • dibenzoxazepines e.g., loxapine
  • dihydroindolones e.g., molindone
  • substituted benzamides e.g., sulpride, amisulpride
  • atypical or 2nd generation antipsychotics such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222 (Organon), and the like; and others such as sonepiprazole, aripiprazole, brexpiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), and the like.
  • atypical or 2nd generation antipsychotics such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sert
  • the "atypical antipsychotic" is selected from the group consisting of aripiprazole, brexpiprazole, quetiapine, olanzapine, risperidone and paliperidone.
  • the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, olanzapine and risperidone; preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine and olanzapine.
  • kits for the treatment and/or prevention of suicidality include, but are not limited to, the prevention of suicidal ideations, suicidal behaviors, suicidal attempts and/or suicide.
  • esketamine shall mean the (S)- enantiomer of ketamine, a its corresponding hydrochloride salt, a compound of formula (I) also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.
  • treating shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.
  • prevention shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and/or (d) delay or avoidance of the development of the disorder or condition.
  • a subject in need of thereof shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented.
  • a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition.
  • the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
  • the terms "subject” and "patient” refer to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the subject or patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the methods of treatment or prevention and the dosing regimens of the present invention are directed to subjects or patients in need of such treatment, prevention or dosing regimen, more particularly to subjects or patients diagnosed with or exhibiting at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) regardless of type or underlying cause.
  • the subject or patient in need thereof is a subject or patient that has been diagnosed with or exhibits at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) and who has further been diagnosed with or exhibits at least one symptom of suicidality (e.g. suicidal ideations and/or behaviors).
  • at least one symptom of depression preferably, meeting the criteria for major depressive disorder or episode
  • suicidality e.g. suicidal ideations and/or behaviors
  • an inadequate response is a non-response. In some embodiments, an inadequate response is defined as >0% - ⁇ 25% improvement of symptoms.
  • an adequate dose is the maximum therapeutic dose of said treatment. In some embodiments, an adequate duration is >6 weeks.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • therapeutically effective amount of combination therapy comprising esketamine and a serotonin reuptake inhibitor would be the amount of esketamine and the amount of the serotonin reuptake inhibitor that when taken together or sequentially have a combined effect that is therapeutically effective, more preferably where the combined effect is synergistic.
  • the amount of each component of the combination individually may or may not be therapeutically effective.
  • the compounds may be co-administered simultaneously, sequentially, separately or in a single pharmaceutical composition.
  • the number of dosages of each compound given per day may not necessarily be the same, e.g. where one compound may have a greater duration of activity, and will therefore, be administered less frequently.
  • the compounds may be administered via the same or different routes of administration, and at the same or different times during the course of the therapy, concurrently in divided or single combination forms. The instant invention is therefore understood as embracing all regimens of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the terms “co-therapy”, “combination therapy”, “adjunctive treatment”, “adjunctive therapy” “administered in conjunction with” and “combined treatment” shall mean treatment of a patient in need thereof by administering esketamine in combination with one or more antidepressant(s), and further, optionally in combination with one or more atypical antipsychotics wherein the esketamine and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Where the esketamine and the antidepressant(s) are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different.
  • the esketamine and the antidepressant(s) may be administered via the same or different routes of administration.
  • suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in) intramuscular (im), subcutaneous (sc), sublingual, transdermal, and rectal.
  • Compounds may also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peri-spinal routes of administration by delivery via intracranial or intravertebral needles and/or catheters with or without pump devices.
  • the esketamine and the antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric add, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium
  • acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2- dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D- gluconic acid
  • the present invention is directed to an aqueous formulation of S-ketamine, comprising water and S-ketamine; wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone hydrochloride is present in a concentration in range of from about 150 mg/ml to about 200 mg/ml, preferably in the range of from about 126 mg/ml to about 162 mg/ml, more preferably in the range of from about 160 mg/ml to about 163 mg/m, based on the total volume of the pharmaceutical composition and may contain one or more additional excipients for example, wetting agents, surfactant components, solubilizing agents, thickening agents, colorant agents, antioxidant components, and the like.
  • antioxidant component examples include, but are not limited to one or more of the following: sulfites; ascorbic acid; ascorbates, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylene diamine tetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallates, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof.
  • the antioxidant component provides long term stability to the liquid compositions. Addition of the antioxidant component can help enhance and ensure the stability of the compositions and renders the compositions stable even after six months at 40° C.
  • a suitable amount of the antioxidant component, if present, is about 0.01 wt.-% to about 3 wt.-%, preferably about 0.05 wt.-% to about 2 wt.-%, of the total weight of the composition.
  • Solubilizing and emulsifying agents can be included to facilitate more uniform dispersion of the active ingredient or other excipient that is not generally soluble in the liquid carrier.
  • a suitable emulsifying agent include, but are not limited to, for example, gelatin, cholesterol, acacia, tragacanth, pectin, methyl cellulose, carbomer, and mixtures thereof.
  • a suitable solubilizing agent include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.
  • the solubilizing agent includes glycerin.
  • the solubilizing or emulsifying agent is/are generally present in an amount sufficient to dissolve or disperse the active ingredient, i.e. S- ketamine, in the carrier.
  • Typical amounts when a solubilizing or an emulsifier are included are from about 1 wt.-% to about 80 wt.-%, preferably about 20 wt.-% to about 65 wt.-%, and more preferably about 25 wt.-% to about 55 wt.-%, of the total weight of the composition.
  • a Suspending agent or viscosity increasing agent can be added to the pharmaceutical compositions of the present invention, to for example, increase the residence time in the nose.
  • Suitably examples include, but are not limited to, hydroxypropyl methylcellulose, sodium carmellose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and the like.
  • ESCAPE-TRD was the first phase I II b randomized trial to compare esketamine NS with the antipsychotic augmentation agent, quetiapine extended release (XR), both in conjunction with a continuing selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI).
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin norepinephrine reuptake inhibitor
  • TRD Treatment resistant depression
  • Antidepressant treatments approved for MDD including oral ADs and adjunctive medications, are used in various physician-defined strategies to treat TRD. 10-12 There is a severe unmet need for effective treatment options approved specifically for TRD, with diverse strategies used in clinical practice. 10 Quetiapine extended release (XR), a guideline-supported antipsychotic augmentation agent approved by the FDA and EMA for patients with MDD who have experienced sub-optimal response to AD monotherapy, is one of the most commonly used TRD treatments. 13-16
  • esketamine primarily targets the glutamatergic pathway.
  • 17, 18 Esketamine, administered as a nasal spray (NS) in conjunction with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) is the only treatment approved specifically for TRD, and is also approved for acute treatment of psychiatric emergency due to MDD.
  • Esketamine NS can reduce depressive symptoms and risk of relapse versus placebo, when both are given in combination with a newly initiated SSRI/SNRL 19-22 [0085]
  • ESCAPE-TRD NCT04338321
  • the first open-label randomized clinical trial to compare flexibly-dosed esketamine NS with quetiapine XR, an active comparator, both in conjunction with a continuing SSRI/SNRI, in patients with TRD.
  • Treatment wi i t l h quetiapine XR (at treatment that includes an , , . , doses >50 mg/day), esketamine or
  • cSSRI/SNRI was continued following randomisation.
  • AD antidepressant
  • DSM-5 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
  • IDS-C30 Inventory of Depressive Symptomatology Clinician-rated, 30-item scale
  • MDD major depressive disorder
  • MDE major depressive episode
  • SNRI serotonin norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • XR extended release.
  • ESCAPE-TRD was a randomized, open-label, rater-blinded, active-controlled, international, study across 171 sites comprising hospitals, inpatient and outpatient clinics and research centres in 24 countries. The study aimed to evaluate the efficacy, safety, and tolerability of esketamine NS versus quetiapine XR, both in conjunction with a continuing SSRI/SNRI, in patients with TRD.
  • ESCAPE-TRD comprised an up-to-14-day screening phase, an 8-week acute treatment phase, a 24-week maintenance phase, and a safety follow-up 2 weeks after the last dose of study treatment (FIG 4).
  • Patients were randomized 1:1 to esketamine NS or quetiapine XR, based on a computer-generated schedule prepared before the study using randomly permuted blocks, stratified by age (18- ⁇ 64 years; 65- ⁇ 75 years) and total number of prior treatment failures (2; >3). Patients who discontinued study treatment remained in the study for all follow-up visits through Week 32.
  • Esketamine NS and quetiapine XR were dosed as per label. 19, 23 Patients self-administered esketamine NS under supervision at their treatment sites and vital signs were monitored from 40 minutes post-administration until considered stable.
  • the starting dose of esketamine NS was dependent on age and ancestry and was flexibly dosed (adult patients [18- ⁇ 64 years]: commencing at 56 mg and flexibly dosed at 56 or 84 mg from Day 4; elderly patients [65-74 years] and adults of Japanese ancestry: commencing at 28 mg, increasing to 56 mg from Day 4 and flexibly dosed at 56 or 84 mg at subsequent visits). Treatments were administered twice weekly during Weeks 1-4, weekly during Weeks 5-8 and weekly or every 2 weeks during Weeks 9-32. 24
  • Quetiapine XR was provided as tablets and self-administered by patients at home before bedtime. Quetiapine XR was flexibly dosed (adult patients: 50 mg/day commencing on Day 1, increasing to >150 mg/day by the end of Week 2 but ⁇ 300 mg/day, based on individual patient evaluation; elderly patients: same schedule, except the increase to ⁇ 300 mg/day occurred no earlier than Day 22). 13
  • Efficacy was assessed according to the Montgomery-Asberg Depression Rating Scale (MADRS), performed on-site by independent blinded raters. Efficacy analyses included all randomized patients. The primary endpoint assessed short-term efficacy, and was the proportion of patients who achieved remission (defined as MADRS score ⁇ 10, 26 and no treatment or study discontinuation) at Week 8. The key secondary endpoint assessed long-term efficacy and was the proportion of patients who were relapse-free through Week 32 (without treatment discontinuation) after remission at Week 8.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • Relapse was defined as any one of: an increase to MADRS score >22, confirmed by one additional MADRS score >22 within the next 5-15 days; hospitalization for worsening depression, suicide or suicidal ideation; prevention of suicide attempt or suicide attempt; completed suicide; or any other event determined by the investigator's clinical judgment as indicative of a relapse.
  • Additional secondary endpoints were CfB in clinician-rated and patient-reported scales/questionnaires. Additional clinician-rated assessments evaluated overall severity of depressive illness, comprising Clinical Global Impression - Change (CGI-C) and Clinical Global Impression - Severity (CGI-S) ratings.
  • CGI-C Clinical Global Impression - Change
  • CGI-S Clinical Global Impression - Severity
  • Patient-reported outcomes assessed depressive symptoms, functional impairment, health-related quality of life and work productivity comprising Patient Health Questionnaire 9-ltem score (PHQ-9), European Quality of Life Group, 5-Dimension, 5-Level questionnaire (EQ-5D-5L), Quality of Life in Depression Scale (QLDS), 36-item Short-Form Health Survey (SF-36), Work Productivity and Activity Impairment: Depression questionnaire (WPAI:D), and the Sheehan Disability Scale (SDS).
  • PHQ-9 Patient Health Questionnaire 9-ltem score
  • PHQ-9 European Quality of Life Group
  • 5-Dimension 5-Level questionnaire
  • QLDS Quality of Life in Depression Scale
  • SF-36 36-item Short-Form Health Survey
  • WPAI:D Work Productivity and Activity Impairment: Depression questionnaire
  • SDS Sheehan Disability Scale
  • Safety analysis included data from all randomized patients who received >1 dose of study treatment.
  • An adverse event was considered a treatment-emergent AE (TEAE) if it started between taking the first dose and completion of the safety follow-up visit (14 days after last dose of study intervention), or up to 30 days after the last dose if it was a serious AE.
  • Safety evaluations were carried out throughout the study.
  • Prespecified TEAEs of special interest were grouped by Medical Dictionary for Regulatory Activities (MedDRA, versions 23-25)-based groups of preferred terms comprising sedation, dissociation, suicidality, suggestive of abuse potential, cystitis, and hepatic impairment.
  • Rates of remission and response over time were compared using unadjusted CMH tests.
  • CfB in MADRS total score at each visit was assessed using a mixed model for repeated measures (with an unstructured covariance structure) based on observed cases (for on-study-treatment visits only).
  • the model included baseline score as a covariate, and study intervention, stratification factors, visit, and visit-by-study-intervention interaction as fixed effects.
  • BMI body mass index
  • CGI-S Clinical Global Impression - Severity
  • IDS-C30 Inventory of Depressive Symptomatology - Clinician-rated, 30-item scale
  • MADRS Montgomery-Asberg Depression Rating Scale
  • MDD major depressive disorder
  • NS nasal spray
  • SD standard deviation
  • SNRI serotonin norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • XR extended release.
  • MDD major depressive disorder
  • MDE major depressive disorder
  • TRD treatment resistant depression.
  • Remission was defined as a MADRS total score of ⁇ 10 and no treatment or study discontinuation before Week 8. a Patients who did not have an available MADRS result at the Week 8 visit but did not discontinue study treatment or withdraw before Week 8 were considered non-responders; b Tested using a Cochran-Mantel-Haenszel test at a two-sided 0.05 significance level without adjustment for multiple testing. Cl: confidence interval; LOCF: last observation carried forward; MADRS: Montgomery- Asberg Depression Rating Scale; NS: nasal spray; OR: odds ratio; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.
  • a greater percentage of patients receiving esketamine NS+SSRI/SNRI achieved remission and response at each timepoint through Week 32 than patients receiving quetiapine XR+SSRI/SNRI (Week 32 remission: 55.0% versus 37.0%, respectively; p ⁇ 0.001; Week 32 response: 75.5% versus 55.5%, respectively; p ⁇ 0.001; FIG 3).
  • patients receiving esketamine NS+SSRI/SNRI consistently demonstrated greater CfB in MADRS total score than patients receiving quetiapine XR+SSRI/SNRI (FIG 5).
  • Remission was defined as a MADRS total score of ⁇ 12 and no treatment or study discontinuation before Week 8.
  • a Missing data for patients continuing study treatment were imputed using LOCF; patients who discontinued were imputed as non-responders;
  • Treatment groups were compared using a Cochran-Mantel-Haenszel chi-square test, adjusted for age group (18-64 years; >65 years) and total number of treatment failures (2; >3);
  • Week 32 endpoint is defined as a participant achieving remission at Week 8 and having no relapse within the consecutive 24 weeks and completed both the treatment and the trial.
  • TEAEs are reported in the table if they occurred in >5% of patients in either treatment group.
  • NS nasal spray;
  • SNRI serotonin norepinephrine reuptake inhibitor;
  • SSRI selective serotonin reuptake inhibitor;
  • TEAE treatment-emergent adverse event;
  • XR extended release.
  • NS nasal spray
  • SNRI serotonin norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • TEAE treatment-emergent adverse event
  • XR extended release
  • ESCAPE-TRD was the first study to compare esketamine NS against a commonly used, guideline-recommended antipsychotic augmentation treatment (quetiapine XR), both in conjunction with a continuing SSRI/SNRI during acute and maintenance treatment phases. 15, 29 Previously, esketamine NS has only been compared with placebo NS, both with a newly initiated oral AD. 20-22, 28, 30 In these studies, esketamine NS+SSRI/SNRI outperformed placebo+SSRI/SNRI during the acute phase, and demonstrated superiority for relapse prevention versus switching to placebo NS.
  • quetiapine XR guideline-recommended antipsychotic augmentation treatment
  • TEAEs observed with esketamine NS were consistent with its established safety profile with no new safety signals identified. 19, 20, 27, 30, 34 No treatment-related suicide attempt was reported during the study. Although TEAEs were more common with esketamine NS+SSRI/SNRI than quetiapine XR+SSRI/SNRI, TEAEs with esketamine NS were typically transient, mild, and occurred on the day of dosing. 19, 35 More patients discontinued study treatment due to TEAEs or a lack of efficacy with quetiapine XR+SSRI/SNRI versus esketamine NS+SSRI/SNRI, whereas discontinuations due to patients refusing further study treatment were comparable.
  • TEAEs arising from esketamine NS may be less burdensome for patients than those from quetiapine XR.
  • LIMITATIONS An open-label design was used to better reflect real-world practice. The use of placebo would have increased the burden on patients through more frequent visits and procedures, with a concomitant risk of functional unblinding due to the distinctive profile of esketamine NS.
  • MADRS score was assessed by an independent blinded rater, who was not otherwise involved in the study. Additionally, no inclusion/exclusion criteria used a MADRS score cut-off, nor was MADRS score used to influence decisions of treatment continuation. In the esketamine NS arm, the absence of blinding and the more frequent clinical interactions, may have influenced perceptions of treatment efficacy; however, patients in the quetiapine XR arm had more frequent clinical interactions than real-world treatment would typically provide. 36 The treatment protocol for esketamine NS reflected real-world clinical practice, and thus provides appropriate guidance for prescribing physicians and patients.
  • Quetiapine XR was chosen as an active comparator due to its approval for, and frequent use as, an add-on treatment in patients with previous treatment failures. 13, 29 However, real-world evidence shows considerable treatment heterogeneity and a lack of clinical consensus, with patients receiving multiple ADs during a single MDE, limiting the generalisability of these findings. 10, 29, 37 CONCLUSIONS
  • ESCAPE-TRD was the first long-term study comparing esketamine NS to a commonly- used antipsychotic augmentation treatment, quetiapine XR, in patients with TRD.
  • esketamine NS in conjunction with a continuing SSRI/SNRI, is a beneficial treatment option for patients with TRD, improving both short- and long-term rates of remission and response, in a population for whom treatment goals are rarely met.
  • FIG 7; p ⁇ 0.001 vs >3 PTFs: HR 2.066 [95% Cl 1.469-2.907]
  • FIG 8 p ⁇ 0.001).
  • response is defined as MADRS score less than or equal to 10 or MADRS improvement greater than or equal to 50%, FIGs 9, 10, and 11.

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Abstract

La présente invention concerne des méthodes et des schémas posologiques pour le traitement de la dépression résistante au traitement chez un patient qui a eu 2 défaillances de traitement antérieures ou plus et qui subit un soulagement de symptôme inadéquat à partir de la combinaison d'un antidépresseur et d'un traitement d'appoint avec de la quétiapine.
PCT/IB2024/052847 2023-03-24 2024-03-25 Eskétamine destinée à être utilisée dans le traitement de la dépression Pending WO2024201274A1 (fr)

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Citations (4)

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WO2019126108A1 (fr) * 2017-12-22 2019-06-27 Janssen Pharmaceutica Nv Eskétamine pour le traitement de la dépression
WO2020178653A1 (fr) * 2019-03-05 2020-09-10 Janssen Pharmaceuticals, Inc. Eskétamine pour le traitement de la dépression
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