US20230117657A1 - Esketamine for the treatment of depression - Google Patents

Esketamine for the treatment of depression Download PDF

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US20230117657A1
US20230117657A1 US17/436,188 US202017436188A US2023117657A1 US 20230117657 A1 US20230117657 A1 US 20230117657A1 US 202017436188 A US202017436188 A US 202017436188A US 2023117657 A1 US2023117657 A1 US 2023117657A1
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esketamine
patient
treatment
drug product
phase
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Jaskaran Singh
Ella Daly
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
Janssen Pharmaceuticals Inc
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Publication of US20230117657A1 publication Critical patent/US20230117657A1/en
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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
    • 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
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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 invention is directed to pharmaceutical products, and to methods for the treatment of depression (e.g., major depressive disorder).
  • depression e.g., major depressive disorder
  • the methods are useful for the treatment of treatment-refractory or treatment-resistant depression.
  • the methods are useful for the treatment of suicidal ideation.
  • the invention comprises administering to a patient in need thereof a clinically proven safe and therapeutically effective amount of esketamine as mono-therapy or as combination therapy with at least one antidepressant.
  • MDD Major depressive disorder
  • TRD treatment resistant depression
  • TRD TRD-related disease .
  • Many patients have depressive episodes lasting years. Severely depressed patients lose the will to carry on with their lives, there is a 7-fold increase in suicide attempts. Life expectancy is lowered by 10 years. In extreme cases they cannot even engage in basic self-care activities such as bathing or eating, or taking care of themselves, leave alone those in their care as a parent, spouse etc. This impacts not only the patient themselves, but also the family and those dependent on them. They also lose the ability to experience pleasure in doing the things that used to enjoy, which robs people of the essence of life and what drives it. In effect their lives are taken away from them by TRD. These effects are theorized to be related to dysregulation of the glutamate pathway.
  • Glutamate is the major excitatory neurotransmitter in the mammalian brain and has a prominent role in synaptic plasticity, learning and memory. At elevated levels, glutamate is a potent neuronal excitotoxin that may provoke rapid or delayed neurotoxicity.
  • glutamate is a potent neuronal excitotoxin that may provoke rapid or delayed neurotoxicity.
  • Ketamine a classic anesthetic drug, showed activity not only in animal models of depression but also in small scale clinical studies in patients with major depressive disorder including subjects with treatment-resistant depression. At low, subanesthetic doses administered by intravenous infusion, ketamine showed a robust antidepressant effect in patients that lasted for a few days after a single dose and could be maintained for several weeks via repeated infusions.
  • Ketamine (a racemic mixture of the corresponding S- and R-enantiomers) is a nonselective antagonist at the phencyclidine binding site of the glutamate N-methyl-D-aspartate (NMDA) receptor, although this may not primarily mediate the antidepressant effect.
  • NMDA glutamate N-methyl-D-aspartate
  • ketamine and esketamine A major concern associated with ketamine and esketamine is the potential for neurotoxicity associated with long-term use and whether repeated doses of ketamine/esketamine in the longer term can maintain a significant antidepressant effect (Molero, et al., “Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review,” CNS Drugs (2016) 32:411-420).
  • esketamine showed greater undesirable psychotomimetic side effects compared with R-ketamine, including a significant reduction in PV-positive cells in the brain that is associated with psychosis and cognitive impairment (id.).
  • the literature does not provide guidance concerning the cumulative effect or tolerability of long term dosing of esketamine.
  • the present invention is directed to methods for the treatment of depression (e.g., major depressive disorder), comprising administering to a patient in need thereof, a clinically proven safe and therapeutically effective amount of esketamine.
  • depression e.g., major depressive disorder
  • the present invention is further directed to a method for the treatment of depression (e.g., major depressive disorder), comprising administering to a patient in need thereof, combination therapy with a clinically proven safe and therapeutically effective amount of esketamine and at least one antidepressant, as herein defined.
  • depression e.g., major depressive disorder
  • the present invention also is directed to methods of maintaining stable remission or stable response achieved by a patient with depression following administration of a therapeutically effective amount of esketamine during an initial administration phase, comprising continuing administration of a therapeutically effective amount of esketamine for at least five months during a subsequent administration phase.
  • the depression is major depressive disorder or treatment resistant depression.
  • the present invention further is directed to methods for the long term treatment of depression in a patient, comprising administering to the patient in need of treatment a clinically proven safe and/or clinically proven effective therapeutically effective amount of esketamine for at least six months.
  • the depression is major depressive disorder or treatment resistant depression.
  • the method of treatment includes long term treatment, including durations of at least about six months.
  • the treatment may be a duration of at least about one year, at least about 18 months, or at least about two years.
  • long term treatment may include a duration range of about six months to about two years. The treatment may extend for much longer periods of time to the extent that the patient is benefiting from the therapy.
  • the at least one antidepressant is independently selected from the group consisting of mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors and hormones.
  • methods for the treatment of depression comprise administering to a patient in need thereof a clinically proven safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of mono-amine oxidase inhibitors (MAOI) such as irreversible MAOI (phenelzine, tranylcypromine), reversible (MOAI) moclobemide, and the like; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, 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; anticholinergics e.g.
  • MAOI mono-amine oxidase inhibitors
  • MOAI reversible mo
  • scopolamine scopolamine
  • serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, and the like
  • serotonin receptor antagonists such as nefazadone, tianeptine and the like
  • serotonin noradrenergic reuptake inhibitors such as venlafaxine, des-venlafaxine, milnacipran, levo-milnacipran, and the like
  • noradrenergic and specific serotonergic agents such as mirtazapine, and the like
  • noradrenaline reuptake inhibitors such as reboxetine, and the like
  • atypical antipsychotics such as bupropion and the like, and the like
  • lithium, triple reuptake inhibitors natural products such as Kava-Kava, St.
  • John's Wort, and the like dietary supplements such as s-adenosylmethionine, and the like; and neuropeptides such as thyrotropin-releasing hormone and the like, and the like; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like; and hormones such as triiodothyronine, and the like.
  • methods for the treatment of depression comprise administering to a patient in need thereof a clinically proven safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of mono-amine oxidase inhibitors; tricyclics; tetracyclics; non-cyclics; triazolopyridines; serotonin reuptake inhibitors; serotonin receptor antagonists; serotonin noradrenergic reuptake inhibitors; serotonin noradrenergic reuptake inhibitors; noradrenergic and specific serotonergic agents; noradrenaline reuptake inhibitors; atypical antipsychotics; natural products; dietary supplements; neuropeptides; compounds targeting neuropeptide receptors; and hormones.
  • esketamine is administered in combination with one or more compounds selected from the group consisting of mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, atypical antipsychotics, and/or adjunctive therapy with antipsychotic medication (e.g. risperidone, olanzapine, quetiapine, aripiprazole and ziprasidone).
  • mono-amine oxidase inhibitors tricyclics
  • serotonin reuptake inhibitors serotonin noradrenergic reuptake inhibitors
  • noradrenergic and specific serotonergic agents e.g. risperidone, olanzapine, quetiapine, aripiprazole and ziprasidone.
  • esketamine is administered in combination with one or more compounds selected from the group consisting of mono-amino oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
  • methods for the treatment of depression comprise administering to a patient in need thereof a clinically proven safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, bupropion, thyrotropin-releasing hormone and triiodothyronine.
  • esketamine is administered in combination with one or more compounds selected from the group consisting of lithium, riluzole, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, levomilnacipran, mirtazapine and bupropion.
  • esketamine is administered in combination with one or more compounds selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram and fluvoxamine. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of fluoxetine, sertraline, paroxetine, citalopram, escitalopram and fluvoxamine.
  • methods for the treatment of depression comprise administering to a patient in need thereof a clinically proven safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of neuropeptides such as thyrotropin-releasing hormone and the like; compounds targeting neuropeptide receptors such as neurokinin receptors antagonists and the like; and hormones such as triiodothyronine and the like.
  • neuropeptides such as thyrotropin-releasing hormone and the like
  • compounds targeting neuropeptide receptors such as neurokinin receptors antagonists and the like
  • hormones such as triiodothyronine and the like.
  • methods for the treatment of depression comprise administering to a patient in need thereof, combination therapy with a clinically proven safe and therapeutically effective amount of esketamine, at least one antidepressant, and at least one atypical antipsychotic, as herein defined.
  • methods for the treatment of depression comprise administering to a patient in need thereof, combination therapy with a clinically proven safe and therapeutically effective amount of esketamine, at least one antidepressant, and at least one atypical antipsychotic selected from the group consisting of quetiapine, aripiprazole, brexpiprazole, olanzapine, lurasidone, risperidone and paliperidone.
  • the methods for treatment of depression may be combined with adjunctive therapies such as anti-psychotic therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or combinations thereof.
  • adjunctive therapies such as anti-psychotic therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or combinations thereof.
  • the present invention is further directed to uses of esketamine in the preparation of a medicament for treating depression (e.g., major depressive disorder) in a patient in need thereof.
  • a medicament for treating depression e.g., major depressive disorder
  • the medicament is for treating treatment-refractory or treatment-resistant depression.
  • the medicament is for treating suicidal ideation.
  • the present invention is further directed to esketamine for use in a method for the treatment of depression (e.g., major depressive disorder), preferably treatment-refractory or treatment-resistant depression, in a subject in need thereof.
  • depression e.g., major depressive disorder
  • esketamine for use in a method for the treatment of depression (e.g., major depressive disorder), preferably treatment-refractory or treatment-resistant depression, in a subject in need thereof.
  • compositions comprising esketamine for the treatment of depression (e.g., major depressive disorder) are provided.
  • the compositions are for the treatment of treatment-refractory or treatment-resistant depression.
  • the medicament is for treating suicidal behavior and/or suicidal ideation.
  • the present invention is also directed to methods of treating depression, comprising administering an approved drug product containing esketamine to a subject with depression in an amount that is described in a drug product label for the approved drug product.
  • the present invention is further directed to methods of selling an approved drug product comprising esketamine, said method comprising selling such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating depression.
  • the present invention also is directed to methods of offering for sale a drug product comprising esketamine, said method comprising offering for sale such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating depression.
  • the present invention is further directed to approved drug products with at least one approved indication, wherein said approved drug product comprises esketamine.
  • the present invention also is directed to methods of using the approved product described herein, wherein the approved product comprises one or more intranasal spray devices, the one or more devices comprise the esketamine, and the one or more devices is configured to administer from about 28 to about 84 mg of esketamine.
  • the present invention is further directed to methods to mitigate the risk of misuse or abuse of esketamine, comprising restricting distribution of an approved esketamine drug product to selected distributors, wherein the distributors are Drug Enforcement Administration registered and deliver the approved esketamine drug product only to a pre-approved site of care.
  • FIG. 1 illustrates a schematic of the study design of the ESKETINTRD3002 Phase 3 clinical trial.
  • FIG. 2 illustrates the least squares mean changes ( ⁇ SE) in MADRS total score over time observed case MMRM during the double-blind induction phase.
  • LS mean and SE were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (intranasal esketamine+oral AD, oral AD+intranasal placebo), day, country, class or oral antidepressant (SNRI or SSRI), and treatment-by-day, and baseline value as a covariate.
  • Negative change in score indicated improvement. *1-sided p ⁇ 0.025.
  • FIG. 3 is a bar graph of the response rates on day 2; a response is a ⁇ 50% improvement on MADRS from baseline for patients taking esketamine and an oral antidepressant.
  • FIG. 4 is a bar graph of the response rates on day 28; a response is a ⁇ 50% improvement on MADRS from baseline for patients taking esketamine and an oral antidepressant.
  • FIG. 5 is a bar graph of the remission rates on day 28; remission is a MADRS total score of ⁇ 12.
  • FIG. 6 is a bar graph showing the percent of subjects reporting problems (levels 2 through 5) with mobility, self-care, activities, pain, and anxiety/depression.
  • FIG. 7 illustrates the arithmetic mean ( ⁇ SE) for systolic blood pressure over time during the double-blind induction phase using the safety analysis set.
  • FIG. 8 illustrates the arithmetic mean ( ⁇ SE) for diastolic blood pressure over time; double-blind induction phase using the safety analysis set.
  • FIG. 9 illustrates the clinician-assessed dissociative symptom scale (CADSS), total score over time during the double-blind phase using the safety analysis set.
  • CADSS clinician-assessed dissociative symptom scale
  • FIG. 10 illustrates the arithmetic mean ( ⁇ SE) modified observer's assessment of alertness/sedation (MOAA/S) score over time; double-blind induction phase using the safety analysis set.
  • ⁇ SE arithmetic mean
  • MOAA/S alertness/sedation
  • FIG. 11 illustrates the Least Square mean change in total MADRS score over time (observed cases) in US patients with TRD.
  • FIG. 12 illustrates patient-rated severity of depressive illness (observed cases) in US patients with TRD, as assessed with the PHQ-9.
  • FIG. 13 illustrates functional impairment (observed case) in US patients with TRD, as assessed with SDS.
  • FIG. 14 illustrates the percentage of US patients with TRD achieving a response 4 weeks post initial dose (observed case).
  • FIG. 15 illustrates the percentage of US patients with TRD achieving clinician-rated remission 4-weeks post initial dose.
  • FIG. 16 illustrates the frequency distribution of PHQ-9 severity categories (observed case) in US patients with TRD.
  • FIG. 17 illustrates the percentage of US patients with TRD who had ⁇ 1-point decrease in the CGI-S (observed case) 4-weeks post initial dose.
  • FIG. 18 illustrates a schematic to the study design of the ESKETINTRD3005 Phase 3 clinical trial.
  • FIG. 19 illustrates the least squares mean changes ( ⁇ SE) in MADRS total score over time observed case MMRM; double-blind induction phase (study ESKETINTRD3005: full analysis set).
  • FIG. 20 illustrates that arithmetic mean ( ⁇ SE) systolic blood pressure over time during the double-blind induction phase using the ESKETINTRD3005 safety analysis set.
  • ⁇ SE arithmetic mean
  • FIG. 21 illustrates that arithmetic mean ( ⁇ SE) diastolic blood pressure over time during the double-blind induction phase using the ESKETINTRD3005 safety analysis set.
  • ⁇ SE arithmetic mean
  • FIG. 22 is a plot of CADSS total score over time during the double-blind phase using the safety analysis set.
  • FIG. 23 illustrates the least squares mean changes ( ⁇ SE) in MADRS total score over time LOCF ANCOVA during the double-blind induction phase using the full analysis set.
  • LS Mean and SE were based on analysis of covariance (ANCOVA) model with change from baseline as the response variable and factors for treatment (intranasal esk+oral AD, oral AD+intranasal placebo), region, and class of oral antidepressant (SNRI or SSRI), and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement.
  • FIG. 24 illustrates the forest plot for MADRS total score showing the least squares mean treatment difference of change from baseline (95% Confidence Interval) to day 28 MMRM by Subgroup during the double-blind induction phase using the full analysis set. Subgroups with fewer than 5 subjects not presented. Results are not adjusted for sample size re-estimation.
  • FIG. 25 illustrates the arithmetic mean changes ( ⁇ SE) in MADRS total score over time observed case for the age 65-74 group during the double-blind induction phase using the full analysis set.
  • FIG. 26 illustrates the arithmetic mean changes ( ⁇ SE) in MADRS total score over time observed case for the age ⁇ 75 group during the double-blind induction phase using the full analysis set.
  • FIG. 27 illustrates the least squares mean changes ( ⁇ SE) in MADRS total score over time (observed cases) MMRM for Stage 1 during the double-blind induction phase using the full analysis set.
  • LS Mean and SE were based on mixed model for repeated measures (MMRM) with change from baseline as the response variable and the fixed effect model terms for treatment (intranasal esk+oral AD, oral AD+intranasal placebo), day, region, class of oral antidepressant (SNRI or SSRI), and treatment-by-day, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement.
  • FIG. 28 illustrates the least squares mean changes ( ⁇ SE) in MADRS total score over time (observed cases) MMRM for stage 2 during the double-blind induction phase using the full analysis set.
  • S Mean and SE were based on mixed model for repeated measures (MMRM) with change from baseline as the response variable and the fixed effect model terms for treatment (intranasal esk+oral AD, oral AD+intranasal placebo), day, region, class of oral antidepressant (SNRI or SSRI), and treatment-by-day, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement.
  • FIG. 29 illustrates that least squares mean change in MADRS total score over time (observed cases) in US patients aged ⁇ 65 years with TRD.
  • MADRS total score ranges from 0 to 60; a higher score indicates a more severe condition.
  • FIG. 30 illustrates that frequency distribution of illness severity based on CGI-S scores at baseline and double-blind phase endpoint (LOCF).
  • CGI-S score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
  • CGI-S score ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
  • FIG. 31 illustrates the percentage of US patients aged ⁇ 65 years with TRD achieving response (observed case), as assessed by MADRS.
  • Clinician-rated response a was defined as a ⁇ 50% decrease from baseline in MADRS total score.
  • FIG. 32 illustrates the percentage of US patients aged ⁇ 65 years with TRD achieving remission (observed case), as assessed by MADRS. Clinician-rated remission was defined as a MADRS total score of ⁇ 12.
  • FIG. 33 illustrates the percentage of US patients aged ⁇ 65 years with TRD achieving patient-rated remission (observed case), as assessed by PHQ-9.
  • FIG. 34 illustrates the percentage of US patients aged ⁇ 65 years with TRD who had a clinically meaningful response, as assessed by CGI-S.
  • FIG. 35 illustrates the percentage of US patients aged ⁇ 65 years with TRD who had a clinically significant response, as assessed by CGI-S.
  • Clinically meaningful and clinically significant responses were defined as a ⁇ 1-point or a ⁇ 2-point decrease in CGI-S from baseline, respectively.
  • FIG. 36 illustrates the frequency distribution of illness severity based on clinical global impression-severity (CGI-S) scores at baseline and double-blind phase endpoint.
  • CGI-S clinical global impression-severity
  • FIG. 37 shows the study design for evaluate the efficacy and safety of intranasal esketamine for the rapid reduction of the symptoms of major depressive disorder, including suicidal ideation, in subjects assessed to be at imminent risk for suicide.
  • FIG. 38 shows least-square mean changes ( ⁇ SE) from baseline for the MADRS total score over time in the double-blind phase using last observation carried forward data.
  • LS Mean and SE was based on analysis of covariance (ANCOVA) model with treatment (placebo, esketamine 84 mg), antidepressant therapy (AD monotherapy, AD plus augmentation therapy) and analysis center as factors, and baseline value as a covariate.
  • FIG. 39 shows the mean changes (SE) in CGJSR from baseline to 4 and 24 hours.
  • Mean change and SE were based on ranks of change from baseline (LOCF) data and analyzed using an ANCOVA model with treatment, analysis center, and SoC as fixed effects and baseline value (unranked as a covariate).
  • FIG. 40 correlates the percentage of patients with the resolution of suicide risk at 4 and 24 hours.
  • FIG. 41 shows the frequency distribution of SIBAT scores at double-blind baseline, Day 1:4-hours postdose, double-blind endpoint, and follow-up endpoint.
  • Clinical global judgment of suicide risk scores range from 0 to 6. 0: Not suicidal; 1: Occasional suicidal ideas present, but no special intervention required; 2: Some clear suicidal ideas present; patient is encouraged to schedule professional contacts as needed; 3: Suicidal risk requires a scheduled outpatient follow-up; but no other immediate intervention; 4: Suicidal risk requires immediate intervention, but not hospitalization (e.g., medication, urgent outpatient follow-up); 5: Suicidal risk requires immediate hospitalization, but without suicide precautions; 6: Suicidal risk requires hospitalization with suicide precautions.
  • FIG. 42 shows the least-square mean changes (SE) from baseline in MADRS score to 4 hours (primary endpoint) and about 24 hours.
  • FIG. 43 correlates the percentage of patients with their respective MADRS response and remission at days 1, 2 and endpoint.
  • FIG. 44 correlates the percentage of patients having remission at DB endpoint and during follow-up.
  • FIG. 45 shows least-square mean changes ( ⁇ SE) from baseline for the BSS total score over time in the double-blind phase using last observation carried forward data.
  • FIGS. 46 and 47 present means for blood pressure over time by treatment group in the double-blind phase.
  • FIG. 48 is a plot of CADSS total score over time during the double-blind phase (Study ESKETINSUI2001: Safety Analysis Set).
  • FIG. 49 is the trial design for Example 4.
  • FIG. 50 is a flowchart summarizing the subject and treatment information of Example 4.
  • FIG. 51 shows the cumulative proportion of subjects who remained relapse free; maintenance phase (Kaplan-Meier estimates) (full (stable remitters) analysis set) for Example 4.
  • FIG. 52 shows the cumulative proportion of subjects who remained relapse free; maintenance phase (Kaplan-Meier estimates) (full (stable responders) analysis set) for Example 4.
  • FIG. 53 shows the arithmetic mean ( ⁇ SE) systolic blood pressure over time; maintenance phase (safety (MA) analysis set) for Example 4.
  • FIG. 54 shows the arithmetic mean ( ⁇ SE) diastolic blood pressure over time; maintenance phase (safety (MA) analysis set) for Example 4.
  • FIG. 55 shows the arithmetic mean ( ⁇ SE) CADSS total score over time; maintenance phase (safety (MA) analysis set) for Example 4.
  • FIG. 56 is a forest plot of hazard ratio by subgroup: Cox Regression (full (stable remitters) analysis set) for Example 4. Hazard ratio estimates for subgroups with no event in either arm not displayed. Subgroups with fewer than 5 subjects not presented.
  • FIG. 57 is the trial design for Example 5. At entry to the trial, transferred entry non-responder subjects continued to receive the same oral antidepressant initiated in the ESKETINTRD3005 study. The new oral AD is for direct entry subjects only.
  • FIG. 58 is shows the frequency distribution for the CGI-S of Example 5.
  • FIG. 59 shows the arithmetic mean ( ⁇ SE) of detection—attention (simple reaction time) (all enrolled analysis set) for the age group ⁇ 65 years in Example 5.
  • FIGS. 60 - 62 shows the level of impairment for the EQ-5D-5L by measuring anxiety/depression, usual activities, and pain/discomfort, respectively.
  • FIG. 63 shows the arithmetic mean ( ⁇ SE) systolic blood pressure over time; induction and optimization/maintenance phases (all enrolled analysis set) for Example 5.
  • FIG. 64 shows the arithmetic mean ( ⁇ SE) diastolic blood pressure over time; induction and optimization/maintenance phases (all enrolled analysis set) for Example 5.
  • FIG. 65 is a plot of CADSS total score over time during the induction and optimization/maintenance phase (all enrolled analysis set) for Example 5.
  • FIG. 66 is a plot showing the mean ( ⁇ ) SE for the of the brief psychiatric rating positive symptom subscale total score over time during the induction and optimization/maintenance phases (all enrolled analysis set) for Example 5.
  • FIG. 67 shows means for the MADRS total score over time in the IND and OP/MA phases based on observed case data for Example 5.
  • FIG. 68 shows the response for patients having a response with a ⁇ 50% reduction from baseline and a remission with a MADRS of ⁇ 12.
  • FIG. 69 shows means for the PHQ-9 total score over time in the IND and OP/MA phases based on observed case data for Example 5.
  • FIG. 70 is an illustration of decreased and increased activity. MK-801-induced changes in activity are described in Section 3.3 of Example 6. Gross pathology did not reveal any tissue changes.
  • FIG. 71 A to FIG. 71 C shows a repeated dose neurotoxicity study.
  • Haematoxylin-eosin (HE) stained retrosplenial cortex shows the absence of neuronal necrosis in an esketamine HCl-treated rat (54 mg/day) and its presence in an (+)MK-801 maleate-treated rat as described in Example 6.
  • FIG. 71 A is an image of the retrosplenial cortex of an esketamine HCl-treated rat (54 mg/day) showing the absence of neuronal necrosis.
  • FIG. 71 B is an image of the retrosplenial cortex from an (+)MK-801 maleate-treated animal.
  • FIG. 71 C is an image of a higher power view of the necrotic neurons (arrows) in the retrosplenial cortex from an (+)MK-801maleate treated animal.
  • FIG. 72 A and FIG. 72 B illustrate a repeated dose neurotoxicity study.
  • Fluoro-Jade (FJ) stained retrosplenial cortex shows the absence of neuronal necrosis in an esketamine HCl-treated rat (54 mg/day) and its presence in an (+)MK-801 treated rat as described in Example 6.
  • FIG. 72 A is an image of the retrosplenial cortex of an esketamine HCl-treated rat (54 mg/day) showing the absence of neuronal necrosis.
  • FIG. 72 B is an image of the retrosplenial cortex from an (+)MK-801 maleate-treated animal.
  • FIG. 73 is a flowchart showing the disposition of patients of Example 7. Seven participants started the follow-up phase earlier than day 74, having received 2 weeks of study drug during the open-label phase of the study.
  • FIG. 75 is a line graph showing the MADRS total score mean change from baseline to follow-up endpoint for participants who entered the open-label phase of Example 7.
  • Period 1 (days 1-8), period 2 (days 8-15), open-label period (days 15-74), and the follow-up period (days 74-130) are discussed in the Design section of the Methods and shown in the vertical axis of FIG. 73 .
  • BL indicates baseline; error bars, SE.
  • FIGS. 76 A and 76 B are line graphs showing the mean ( ⁇ SE) MADRS total score over time in the double-blind phase of Example 7.
  • modified MADRS was used, with baseline scores for sleep and appetite items carried forward.
  • FIG. 77 is a plot of mean systolic blood pressure over time by period for participants who received the same treatment for both periods during the double-blind phase in Example 7.
  • FIG. 78 is a plot of mean diastolic blood pressure over time by period for participants who received the same treatment for both periods during the double-blind phase in Example 7.
  • FIG. 79 is a plot of mean CADSS total score over time for participants who received the same treatment for both periods in Example 7.
  • FIG. 80 is a plot of the mean plasma concentration-time profile of esketamine.
  • FIG. 81 is a plot of the mean plasma concentration-time profile of noresketamine.
  • FIG. 83 A to 83 E depict instructions for use for an exemplary nasal spray device.
  • FIG. 84 is a flow diagram of an approved esketamine drug product through possible medical systems.
  • FIG. 85 are the administration instructions for Example 11.
  • FIG. 86 shows the effect of specific populations on the pharmacokinetics of esketamine.
  • FIG. 87 shows the effect of co-administered drugs on the pharmacokinetics of esketamine.
  • FIG. 88 shows the effect of esketamine on the pharmacokinetics of co-administered drugs.
  • FIG. 89 is a line graph of the least squares mean change from baseline in MADRS total score over time in patients with TRD in study 1* (Full Analysis Set)—MMRM analysis. Note: In this flexible-dose study, dosing was individualized based on efficacy and tolerability. Few subjects ( ⁇ 10%) had reduction in SPRAVATO dosage from 84 mg to 56 mg twice weekly.
  • FIG. 90 is a plot of the time to relapse in patients with TRD in stable remission in study 2* (Full Analysis Set). Note: The estimated hazard ratio (95% CI) of SPRAVATO+Oral AD relative to Placebo nasal spray+Oral AD based on weighted estimates was 0.49 (95% Cl: 0.29, 0.84). However, the hazard ratio did not appear constant throughout the trial.
  • FIG. 91 is a plot of time to relapse in patients in stable response in TRD patients in study 2* (Full Analysis Set). Note: The estimated hazard ratio (95% CI) of SPRAVATO+Oral AD relative to Placebo nasal spray+Oral AD based on Cox proportional hazards model was 0.30 (95% Cl: 0.16, 0.55).
  • the present invention is directed to methods for the treatment of depression (e.g., major depressive disorder), comprising administering to a patient in need thereof, a clinically proven safe and therapeutically effective amount of esketamine.
  • the methods are for the treatment of treatment refractory depression or treatment resistant depression.
  • the medicament is for treating suicidal ideation.
  • Such methods advantageously permit tailoring an effective regimen to patients who have depression.
  • Such patients include those who have already been diagnosed with MDD, TRD, are suicidal, or have otherwise been untreated for depression.
  • Methods of maintaining stable remission or stable response achieved by a patient with depression following administration of a therapeutically effective amount of esketamine during an initial administration phase include continuing administration of a therapeutically effective amount of esketamine for at least five months during a subsequent administration phase.
  • methods for the long term treatment of depression in a patient comprise administering to the patient in need of the treatment a clinically proven safe and clinically proven effective therapeutically effective amount of esketamine for at least six months.
  • cognitive performance of the patient remains stable, based on a baseline measurement, following six months of treatment.
  • the treatment may be a duration of at least about one year, at least about 18 months, or at least about two years.
  • long term treatment may include a duration range of about six months to about two years.
  • Treatment may also be continued for longer periods of time including, without limitation, 4, 5, 6, 7, 8, 9, 10, or longer years, as determined by the attending physician.
  • the esketamine is initially dosed twice a week for up to four weeks during an induction phase, and, thereafter, dosed less frequently than twice a week.
  • esketamine may be administered in combination with one or more antidepressants, as herein described, preferably in combination with one to three antidepressants, more preferably in combination with one to two antidepressants.
  • esketamine may be administered in combination with one or more antidepressants, and further in combination with one or more atypical antipsychotics, herein described.
  • the present invention is directed to combination therapy comprising esketamine and one or more antidepressants; wherein the esketamine is administered as acute treatment.
  • the present invention is directed to combination therapy comprising esketamine and one or more antidepressants wherein the esketamine is administered as acute treatment and wherein the one or more antidepressants are administered as chronic treatment.
  • the esketamine may be used as a mono-therapy and not in combination with any other active compounds.
  • ketamine shall mean the (S)-enantiomer of ketamine, i.e., a compound of formula (I):
  • ketamine shall also mean a salt, e.g., a chloride salt such as the hydrochloride salt, of the (S)-enantiomer of ketamine, i.e., a compound of formula (11):
  • the esketamine is substantially free of the (R)-enantiomer of ketamine, i.e. a compound of formula (III):
  • the esketamine contains less than about 10% by weight, based on the weight of the esketamine sample, of the (R)-enantiomer of ketamine. In further embodiments, the esketamine contains less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.005, or 0.001% by weight, based on the weight of the esketamine sample, of the (R)-enantiomer of ketamine. In yet other embodiments, the esketamine contains about 0.001 to about 10% by weight, based on the weight of the esketamine sample, of the (R)-enantiomer of ketamine.
  • the esketamine contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight, based on the weight of the esketamine sample, of the (R)-enantiomer of ketamine.
  • esketamine may also include other pharmaceutically acceptable salts thereof, which may readily be selected by those skilled in the art.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of esketamine that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G. S. Paulekuhn, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S. M.
  • Examples of other pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesul
  • the esketamine is administered intranasally. In certain embodiments of the present invention, the esketamine is administered intranasally as its corresponding hydrochloride salt. In certain embodiments of the present invention, the esketamine is administered intranasally as its corresponding hydrochloride salt in an 16.14% weight/volume solution (equivalent to 14% weight/volume of esketamine base).
  • the esketamine is administered intranasally as a solution comprising 161.4 mg/mL of esketamine hydrochloride (equivalent to 140 mg/mL of esketamine base), 0.12 mg/mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg/mL citric acid, at a pH of 4.5 in water.
  • the esketamine is administered intranasally, wherein the intranasal delivery administers 100 ⁇ L of a solution comprising 161.4 mg/mL of esketamine hydrochloride (equivalent to 140 mg/mL of esketamine base), 0.12 mg/mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg/mL citric acid, at a pH of 4.5 in water.
  • a solution comprising 161.4 mg/mL of esketamine hydrochloride (equivalent to 140 mg/mL of esketamine base), 0.12 mg/mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg/mL citric acid, at a pH of 4.5 in water.
  • EDTA ethylenediaminetetraacetic acid
  • the esketamine is delivered intranasally using a nasal spray pump, wherein the pump delivers 100 ⁇ L of a solution comprising 161.4 mg/mL of esketamine hydrochloride (equivalent to 140 mg/mL of esketamine base), 0.12 mg/mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg/mL citric acid, at a pH of 4.5 in water.
  • a nasal spray pump delivers 100 ⁇ L of a solution comprising 161.4 mg/mL of esketamine hydrochloride (equivalent to 140 mg/mL of esketamine base), 0.12 mg/mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg/mL citric acid, at a pH of 4.5 in water.
  • EDTA ethylenediaminetetraacetic acid
  • a single pump from a nasal spray device may be configured to deliver about 50 ⁇ L to about 200 ⁇ L of an esketamine solution to a nostril of the subject, including about 60 ⁇ L, about 70 ⁇ L, about 80 ⁇ L, about 90 ⁇ L, about 100 ⁇ L, about 110 ⁇ L, about 120 ⁇ L, about 130 ⁇ L, about 140 ⁇ L, about 150 ⁇ L, about 160 ⁇ L, about 170 ⁇ L, about 180 ⁇ L, and about 200 ⁇ L. Accordingly, two pumps deliver about 100 ⁇ L to about 400 ⁇ L to the subject.
  • a patient in need of treatment with a clinically proven safe and therapeutically effective amount of esketamine is a patient suffering from an episode of depression (e.g., major depressive disorder).
  • a patient in need thereof is suffering from an episode of depression (e.g., major depressive disorder), wherein the episode of depression (e.g., major depressive disorder) has not responded to treatment with at least two oral antidepressants (i.e. the patient has not responded to treatment with at least two oral antidepressants).
  • a geriatric patient in need thereof is suffering from an episode of depression (e.g., major depressive disorder), wherein the episode of depression (e.g., major depressive disorder) has not responded to treatment with two oral antidepressants (i.e. the geriatric patient has not responded to treatment with two oral antidepressants).
  • an episode of depression e.g., major depressive disorder
  • the episode of depression e.g., major depressive disorder
  • two oral antidepressants i.e. the geriatric patient has not responded to treatment with two oral antidepressants
  • a patient in need thereof is suffering from depression (e.g., major depressive disorder).
  • depression e.g., major depressive disorder
  • depression includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, mid-life depression, late-life depression, depression due to identifiable stressors, treatment resistant depression, or combinations thereof.
  • the depression is major depressive disorder.
  • the major depressive disorder is with melancholic features or anxious distress.
  • the depression is treatment-resistant depression.
  • non-responder means patients that do not recover fully on an antidepressant medication (e.g. 25% or less change from baseline in total MADRS score).
  • the term “episode of major depressive disorder” means a continuous period (e.g., about 2 weeks or more) in which a patient has symptoms of a major depressive disorder sufficient to meet criteria for major depression as specified in the Diagnostic and statistical Manual of Mental Disorders, 5 th Edition: DSM 5.
  • Suicide is the “act of taking one's own life”. See, http://en.wikipedia.org/wiki/Suicide—cite_note-7. Suicide includes attempted suicide or non-fatal suicidal behavior, which is self-injury with the desire to end one's life that does not result in death. Suicide attempt is a self-initiated sequence of behaviors by an individual who, at the time of initiation, expected that the set of actions would lead to his or her own death.
  • suicidal ideation refers to 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.
  • the range of suicidal ideation varies greatly from fleeting to chronic and progresses to detailed planning, role playing, and unsuccessful attempts, which may be deliberately constructed to fail or be discovered, or may be fully intended to result in death.
  • a patient is classified as being “suicidal” when the patient has a mean baseline MADRS total score of about 38 or greater.
  • a patient is classified as being suicidal when the patient has a mean baseline BBSS score of 22 or greater.
  • a patient is classified as being suicidal when the patient has a score of 6 or greater in the SIBAT clinical global judgement of suicide risk.
  • the patient has one or more combinations of these scores.
  • co-therapy shall mean treatment of a patient in need thereof by administering esketamine in combination with one or more antidepressant(s), wherein the esketamine and the antidepressant(s) are administered by any suitable means.
  • esketamine is administered in a regimen with one to five antidepressants.
  • esketamine is administered in a regimen with one, two, three, four, or five antidepressants.
  • esketamine is administered in a regimen with one or two antidepressants.
  • the esketamine is administered in a regimen with the antidepressant currently being administered to the patient. In other embodiments, the esketamine is administered in a regimen with a different antidepressant. In yet further embodiments, the esketamine is administered in a regimen with an antidepressant not previously administered to the patient. In still other embodiments, the esketamine is administered in a regimen with an antidepressant previously administered to the patient. 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 and more typically different. The antidepressant may be dosed as prescribed by the attending physician and/or by its label and the esketamine is dosed as described herein.
  • a patient is under concurrent treatment with both an antidepressant and esketamine, where both are administered by their prescribed dosing regimens.
  • 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), transdermal, buccal, or rectal.
  • esketamine is administered intranasally.
  • the term “antidepressant” shall mean any pharmaceutical agent which can be used to treat depression.
  • Suitable examples include, without limitation, a mono-amine oxidase inhibitor, tricyclic, serotonin reuptake inhibitor, serotonin noradrenergic reuptake inhibitor, noradrenergic and specific serotonergic agent, or atypical antipsychotic.
  • John's Wort, and the like dietary supplements such as s-adenosylmethionine, and the like; and neuropeptides such as thyrotropin-releasing hormone and the like; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like; and hormones such as triiodothyronine, and the like.
  • the antidepressant is imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St.
  • the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline.
  • Therapeutically effective amounts/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), may be readily determined by one of ordinary skill in the art.
  • 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 antipsychotics and mood stabilizers 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, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), divalproate (mood stabilizer) and the like.
  • the “atypical antipsychotic” is selected from the group consisting of aripiprazole, 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.
  • treatment-refractory or treatment-resistant depression and the abbreviation “TRD” shall be defined as major depressive disorder in a patient that does not respond adequately to at least two different antidepressants, preferably between two and five antidepressants, in the current depressive episode.
  • TRD is defined as major depressive disorder in a patient that has not responded to at least two oral antidepressants of adequate dose and duration in the current depressive episode.
  • the failure to respond to an adequate course of a given antidepressant may be determined retrospectively or prospectively. In an embodiment, at least one of the failures to respond to an adequate course of antidepressant is determined prospectively. In another embodiment, at least two of the failures to respond to an adequate course of antidepressant are determined prospectively. In another embodiment, at least one of the failures to respond to an adequate course of antidepressant is determined retrospectively. In another embodiment, at least two of the failures to respond to an adequate course of antidepressant are determined retrospectively in a current depressive episode.
  • the “at least two oral antidepressants” or “at least two different oral depressants” has been administered to the patient at an adequate dose which may be determined by the attending physician. Similarly, the antidepressant has been administered for a suitable duration, as determined by the attending physician.
  • 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.
  • the term “clinically proven” (used independently or to modify the terms “safe” and/or “effective”) shall mean that proof has been proven by a Phase III clinical trial that are sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by EMEA.
  • esketamine studies an adequately sized, randomized, double-blinded controlled study will be used to clinically prove the effects of esketamine.
  • the term “clinically proven effective” means the efficacy of treatment has been proven by a Phase III clinical trial as statistically significant i.e., the results of the clinical trial are not likely to be due to chance with an alpha level less than 0.05 or the clinical efficacy results are sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by EMEA.
  • esketamine was clinically proven effective for the treatment for patients with major depressive disorder, e.g., treatment resistant depression, when flexibly dosed intranasally in a therapeutically effective dose of from 28 mg, 56 mg or 84 mg ( ⁇ 25%) and co-administered with a newly or currently initiated oral antidepressant in reducing patient MADRS scores by at least about 50% relative to the patients measured baseline MADRS score as part of a dosing regimen including induction and maintenance phases described herein, and as specifically set forth in the examples.
  • major depressive disorder e.g., treatment resistant depression
  • the term “safe” when referring to a pharmaceutical treatment (therapy) or combination therapy shall mean without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • the term “clinically proven safe” means the safety of treatment has been proven by a Phase III clinical trial by analysis of the trial data and results establishing that the treatment is without undue adverse side effects and commensurate with the statistically significant clinical benefit (e.g. efficacy) sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by EMEA.
  • esketamine was clinically proven safe for the treatment for patients with major depressive disorder, e.g., treatment resistant depression, when flexibly dosed intranasally in a therapeutically effective dose of from 28 mg, 56 mg or 84 mg ( ⁇ 25%) and co-administered with a newly or currently initiated oral antidepressant as part of a dosing regimen including induction and maintenance phases described herein, and as specifically set forth in the examples.
  • therapeutically 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.
  • the therapeutically effective amount is a clinically proven safe and clinically proven effective amount.
  • the antidepressant is utilized in a therapeutically effective amount as determined by the attending physician.
  • esketamine is utilized in a therapeutically effective amount.
  • the therapeutically effective amount of esketamine and/or antidepressant may be administered during the initial phase(s) and/or subsequent phase(s) as described herein.
  • the therapeutically effective amount of esketamine is about 20 to about 100 mg.
  • the therapeutically effective amount of esketamine is about 30 to about 90 mg.
  • the therapeutically effective amount of esketamine is about 40 to about 80 mg.
  • the therapeutically effective amount of esketamine is about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg.
  • the therapeutically effective amount is about 28 mg, about 56 mg, or about 84 mg. In other embodiments, the therapeutically effective amount is about 56 mg or about 84 mg. In yet further embodiments, the therapeutically effective amount of esketamine is about 28 mg. In other embodiments, the therapeutically effective amount of esketamine is about 56 mg. In still further embodiments, the therapeutically effective amount is of esketamine about 84 mg.
  • 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. Preferably, 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 subject or patient is an adult.
  • adult refers to a human that is about 18 years of age to about 65 years of age.
  • the subject or patient is geriatric or elderly.
  • the terms “geriatric” and “elderly” are used interchangeably to refer to a human subject of about 65 years of age or older. Elderly patients between the ages of ⁇ 65 to ⁇ 75 appear to be more responsive to treatment than a patient of ⁇ 75.
  • the subject or patient is a pediatric subject.
  • the term “pediatric” refers to a human subject of younger than about 18 years of age.
  • 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.
  • stable remission refers to a patient having a MADRS total score of 12 or less for at least 3 of the last 4 weeks following the patient having achieved a substantially complete response to the esketamine during an induction phase.
  • patients in “stable remission” include those having one excursion of a MADRS total score greater than 12 or one missing a MADRS assessment at week 13 or 14 following an induction phase.
  • patients in “stable remission” include those having a MADRS total score at weeks 15 and 16 of 12 or less following an induction phase.
  • stable response refers to a patient having a 50% or greater reduction in the MADRS total score from baseline (Day 1 of induction phase; pre-randomization/prior to the first intranasal dose) in each of the last 2 weeks following the patient having achieved a substantially complete response to the esketamine during the induction phase, but does not meet criteria for stable remission.
  • the methods include administering esketamine in one, two or optionally three phases, i.e., initial and subsequent administration phases.
  • the phases include an initial induction phase, an extended induction phase, a maintenance phase, or any combination thereof.
  • an effective amount of esketamine is administered in each phase.
  • a physician can assess the patient's condition to determine the most beneficial initiation/induction and maintenance doses for the patient from the dosage range and administration frequencies from those specified herein.
  • the effective amount of esketamine may be the same in each phase or may differ.
  • the methods described herein permit optimizing dosages of esketamine for administration to a patient having or being predisposed to depression in an “optimization phase”. Optimization may be considered part of the maintenance phase that follows the induction phase. In some embodiments, the methods described herein do not require adjustment of the esketamine dosage. In fact, esketamine may be administered during the phases discussed herein (e.g., induction and maintenance) at the lowest dosing frequency at which an esketamine response is observed and maintained in a patient. An effective amount of esketamine has been found to be from about 28 to about 84 mg.
  • an “Induction phase” or “acute dosing phase” is a period of time that esketamine is initially administered to the patient.
  • the induction phase is sufficiently long as to achieve a robust, stable reduction of depressive symptoms.
  • the induction phase may depend on factors including, without limitation, the particular patient and/or the patient's sex, age, weight, time of administration, administration frequency and concomitant diseases.
  • the induction phase may include an initial induction phase and an extended induction phase.
  • the totality of the induction phase may be a period of about 4 to about 12 weeks, about 4 to about 11 weeks, about 4 to about 10 weeks, about 4 to about 9 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 12 weeks, about 5 to about 11 weeks, about 5 to about 10 weeks, about 5 to about 9 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 5 to about 6 weeks, about 6 to about 12 weeks, about 6 to about 11 weeks, about 6 to about 10 weeks, about 6 to about 9 weeks, about 6 to about 8 weeks, about 7 to about 12 weeks, about 7 to about 11 weeks, about 7 to about 10 weeks, about 7 to about 9 weeks, about 8 to about 12 weeks, about 8 to about 11 weeks, or about 8 to about 10 weeks.
  • the entire induction period is about 4 to about 8 weeks.
  • a patient is administered a therapeutically effective amount of esketamine at a given frequency of at least twice a week.
  • a patient is administered a therapeutically effective amount of esketamine at a given frequency of 3 times a week.
  • the initial induction phase is typically a period of time in which the patient is shown to be responsive to the treatment, but is not ready to progress to the maintenance phase.
  • the patient's response is assessed by one skilled in the art.
  • the patient's response is assessed daily.
  • the patient's response is assessed twice weekly.
  • the patient's response is assessed every other day.
  • the patient's response is assessed at the end of the initial induction phase.
  • the patient's response may be assessed using techniques and tests known to those skilled in the art.
  • the patient's MADRS score is determined and used as the determination as to whether the initial induction phase has concluded.
  • the initial induction phase is desirably long as to achieve a reduction of depressive symptoms.
  • the initial induction phase is a period of about 1 to about 4 weeks. In other embodiments, the induction phase is a period of up to about 1 week, up to about 2 weeks, up to about 3 weeks, or up to about 4 weeks.
  • the initial induction period is about 1 to about 3 weeks, about 1 to about 2 weeks, about 2 to about 4 weeks, about 2 to about 3 weeks, about 3 to about 4 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, up to 1 week, up to 2 weeks, up to 3 weeks, or up to 4 weeks.
  • the effective amount of esketamine administered during the initial induction phase may be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the initial induction phase is about 28 mg. In some embodiments, the effective amount of esketamine administered during the initial induction phase is about 56 mg. In other embodiments, the effective amount of esketamine administered during the initial induction phase is about 84 mg.
  • twice weekly refers to a frequency that is two times in a weekly (7-day) period.
  • twice weekly may refer herein to the administration of esketamine.
  • Twice weekly may also refer to a frequency of monitoring a patient in one or more phases discussed herein.
  • twice weekly refers to a frequency that is day 1 and day 2 of a week.
  • twice weekly refers to a frequency that is day 1 and day 3 of a week.
  • twice weekly refers to a frequency that is day 1 and day 4 of a week.
  • twice weekly refers to a frequency that is day 1 and day 5 of the week.
  • the “day 1” may be any day of the week, including, Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday.
  • twice weekly refers to a frequency that is day 1 and day 4 of a week.
  • the dose may be taken as soon as possible thereafter and the prescribed regimen thereafter continued.
  • the reduction of depressive symptoms during the initial induction phase is insufficient, and an extended induction phase is necessary.
  • continued administration of a therapeutically effective amount of esketamine at a given frequency of at least twice a week is performed.
  • the patient's response is again assessed by one skilled in the art. In some embodiments, the patient's response is assessed daily.
  • the patient's response is assessed twice weekly. In further embodiments, the patient's response is assessed every other day. Typically, the patient's response may be assessed using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used as the determination as to whether the extended induction period has concluded.
  • the extended induction phase is desirably long as to achieve a substantial reduction of depressive symptoms, thus achieving a substantially complete response to esketamine.
  • substantially complete response to esketamine refers to a patient having a reduction of the MADRS score from baseline to at least a 50% improvement from baseline.
  • a substantially complete response to esketamine refers to a patient having either a MADRS score of at least 50% improvement from baseline or about ⁇ 20 lower than the patients baseline score.
  • a substantially complete response includes a MADRS score of a reduction of about ⁇ 20 or less, ⁇ 19, or less, ⁇ 18 or less, ⁇ 17 or less, ⁇ 16 or less, ⁇ 15 or less, ⁇ 14 or less, ⁇ 13 or less, ⁇ 12 or less, ⁇ 11 or less, or ⁇ 10 or less.
  • a substantially complete response results in a patient having a reduction from MADRS baseline score of about ⁇ 15 to about ⁇ 20.
  • a substantially complete response to esketamine may also be obtained if the patient's MADRS scores is reduced by about 50% from the MADRS score at the start of the treatment. Such a substantially complete response may be observed at any point during esketamine treatment. In some embodiments, the substantially complete response is observed when the patient has a reduction of the MADRS total score from the baseline 4 hours following treatment.
  • the substantially complete response is observed where the patient has a reduction of the MADRS total score from the baseline 2 days following treatment.
  • the extended induction phase is a period of time that results in the substantially complete response to esketamine. In some embodiments, extended induction phase is about 1 to about 8 weeks. In other embodiments, the extended induction phase is a period of up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 5 weeks, up to about 6 weeks, up to about 7 weeks, or up to about 8 weeks.
  • the extended induction period is about 1 to about 8 weeks, about 1 to about 7 weeks, about 1 to about 6 weeks, about 1 to about 5 weeks, about 1 to about 4 weeks, about 1 to about 3 weeks, about 2 to about 8 weeks, about 2 to about 7 weeks, about 2 to about 7 weeks, about 2 to about 6 weeks, about 2 to about 5 weeks, about 2 to about 4 weeks, about 3 to about 8 weeks, about 3 to about 7 weeks, about 3 to about 6 weeks, about 3 to about 5 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks.
  • the effective amount of esketamine administered during the extended induction phase may be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the extended induction phase is about 56 mg. In other embodiments, the effective amount of esketamine administered during the extended induction phase is about 84 mg.
  • the administration may further comprise an optimization/maintenance phase that follows the induction phase and wherein after the patient achieves a substantially complete response to the esketamine during the induction phase, the esketamine is administered at a frequency of less than twice a week during the optimization/maintenance phase.
  • the frequency of administration during the optimization/maintenance phase is once every week, once every two weeks, once a month, or a combination thereof.
  • the patient's response to the treatment may be assessed using techniques described herein. This assessment may be performed until the patient is considered by one skilled in the art to have achieved a suitable response to the treatment regimen.
  • the induction period may be said to have completed when a patient's MADRS score is reduced by 250% from baseline or from about 20 to about 13.
  • the patient's MADRS score may be about 19, about 18, about 17, about 16, about 15, about 14, or about 13.
  • Patients with MADRS scores ⁇ 12 are considered in remission and if stable for four weeks should be moved to or maintained in the maintenance phase.
  • the treating physician should evaluate the patient to optimize the dosing amount and frequency for any subsequent administration phases such as the “maintenance phase” or “long-term therapy phase”. It is anticipated that the intranasal treatment frequency during the subsequent administration such as the maintenance phase will be reduced from that in the induction phase or extended induction phase (at least twice weekly) to once weekly dosing for at least 4 weeks.
  • the subsequent administration such as the maintenance phase is at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 week, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 1 year, or about 2 years.
  • the continuing administration of the esketamine during the subsequent administration phase is for at least six months.
  • the continuing administration of the esketamine during the subsequent administration phase is at least one year.
  • the frequency of administration during the subsequent administration phase is once every week or once every two weeks, or a combination thereof.
  • the dosing frequency and effective amount of esketamine during the subsequent administration phase is the minimum frequency and amount to maintain the stable remission or stable response.
  • the subsequent administration may include longer periods of time depending on the patient's condition.
  • those longer periods may be at least about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years, including indefinitely.
  • treatment may be indefinite.
  • the treatment frequency is reduced to biweekly.
  • the treatment frequency is reduced to every three weeks.
  • the treatment frequency is reduced to monthly. The patients will be maintained on schedule until the patient achieves remission, maintains a response, or fails treatment.
  • the frequency of intranasal treatment sessions may be decreased to a maintenance dose of once every other week based on the severity of depressive symptoms and for some patient populations the frequency of treatment may be reduced to about once every three or four weeks as discussed above.
  • the maintenance phase described herein may continue until further treatment is not required and as indicated by, for example, prolonged remission of the depression (including for example, the remission of one or more symptoms associated with depression), social and/or occupational functional improvement to normal or premorbid levels, or other known measures of depression.
  • an effective amount of esketamine is administered to the patient during the maintenance phase.
  • the amount of esketamine administered during the maintenance phase is an amount that elicits the biological or medicinal response in a tissue system discussed above for the induction phase.
  • the effective amount of esketamine is the amount which maintains a pharmacodynamic steady state of esketamine attained in the induction phase.
  • the dosing of esketamine will be increased to stabilize the patient. For example if the patient is being dosed every other week and their symptoms begin to worsen, esketamine can be administered once per week to maintain response during the maintenance phase. Again, at any time during the maintenance phase the patient's response maybe reassessed.
  • the recommended dose of esketamine is about 28 to about 84 mg.
  • the initial dose (at the first treatment session) is recommended to be about 28 mg of esketamine.
  • the dose at the next treatment session may remain at about 28 mg or be increased to about 56 mg.
  • the dose at subsequent treatment session may remain at about 56 mg or be increased to about 84 mg, or reduced to about 28 mg.
  • the dose at subsequent treatment sessions may remain at about 84 mg or be reduced to about 56 mg.
  • the recommended dose of esketamine is about 28 to about 56 mg.
  • the initial dose (at the first treatment session) is recommended to be about 28 mg of esketamine.
  • the dose at the next treatment session may remain at about 28 mg or be increased to about 56 mg.
  • Physicians should regularly monitor the hepatically impaired patients for drug tolerability, because esketamine is extensively metabolized in the liver.
  • the methods include administering esketamine in one or two phases, i.e., an initial induction phase, and optionally in certain circumstances a maintenance phase. Due to the imminent risk to the patient's life the initial dose of esketamine is dosed at the highest effective amount of esketamine that the patient may tolerate twice a week in the induction phase. In some embodiments, the patient continues on therapy with the existing (i.e. currently initiated) antidepressant agent simultaneously with the beginning of therapy on esketamine during the induction phase.
  • the patient is initiated on a new antidepressant agent simultaneously with the beginning of therapy on esketamine during the induction phase.
  • the patient continues on therapy with a previously administered antidepressant agent simultaneously with the beginning of therapy on esketamine during the induction phase.
  • the antidepressant should be dosed as labeled for the treatment of MDD, in a manner appropriate for the patient's condition/health.
  • the induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, most preferably about 4 weeks.
  • the esketamine dosing should cease, if the patient adequately responds to treatment or is in remission.
  • the patient should be monitored to ensure that the patient remains stable/or in remission on the antidepressant alone. Should the patient fail to stabilize on the first combination of esketamine and antidepressant or fail treatment on the antidepressant that was initiated with esketamine after the dosing with esketamine ceases, a second induction phase may be begun.
  • the patient In the second induction phase, the patient would be reinitiated on esketamine at the highest tolerable dose and simultaneously with a second new antidepressant.
  • the patient would be reinitiated on esketamine at the highest tolerable dose and simultaneously with the same antidepressant that was used during the previous induction phase.
  • the esketamine being dosed twice a week.
  • the antidepressant would be dosed as labeled for the treatment of MDD, in a manner appropriate for the patient's condition/health.
  • the second induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, most preferably about 4 weeks.
  • the esketamine dosing should cease and the patient should be monitored to ensure that the patient remains stable/or is in stable remission on the antidepressant alone. Should the patient fail to stabilize or fail treatment on the antidepressant that was initiated with esketamine after the dosing with esketamine ceases, a third induction phase may be begun.
  • the patient In the third induction phase the patient would be reinitiated on esketamine at the highest tolerable dose and simultaneously with a third new antidepressant. Alternatively, the patient would be reinitiated on esketamine at the highest tolerable dose and simultaneously with the same antidepressant that was used during the second induction phase.
  • the esketamine being dosed twice a week.
  • the antidepressant would be dosed as labeled for the treatment of MDD in a manner appropriate for the patient's condition/health.
  • the third induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, most preferably about 4 weeks.
  • the patient would proceed to the maintenance phase specified for TRD, since the patient now qualifies as a TRD patient.
  • the methods described herein permit optimizing dosages of esketamine for administration to a patient having or being predisposed to depression. In some embodiments, the methods described herein do not require adjustment of the esketamine dosage.
  • the patient may be reinitiated on esketamine at the highest tolerable dose and simultaneously with the same antidepressant that was used during any previous induction phase, including with an antidepressant in which the patient failed to stabilize or otherwise failed treatment.
  • the patient in a method for treating treatment-resistant depression in a patient wherein the patient has not responded to at least two oral antidepressants in the current depressive episode, the patient may be administered esketamine at least twice weekly solely with esketamine or along with a first oral antidepressant that is the same or different than the previously ineffective oral antidepressant in a first induction phase.
  • the patient can be reinitiated at the highest tolerable dose of esketamine alone or simultaneously with a second oral depressant that is the same or different than the first oral antidepressant in a second induction phase.
  • the patient can then be administered a therapeutically effective amount of esketamine less than twice weekly during a subsequent maintenance phase.
  • the next dose is scheduled when possible based on the dosing frequency regimen. If more than 2 doses are missed, per clinical judgement, adjustment of the dose or frequency of esketamine may be required.
  • composition of the present invention S-ketamine hydrochloride as the active ingredient is intimately admixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration.
  • a pharmaceutical carrier preferably water
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • One suitable aqueous formulation of S-ketamine comprises water and S-ketamine; wherein the S-ketamine is present in an amount in the range of from about 25 mg/mL to about 250 mg/mL, preferably about 55 mg/mL to about 250 mg/mL or about 100 mg/mL to about 250 mg/mL, or any amount or range therein, based on the total volume of the pharmaceutical composition.
  • the S-ketamine is present in an amount in the range of from about 150 mg/ml to about 200 mg/mL, or any amount or range therein. More preferably, the S-ketamine is present in an amount in the range of from about 150 mg/mL to about 175 mg/mL, or any amount or range therein.
  • the S-Ketamine is present in an amount in the range of from about 160 mg/mL to about 163 mg/mL, for example, in an amount of about 161.4 mg/mL
  • Another suitable aqueous formulation of S-ketamine comprises water and S-ketamine; wherein the S-ketamine is present in an amount in the range of from about eq. 100 mg/mL to about eq. 250 mg/mL, or any amount or range therein, based on the total volume of the pharmaceutical composition.
  • the S-ketamine is present in an amount in the range of from about eq. 125 mg/ml to about eq. 180 mg/mL, or any amount or range therein.
  • the S-ketamine is present in an amount in the range of from about eq. 140 mg/mL to about eq. 160 mg/mL, or any amount or range therein, for example, in an amount of about eq. 140 mg/mL.
  • Suitable pharmaceutical compositions for use in the present invention are preferably an aqueous formulation.
  • aqueous shall mean that the primary liquid component of the formulation is water.
  • water constitutes greater than about 80 wt-% of the liquid component of the pharmaceutical composition, more preferably greater than about 90 wt-%, more preferably greater than about 95 wt-%, more preferably about 98 wt-%.
  • the water content of the composition is within the range of 85 ⁇ 14 wt.-%, more preferably 85 ⁇ 12 wt.-%, still more preferably 85 ⁇ 10 wt.-%, most preferably 85 ⁇ 7.5 wt.-% and in particular 85 ⁇ 5 wt.-%, based on the total weight of the composition.
  • the water content of the composition is within the range of 90 ⁇ 14 wt.-%, more preferably 90 ⁇ 12 wt.-%, still more preferably 90 ⁇ 10 wt.-%, most preferably 80 ⁇ 7.5 wt.-% and in particular 90 ⁇ 5 wt.-%, based on the total weight of the composition.
  • the water content of the composition is within the range of 95 ⁇ 4.75 wt.-%, more preferably 95 ⁇ 4.5 wt.-%, still more preferably 95 ⁇ 4 wt.-%, yet more preferably 95 ⁇ 3.5 wt.-%, most preferably 95 ⁇ 3 wt.-% and in particular 95 ⁇ 2.5 wt.-%, based on the total weight of the composition.
  • the water content of the composition is within the range of from 75 to 99.99 wt.-%, more preferably 80 to 99.98 wt.-%, still more preferably 85 to 99.95 wt.-%, yet more preferably 90 to 99.9 wt.-%, most preferably 95 to 99.7 wt.-% and in particular 96.5 to 99.5 wt.-%, based on the total weight of the composition.
  • composition for use in the present invention, further comprises one or more buffers and/or buffer systems (i.e. conjugate acid-base-pairs).
  • buffers and/or buffer systems i.e. conjugate acid-base-pairs.
  • buffer shall mean any solid or liquid composition (preferably an aqueous, liquid composition) which when added to an aqueous formulation adjusts the pH of said formulation.
  • a buffer may adjust the pH of the aqueous formulation in any direction (toward more acidic, more basic or more neutral pH).
  • the buffer is pharmaceutically acceptable.
  • the buffer or buffer system is selected from the group consisting of NaOH, citric acid, sodium dihydrogen phosphate and disodium hydrogen phosphate.
  • the buffer is selected to adjust the pH of the S-ketamine hydrochloride pharmaceutical compositions of the present invention (e.g. the aqueous formulations described herein) into a pH in the range of from about pH 3.5 to about pH 6.5, or any amount or range therein.
  • the buffer is selected to adjust the pH of the S-ketamine hydrochloride compositions of the present invention to about in the range of from about pH 4.0 to about pH 5.5, or any amount or range therein, more preferably, in the range of from about pH 4.5 to about pH 5.0, or any amount or range therein.
  • the concentration of the buffer and buffer system, respectively, preferably NaOH, is adjusted to provide a sufficient buffer capacity.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising S-ketamine hydrochloride, water, and a buffer or buffer system, preferably NaOH; wherein the buffer or buffer system is present in an amount sufficient to yield a formulation with a pH in the range of from about pH 4.0 to about pH 6.0, or any amount or range therein.
  • compositions of the present invention may contain a preservative.
  • the terms “antimicrobial preservative” and “preservative” preferably refer to any substance that is usually added to pharmaceutical compositions in order to preserve them against microbial degradation or microbial growth.
  • microbial growth typically plays an essential role, i.e. the preservative serves the main purpose of avoiding microbial contamination.
  • preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate.
  • the concentration of S-ketamine hydrochloride is at least eq. 120 mg/mL, preferably in the range of from about eq. 120 mg/mL to about eq. 175 mg/ml, or any amount or range therein, more preferably in an amount in the range of from about eq. 125 mg/mL to about eq. 150 mg/mL, or any amount or range therein, for example at about eq. 126 mg/mL or at about eq. 140 mg/mL.
  • the terms “penetration agent”, “penetration enhancer”, and “penetrant” refer to any substance that increases or facilitates absorption and/or bioavailability of the active ingredient (e.g. S-ketamine hydrochloride) of a pharmaceutical composition.
  • the penetration agents increases or facilitates absorption and/or bioavailability of the active ingredient (e.g. S-ketamine hydrochloride) of a pharmaceutical composition, following nasal administration (i.e. increases or facilitates absorption and/or bioavailability of the active ingredient through the mucosal membrane).
  • Suitable examples include, but are not limited to tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid (TUDCA), lecithines, and the like; and chitosan (and salts), and surface active ingredients such as benzalkonium chloride, sodium dodecyl sulfate, sodium docusate, polysorbates, laureth-9, oxtoxynol, sodium deoxycholate, polyarginine, and the like.
  • the penetration agent is tauroursodeoxycholic acid (TUDCA).
  • the penetration agent may work via any mechanism, including for example by increasing the membrane fluidity, creating transient hydrophilic pores in the epithelial cells, decreasing the viscosity of the mucus layer or opening up tight junctions.
  • Some penetration agents for example bile salts and fusidic acid derivatives may also inhibit the enzymatic activity in the membrane, thereby improving bioavailability of the active ingredient.
  • the penetration agent is selected to meet one or more, more preferably all, of the following general requirements:
  • the penetration agent is selected to increase penetration (absorption and/or bioavailability of the S-ketamine hydrochloride) without nasal irritation. In another embodiment of the present invention, the penetration agent is selected to improve absorption and/or bioavailability of the S-ketamine hydrochloride; and further selected to enhance uniform dosing efficacy.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising S-ketamine and water; herein the pharmaceutical composition does not contain an antimicrobial preservative; and wherein the pharmaceutical compositions further contains a penetration enhancer, preferably TUDCA.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising S-ketamine and water; herein the pharmaceutical composition does not contain an antimicrobial preservative; and wherein the pharmaceutical compositions further contains tauroursodeoxycholic acid (TUDCA); wherein the TUDCA is present in a concentration in the range of from about 1.0 mg/mL to about 25.0 mg/mL, or any amount or range therein, preferably in a concentration in the range of from about 2.5 mg/mL to about 15 mg/mL, or any amount or range therein, preferably in a concentration in the range of from about 5 mg/mL to about 10 mg/mL, or any amount or range therein.
  • TUDCA tauroursodeoxycholic acid
  • the present invention is directed to pharmaceutical composition wherein the TUDCA is present at a concentration of about 5 mg/mL. In another embodiment, the present invention is directed to pharmaceutical composition wherein the TUDCA is present at a concentration of about 10 mg/mL.
  • compositions for use in the present invention may further contain one or more additional excipients for example, wetting agents, surfactant components, solubilizing agents, thickening agents, colorant agents, antioxidant components, and the like.
  • a suitable 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 suitable isotonizing agent includes sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof.
  • a suitable amount of the isotonizing agent, when included, is typically about 0.01 wt.-% to about 15 wt.-%, more preferably about 0.3 wt.-% to about 4 wt.-%, and more preferably about 0.5 wt.-% to about 3 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.
  • suitable 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.
  • esketamine may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily, preferably two times daily. Typically, divided doses should be made closer in time. In some embodiments, divided doses are administered about within 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, about 1 minute, or less of each other. Additionally, in a flexible dosing regimen a patient could be dosed daily, twice a week, once a week, once every other week or once monthly.
  • one dose of the esketamine is administered on day 1 and another dose of the esketamine is administered on day 2, or one dose of the esketamine is administered on day 1 and another dose of the esketamine is administered on day 3, or one dose of the esketamine is administered on day 1 and another dose of the esketamine is administered on day 4, or one dose of the esketamine is administered on day 1 and another dose of the esketamine is administered on day 5.
  • esketamine is preferably administered in intranasal form via topical use of suitable intranasal vehicles, such as a nasal spray pump.
  • the methods of administering esketamine to a patient result in a pharmacokinetic profile that achieves a maximum plasma concentration (C max ) of esketamine of about 45 to about 165 ng/mL.
  • C max maximum plasma concentration
  • the C max is about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, or about 165 ng/mL.
  • the C max is about 50 to about 150, about 50 to about 125, about 50 to about 100, about 50 to about 75, about 75 to about 150, about 75 to about 125, or about 75 to about 100 ng/mL. In further embodiments, the C max is about 45 to about 75, about 50 to about 70, about 55 to about 65, about 45 to about 70, about 45 to about 65, about 45 to about 60, about 45 to about 55, about 55 to about 75, or about 60 to about 70 ng/mL, when about 28 mg of esketamine is administered.
  • the C max is about 65 to about 120, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 120, about 80 to about 110, about 80 to about 90, about 90 to about 120, or about 90 to about 110 ng/mL, when about 56 mg of esketamine is administered.
  • the C max is about 90 to about 165, about 95 to about 165, about 95 to about 155, about 95 to about 145, about 95 to about 135, about 95 to about 125, about 95 to about 115, about 105 to about 165, about 105 to about 155, about 105 to about 145, about 105 to about 135, about 105 to about 125, about 105 to about 115, about 115 to about 165, about 115 to about 155, about 115 to about 145, about 115 to about 135, about 115 to about 125, about 125 to about 165, about 125 to about 155, about 125 to about 145, about 125 to about 135, about 135 to about 165, about 135 to about 155, about 135 to about 145, or about 145 to about 165 ng/mL, when about 84 mg of esketamine is administered.
  • the methods of administering esketamine to a patient results in a pharmacokinetic profile that achieves an area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC last ) of about 125 to about 490 ng*h/mL.
  • AUC last refers to the area under the plasma concentration-time curve from time zero to time of last measurable concentration.
  • Time zero in a general context refers to the start point of the intended dose. For example, in Example 1 regarding intranasal administration, time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal device.
  • time 0 is the time of administration of the first tablet.
  • the AUC last is about 125, about 130, about 135, about 140, about 145, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, or about 490 ng*h/mL.
  • the AUC last is about 150 to about 450, about 200 to about 400, about 250 to about 350, about 150 to about 350, or about 200 to about 300 ng*h/mL. In further embodiments, the AUC last is about 125 to about 185, about 130 to about 180, about 135 to about 175, about 140 to about 170, about 145 to about 165, or about 150 to about 160 ng*h/mL, when about 28 mg of esketamine is administered.
  • the AUC last is about 210 to about 320, about 220 to about 310, about 230 to about 300, about 240 to about 290, about 250 to about 280, or about 260 to about 270 ng*h/mL, when about 56 mg of esketamine is administered.
  • the AUC last is about 305 to about 490, about 310 to about 480, about 320 to about 470, about 330 to about 460, about 340 to about 450, about 350 to about 450, about 360 to about 440, about 370 to about 430, about 380, about 420, or about 390 to about 410 ng*h/mL, when about 84 mg of esketamine is administered.
  • the methods of administering esketamine may also result in a pharmacokinetic profile that achieves combinations of the C max and AUC last individual values and ranges described above.
  • a representative nasal spray device is disclosed in U.S. Pat. No. 6,321,942, incorporated by reference herein.
  • a disposable atomizer for discharging successive partial discharge amounts as a spray may be utilized to carry out the methods discloses herein.
  • such devices allow a medicament to be sprayed into both nostrils of a patient in two successive strokes.
  • the device may be ready-to-use wherein the medicament is discharged from a medium container.
  • the device is typically able to separate a first discharge stroke from a second discharge stroke to prevent complete emptying of the medium container in a single motion.
  • the device may take the form of a double-stroke disposable pump, which is disposed of after a single use and enables individual partial discharges with high dosing precision and reliability.
  • the nasal spray device is a single-use device that delivers a total of 28 mg of esketamine in two sprays, one spray per nostril.
  • the device may be operated by the patient under the supervision of a healthcare professional. With respect to dosage amounts, one device may be used for a 28 mg dose, two devices for a 56 mg dose, or three devices for an 84 mg dose. It is also preferable to have a 5-minute interval between the use of each device. As described in Example 1, time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal device.
  • instructions for use will accompany a esketamine nasal spray drug product according to the present disclosure.
  • the instructions for use are on the drug product label of an approved drug product.
  • the drug product comprises one or more intranasal spray devices, with the one or more devices comprising esketamine.
  • the one or more devices is configured to administer the esketamine in two or more sprays, preferably two sprays, 1 spray per nostril of the patient.
  • FIG. 83 A An exemplary device is illustrated in FIG. 83 A and comprises a tip, a nose rest, an indicator, a finger rest, and a plunger.
  • the indicator indicates if the device is full, how many sprays have been administered, and/or whether or not the device is empty.
  • the indication may be accomplished, for example, by using colored dots, where two colored dots indicate a full device, one colored dot indicates one spray has been administered, and no colored dots signifies an empty device.
  • the device is intended for administration by the patient under the supervision of a health care professional (HCP).
  • HCP health care professional
  • the health care professional may be, for example, a doctor, psychiatrist, or nurse that preferably has completed an education and training program for informing healthcare professionals about the appropriate use of esketamine according to United States Prescribing Information (USPI).
  • USPI United States Prescribing Information
  • a first step includes an instruction for the patient to blow their nose before using a first device.
  • a device may be configured to administer from about 28 to about 84 mg of esketamine.
  • each device contains about 28 mg of esketamine, with additional devices utilized if administering 56 mg or 84 mg of esketamine.
  • three devices may be used to administer 84 mg of esketamine.
  • the device should not be primed as this will result in loss of medication.
  • the patient's head is preferably reclined at about 45 degrees to keep the medication inside the nose.
  • the tip of the device is inserted into a first nostril, and the patient should close the opposite nostril and breathe through the nose while activating the plunger to release the medication.
  • the tip of the device is then inserted into the second nostril to deliver the remaining amount of esketamine.
  • the HCP may take the device from the patient and confirm that the device is empty. If not, the patient should spray again into the second nostril.
  • the patient Before a next administration from a second device, the patient should rest, preferably in a reclined position, for about 5 minutes before administering additional esketamine from a second device. The steps may be repeated for the second device.
  • a third device the patient should again wait about 5 minutes following the second spray to the second nostril before administering additional esketamine to the first nostril from a third device. Having the patient wait about 5 minutes after each device allows the medication to absorb.
  • a used device may be disposed in accordance with local requirements.
  • methods of selling a drug product comprising esketamine are also provided.
  • the terms “sale” or “selling” as used herein refers to transferring a drug product, e.g., a pharmaceutical composition or a dosage form, from a seller to a buyer.
  • a drug product label for a reference listed drug for the drug product includes instructions for treating depression, including treatment-resistant depression.
  • the methods also include offering for sale a drug product comprising esketamine.
  • offering for sale refers to the proposal of a sale by a seller to a buyer for a drug product, e.g., a pharmaceutical composition or a dosage form. These methods comprise offering the drug product for sale.
  • drug product is product that contains an active pharmaceutical ingredient that has been approved for marketing by a governmental authority, e.g., the Food and Drug Administration or the similar authority in other countries.
  • label or drug product label refers to information provided to a patient which provides relevant information regarding the drug product. Such information includes, without limitation, one or more of the description of the drug, clinical pharmacology, indications (uses for the drug product), contraindication (who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and older patients, how the drug is supplied, safety information for the patient, or any combination thereof.
  • the label or drug product label provides an instruction for use in a patient with treatment-resistant depression.
  • the drug product label comprises data directed to the reduction of depressive symptoms relative to a placebo and/or standard of care.
  • the label or drug product label identifies esketamine as a regulatory approved chemical entity.
  • the label provides instructions for use in a patient with depression, including treatment-resistant depression.
  • RTD reference listed drug
  • a drug product to which new generic versions are compared to show that they are bioequivalent. It is also a medicinal product that has been granted marketing authorization by a member state of the European Union or by the Commission on the basis of a completed dossier, i.e., with the submission of quality, pre-clinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which the application for marketing authorization for a generic/hybrid medicinal product refers, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies.
  • a company seeking approval to market a generic equivalent must refer to the RLD in its Abbreviated New Drug Application (ANDA).
  • ANDA Abbreviated New Drug Application
  • an ANDA applicant relies on the FDA's finding that a previously approved drug product, i.e., the RLD, is safe and effective, and must demonstrate, among other things, that the generic drug product is the same as the RLD in certain ways.
  • a drug product for which an ANDA is submitted must have, among other things, the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the RLD.
  • the RLD is the listed drug to which the ANDA applicant must show its ANDA drug product is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling and conditions of use, among other characteristics.
  • active ingredient(s) in the electronic Orange Book, there is a column for RLDs and a column for reference standards.
  • the RLDs and reference standards are identified by specific symbol.
  • a reference standard is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval.
  • FDA generally selects a single reference standard that ANDA applicants must use in in vivo bioequivalence testing. Ordinarily, FDA will select the reference listed drug as the reference standard. However, in some instances (e.g., where the reference listed drug has been withdrawn from sale and FDA has determined it was not withdrawn for reasons of safety or effectiveness, and FDA selects an ANDA as the reference standard), the reference listed drug and the reference standard may be different.
  • FDA identifies reference listed drugs in the Prescription Drug Product, OTC Drug Product, and Discontinued Drug Product Lists. Listed drugs identified as reference listed drugs represent drug products upon which an applicant can rely in seeking approval of an ANDA. FDA intends to update periodically the reference listed drugs identified in the Prescription Drug Product, OTC Drug Product, and Discontinued Drug Product Lists, as appropriate.
  • FDA also identifies reference standards in the Prescription Drug Product and OTC Drug Product Lists. Listed drugs identified as reference standards represent the FDA's best judgment at this time as to the appropriate comparator for purposes of conducting any in vivo bioequivalence studies required for approval.
  • FDA has not designated a listed drug as a reference listed drug
  • such listed drug may be shielded from generic competition. If FDA has not designated a reference listed drug for a drug product the applicant intends to duplicate, the potential applicant may ask FDA to designate a reference listed drug for that drug product.
  • FDA may, on its own initiative, select a new reference standard when doing so will help to ensure that applications for generic drugs may be submitted and evaluated, e.g., in the event that the listed drug currently selected as the reference standard has been withdrawn from sale for other than safety and efficacy reasons.
  • Applicants identify in the application form for its generic/hybrid medicinal product, which is the same as an ANDA or supplemental NDA (sNDA) drug product, the reference medicinal product (product name, strength, pharmaceutical form, marketing authorization holder (MAH, first authorization, Member State/Community), which is synonymous with a RLD, as follows:
  • EAA European Economic Area
  • This reference medicinal product, identified for the purpose of calculating expiry of the period of data protection, may be for a different strength, pharmaceutical form, administration route or presentation than the generic/hybrid medicinal product.
  • the medicinal product the dossier of which is cross-referred to in the generic/hybrid application (product name, strength, pharmaceutical form, MAH, marketing authorization number).
  • This reference medicinal product may have been authorized through separate procedures and under a different name than the reference medicinal product identified for the purpose of calculating expiry of the period of data protection.
  • the product information of this reference medicinal product will, in principle, serve as the basis for the product information claimed for the generic/hybrid medicinal product.
  • the medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the bioequivalence study(ies) (where applicable).
  • NDAs and ANDAs can be divided into the following four categories:
  • a “stand-alone NDA” is an application submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use.
  • a section 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use.
  • An ANDA is an application for a duplicate of a previously approved drug product that was submitted and approved under section 505(j) of the FD&C Act.
  • An ANDA relies on the FDA's finding that the previously approved drug product, i.e., the reference listed drug (RLD), is safe and effective.
  • RLD previously approved drug product
  • An ANDA generally must contain information to show that the generic product (a) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and (b) is bioequivalent to the RLD.
  • An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the product.
  • a petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient) and for which FDA has determined, in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act (suitability petition), that studies are not necessary to establish the safety and effectiveness of the drug product.
  • a scientific premise underlying the Hatch-Waxman Act is that a drug product approved in an ANDA under section 505(j) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling.
  • a section 505(b)(2) application allows greater flexibility as to the characteristics of the product.
  • a section 505(b)(2) application will not necessarily be rated therapeutically equivalent to the listed drug it references upon approval.
  • terapéuticaally equivalent to a reference listed drug is means that the drug product is a generic equivalent, i.e., pharmaceutical equivalents, of the reference listed drug product and, as such, is rated an AB therapeutic equivalent to the reference listed drug product by the FDA whereby actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.
  • “Pharmaceutical equivalents” means drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient as the reference listed drug.
  • the rate and extent of absorption of the [test] drug do not show a significant difference from the rate and extent of absorption of the [reference] drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or
  • the extent of absorption of the [test] drug does not show a significant difference from the extent of absorption of the [reference] drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the [reference] drug in the rate of absorption of the drug is intentional, is reflected in its labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.
  • bioequivalence may sometimes be demonstrated using an in vitro bioequivalence standard, especially when such an in vitro test has been correlated with human in vivo bioavailability data. In other situations, bioequivalence may sometimes be demonstrated through comparative clinical trials or pharmacodynamic studies.
  • the methods may also comprise, consist of, or consist essentially of placing esketamine into the stream of commerce.
  • the esketamine drug product includes a package insert that contains instructions for safely and effectively treating depression, including treatment-resistant depression, using esketamine.
  • described herein are methods of offering for sale esketamine comprising, consisting of, or consisting essentially of offering an esketamine drug product into the stream of commerce.
  • the esketamine drug product includes a package insert that contains instructions for safely and effectively treating depression, including treatment-resistant depression, using esketamine.
  • the present disclosure pertains to and includes at least the following aspects.
  • a method for treating major depressive disorder comprising intranasally administering to a patient in need thereof, a clinically proven safe and clinically proven effective therapeutically effective amount of esketamine;
  • the patient in need thereof is a human patient having a major depressive episode and wherein the patient has not responded to at least two oral antidepressants in the current depressive episode.
  • a method of treating major depressive disorder comprising administering esketamine to a patient in need thereof;
  • the patient in need thereof is having a major depressive episode and wherein the patient has not responded to at least two oral antidepressants in the current depressive episode;
  • the therapeutically effective amount of esketamine administered to the patient is clinically proven safe and effective.
  • a method for treating major depressive disorder in a human patient comprising the steps of:
  • the therapeutically effective amount improves said MADRS score of at least 50% relative to the measured baseline MADRS score
  • step (c) re-evaluating said human patient at regular intervals following step (b) to determine relative effectiveness
  • the re-evaluation comprises measurement of said human patient's MADRS score.
  • each antidepressant is independently selected from the group consisting of imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St. John's Wart, s-adenosylmethionine, thyrotropin releasing hormone, neurokinin receptor antagonists and triiodothyronine.
  • each antidepressant is independently selected from the group consisting of mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors; noradrenergic and specific serotonergic agents and atypical antidepressants.
  • each antidepressant is independently selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine and bupropion.
  • the combination therapy comprises esketamine and one to two antidepressants independently selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline.
  • atypical antidepressant is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone and paliperidone.
  • atypical antidepressant is selected from the group consisting of aripiprazole, quetiapine and olanzapine.
  • a pharmaceutical composition for the treatment of treatment-refractory or treatment-resistant depression comprising esketamine, optionally at least one antidepressant, and a at least one pharmaceutically acceptable carrier.
  • Esketamine for use in a method for the treatment of treatment-refractory or treatment-resistant depression, in a patient in need thereof.
  • a composition comprising esketamine for the treatment of treatment-refractory or treatment-resistant depression.
  • a pharmaceutical product comprising esketamine for administration to a patient suffering from treatment resistant depression wherein the esketamine is administered intranasally to said patient in a clinically proven safe and effective amount.
  • a method of maintaining stable remission or stable response achieved by a patient with depression following administration of a therapeutically effective amount of esketamine during an initial administration phase comprising continuing administration of a therapeutically effective amount of esketamine for at least five months during a subsequent administration phase.
  • each antidepressant is, independently, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St. John's Wart, s-adenosylmethionine, thyrotropin releasing hormone, a neurokinin receptor antagonist, or triiodothyronine.
  • each antidepressant is, independently, a mono-amine oxidase inhibitor, tricyclic, serotonin reuptake inhibitor, serotonin noradrenergic reuptake inhibitor, noradrenergic and specific serotonergic agent, or atypical antidepressant.
  • each antidepressant is, independently, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion.
  • each antidepressant is, independently, fluoxetine, imipramine, bupropion, venlafaxine, or sertraline.
  • the initial administration phase comprises an induction phase wherein the esketamine is administered at a frequency of at least twice a week.
  • the initial administration phase further comprises an optimization phase that follows the induction phase and wherein after the patient achieves a substantially complete response to the esketamine during the induction phase, the esketamine is administered at a frequency of less than twice a week during the optimization phase.
  • a method for the long term treatment of depression in a patient comprising administering to the patient in need of the treatment a clinically proven safe and clinically proven effective therapeutically effective amount of esketamine for at least six months.
  • each antidepressant is, independently, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St. John's Wart, s-adenosylmethionine, thyrotropin releasing hormone, a neurokinin receptor antagonist, or triiodothyronine.
  • each antidepressant is, independently, a mono-amine oxidase inhibitor, tricyclic, serotonin reuptake inhibitor, serotonin noradrenergic reuptake inhibitor, noradrenergic and specific serotonergic agent, or atypical antidepressant.
  • each antidepressant is, independently, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion.
  • each antidepressant is, independently, fluoxetine, imipramine, bupropion, venlafaxine, or sertraline.
  • atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone.
  • a method for treating major depressive disorder in an elderly patient comprising
  • the method aspect 72 further comprising assessing the patient's response periodically during the optimization phase.
  • each antidepressant is, independently, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St. John's Wart, s-adenosylmethionine, thyrotropin releasing hormone, a neurokinin receptor antagonist, or triiodothyronine.
  • each antidepressant is, independently, a mono-amine oxidase inhibitor, tricyclic, serotonin reuptake inhibitor, serotonin noradrenergic reuptake inhibitor, noradrenergic and specific serotonergic agent, or atypical antidepressant.
  • each antidepressant is, independently, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion.
  • any one of aspects 77 to 80 comprising one or two antidepressants that are, independently, fluoxetine, imipramine, bupropion, venlafaxine, or sertraline.
  • atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone.
  • a method for treating a patient with major depressive disorder comprising administering to the patient in need of treatment for major depressive disorder a clinically proven safe and clinically proven effective therapeutically effective amount of esketamine.
  • each antidepressant is, independently, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St. John's Wart, s-adenosylmethionine, thyrotropin releasing hormone, a neurokinin receptor antagonist, or triiodothyronine.
  • each antidepressant is, independently, a mono-amine oxidase inhibitor, tricyclic, serotonin reuptake inhibitor, serotonin noradrenergic reuptake inhibitor, noradrenergic and specific serotonergic agent, or atypical antidepressant.
  • each antidepressant is, independently, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion.
  • each antidepressant is, independently, fluoxetine, imipramine, bupropion, venlafaxine, or sertraline.
  • atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone.
  • a pharmaceutical composition for the treatment of major depressive disorder comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of treatment refractory depression or treatment resistant depression comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of suicidal ideation comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier.
  • aspect 107 wherein the patient is suffering from treatment refractory depression or treatment resistant depression.
  • Esketamine for use in a method for the treatment of major depressive disorder in a patient in need thereof.
  • Esketamine of aspect 110 wherein the patient is suffering from treatment refractory depression or treatment resistant depression.
  • composition comprising esketamine for the treatment of major depressive disorder.
  • a composition comprising esketamine for the treatment of treatment refractory depression or treatment resistant depression.
  • a composition comprising esketamine for the treatment of suicidal ideation.
  • a pharmaceutical product comprising esketamine for administration to a patient suffering from major depressive disorder, wherein the esketamine is administered intranasally to said patient in a clinically proven safe and effective amount.
  • a method of administering esketamine to a patient comprising a first phase, of a duration of about one week to about four weeks, wherein about 28 mg to about 84 mg of esketamine is administered to the patient at a frequency of twice per week, and wherein the method is clinically proven safe.
  • a pharmaceutical product comprising one or more intranasal spray devices, wherein the one or more devices comprise an esketamine composition and the one or more devices is configured to administer from about 28 to about 84 mg of esketamine, and wherein the pharmaceutical product is clinically proven safe and/or clinically proven effective to treat a major depressive disorder.
  • each device is a single use device.
  • a method of treating major depressive disorder with suicidal ideation comprising
  • a method for treating treatment-resistant depression in a patient wherein the patient has not responded to at least two oral antidepressants in the current depressive episode comprising:
  • the patient fails to achieve a substantially complete response to the esketamine, reinitiating the patient on the highest tolerable dose of esketamine and simultaneously with a second oral depressant in a second induction phase of a defined duration.
  • a method of treating treatment-resistant depression in a patient comprising:
  • AD antagonistidepressant
  • AE reverse event
  • ESK esketamine nasal spray
  • PBO placebo nasal spray
  • PHQ-9 Patient Adherence Questionnaire
  • SDS Sheehan Disability Scale
  • CGI-S Clinical Global Impression—Severity
  • MADRS Montgomery-Asberg Depression Rating Scale
  • SD standard deviation
  • SNRI serotonin and norepinephrine reuptake inhibitors
  • SSRI selective serotonin reuptake inhibitors
  • LS least square
  • SE standard error
  • BMI body mass index
  • BPIC-SS Bladder Pain/interstitial Cystitis Symptom Score
  • BPRS+ 4-item positive symptom subscale of the Brief Psychiatric Rating Scale
  • C clinic visit
  • CADSS Clinician Administered Dissociative States Scale
  • CGADR Clinical Global Assessment of Discharge Readiness
  • C-SS Clinical Global Assessment
  • TRD treatment-refractory or treatment-resistant depression
  • the primary objective of this study was to evaluate the efficacy of switching adult subjects with TRD from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as assessed by the change from baseline in the MADRS total score from Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase.
  • the key secondary objectives were to assess the effect of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo on the following parameters in adult subjects with TRD: (a) Depressive symptoms (subject-reported), (b) Onset of clinical response by Day 2, and (c) Functioning and associated disability. Additional secondary objectives included (a) Depression response rates, (b) Depression remission rates, (c) Overall severity of depressive illness, (d) Anxiety symptoms and (e) Health-related quality of life and health status.
  • the PK of intranasal esketamine in adult subjects with TRD receiving intranasal esketamine plus a newly-initiated oral antidepressant was also assessed as part of the secondary objectives.
  • Esketamine was supplied as a clear, colorless intranasal solution of esketamine hydrochloride (16.14% weight/volume [w/v]; equivalent to 14% w/v of esketamine base) in a nasal spray pump.
  • the solution consisted of 161.4 mg/mL esketamine hydrochloride (equivalent to 140 mg of esketamine base) formulated in 0.12 mg/mL ethylenediaminetetraacetic acid (EDTA) and 1.5 mg/mL citric acid at a pH of 4.5 in water for injection. It is provided in a nasal spray pump, which delivered 16.14 mg esketamine hydrochloride (14 mg esketamine base) per 100- ⁇ L spray.
  • Each individual nasal spray pump (device) contained a total of 28 mg (i.e., 2 sprays).
  • the placebo solution was supplied as a clear, colorless intranasal solution of water for injection, with a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 0.001 mg/mL) added to simulate the taste of the intranasal solution with active drug.
  • the placebo solution was provided in matching nasal spray pump devices. Benzalkonium chloride was added as a preservative at a concentration of 0.3 mg/mL. Each individual nasal spray pump (device) contained 2 sprays.
  • Duloxetine 30 mg was obtained from commercial stock and provided under the responsibility of the sponsor. Please refer to the package insert/SmPC for the physical description and a list of excipients.
  • Escitalopram 10 mg was obtained from commercial stock and provided under the responsibility of the sponsor. Please refer to the package insert/SmPC for the physical description and a list of excipients.
  • Sertraline 50 mg and 25 mg were obtained from commercial stock and provided under the responsibility of the sponsor. Please refer to the package insert/SmPC for the physical description and a list of excipients.
  • Venlafaxine 75 mg and 37.5 mg (as applicable) were obtained from commercial stock and provided under the responsibility of the sponsor. Please refer to the package insert/SmPC for the physical description and a list of excipients.
  • This phase prospectively assessed treatment response to the subject's current oral antidepressant treatment regimen. After 4 weeks of continuing the same treatment regimen (at the same dosage), subjects who were non-responders to their current oral antidepressant treatment (as assessed by independent, remote raters) were eligible to proceed to the double-blind induction phase. The site investigators were blinded to the study criteria for non-response.
  • Eligible subjects who entered the double-blind induction phase discontinued their current oral antidepressant medication(s). If clinically indicated, a subject's current antidepressant medication(s) could be tapered and discontinued over an additional, optional period of up to 3 weeks per the local prescribing information or clinical judgment.
  • the study included 227 randomized subjects (4 of whom did not receive intranasal and/or oral AD study drug and were therefore not included in the analysis sets), who were randomly assigned at a 1:1 ratio (n 98 subjects per treatment arm) to receive double-blind treatment with either intranasal esketamine or intranasal placebo.
  • the assigned oral antidepressant was 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]), that the subject had not previously had a nonresponse to in the current depressive episode, had not been previously intolerant to (lifetime), and was available in the participating country.
  • ESKETINTRD3003 is a longer-term efficacy maintenance study involving repeated treatment sessions of intranasal esketamine.
  • This phase included all subjects who were not eligible or who chose to not participate in the maintenance of effect study ESKETINTRD3003 and had received at least 1 dose of intranasal study medication in the double-blind induction phase. There were no intranasal treatment sessions administered during this phase.
  • the follow-up phase also allowed collection of additional informative data to assess the course of the subject's major depressive episode over a 6-month period.
  • the duration of a subject's study participation was 11 weeks (for subjects continuing into ESKETINTRD3003) or 35 weeks (for subjects completing the follow-up phase).
  • the inclusion criteria for enrolling subjects in this study were as follows. Each potential subject satisfied all of the following criteria to be enrolled in the study.
  • the exclusion criteria for enrolling subjects in this study were as follows. Any potential subject who met any of the following criteria was excluded from participating in the study.
  • the investigator was not provided with randomization codes.
  • the codes were maintained within the IWRS, which had the functionality to allow the investigator to break the blind for an individual subject.
  • the blind should not be broken until all subjects had completed the study and the database was finalized. Otherwise, the blind could be broken only if specific emergency treatment/course of action was dictated by knowing the treatment status of the subject. In such cases, the investigator could in an emergency determine the identity of the treatment by contacting the IWRS. It was recommended that the investigator contact the sponsor or its designee, if possible, to discuss the particular situation, before breaking the blind. Telephone contact with the sponsor or its designee was available 24 hours per day, 7 days per week. In the event the blind was broken, the sponsor was informed as soon as possible. The date and time of the unblinding was documented by the IWRS, and reason for the unblinding documented by the electronic case report form (eCRF) and in the source document. The documentation received from the IWRS indicating the code break was retained with the subject's source documents in a secure manner.
  • eCRF electronic case report form
  • randomization codes were disclosed fully only if the study was completed and the clinical database was closed.
  • the randomization codes and, if required, the translation of randomization codes into treatment and control groups were disclosed to those authorized and only for those subjects included in the interim analysis.
  • Demographic and baseline characteristics for the subjects in the study were as listed in Table 1, below. In general, the treatment groups were similar with respect to the baseline characteristics. The majority of subjects entering the study were female, with a mean age of all subjects of 45.7 years, ranging from 19 to 64 years.
  • Baseline psychiatric history was as presented in table 3, below.
  • the mean (SD) baseline MADRS total score was 37.1, ranging from 21 to 52.
  • the antidepressant medication could be tapered and discontinued over a period of up to 3 weeks per the local prescribing information or clinical judgment (e.g., antidepressant treatments with short half-lives, such as paroxetine and venlafaxine XR; or tolerability concerns).
  • esketamine 56 mg or 84 mg
  • placebo twice per week for 4 weeks as a flexible dose regimen at the study site.
  • subjects simultaneously initiated a new, open-label oral antidepressant i.e., duloxetine, escitalopram, sertraline, or venlafaxine XR
  • a new, open-label oral antidepressant i.e., duloxetine, escitalopram, sertraline, or venlafaxine XR
  • CPR cardiopulmonary resuscitation
  • Each individual intranasal device contained 2 sprays.
  • the intranasal devices containing esketamine delivered 14 mg per spray, for a total of 28 mg per individual device (i.e., 2 sprays).
  • Subjects were not to drive a car or work with machines for 24 hours after the last dose of intranasal study drug on each dosing day.
  • the oral antidepressant was 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR).
  • the antidepressant medication was assigned by the investigator based on a review of the MGH-ATRQ and relevant information regarding prior antidepressant treatments, and was one that the subject has not previously had a non-response to in the current depressive episode, had not been previously intolerant to (lifetime), and was available in the participating country.
  • the subject's maximum tolerated dose should not be lower than the following minimum therapeutic doses: Sertraline (50 mg/day), venlafaxine XR (150 mg/day), escitalopram (10 mg/day), and duloxetine (60 mg/day). While subjects requiring lower doses could continue in the study and complete the double-blind induction phase, such subjects were not eligible to participate in the maintenance of effect study ESKETINTRD3003 and proceeded to the follow-up phase after completion of the double-blind induction phase.
  • oral antidepressant treatment On intranasal treatment sessions, it was recommended that oral antidepressant treatment be taken in the evening and at the same time of day during the double-blind induction phase. In addition, on intranasal dosing days, if the oral antidepressant medication frequency was greater than once daily (e.g., twice a day), it was recommended that the dose should not be taken until at least 3 hours after the intranasal treatment session.
  • intranasal dosing days If subsequent to fulfilling the inclusion and exclusion criteria on Day 1, a subject's pre-dose systolic blood pressure (SBP) was ⁇ 160 mmHg and/or diastolic blood pressure (DBP) was ⁇ 100 mmHg, it was recommended to repeat the blood pressure measurement after subject rested for 10 minutes in sitting or recumbent position. If repeated pre-dose SBP was ⁇ 160 mmHg and/or DBP is ⁇ 100 mmHg, then dosing was postponed and the subject scheduled to return on the following day or within the given visit window. If the blood pressure elevation persisted on the next visit, the subject was scheduled for a consultation by cardiologist or primary care physician, prior to further dosing.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • the SBP was ⁇ 180 mmHg but ⁇ 200 mmHg and/or the DBP was ⁇ 110 mmHg but ⁇ 120 mmHg, further intranasal dosing was interrupted and the subject was referred to a cardiologist or primary care physician for a follow-up assessment.
  • the subject could continue with intranasal dosing if the pre-dose blood pressure at the next scheduled visit was within the acceptable range.
  • the subject was to discontinue from further dosing and the subject referred to a cardiologist or primary care physician for a follow-up assessment.
  • assessments should continue every 30 minutes until the blood pressure was ⁇ 160 mmHg SBP and ⁇ 100 mmHg DBP or until the subject was referred for appropriate medical care, if clinically indicated.
  • Antidepressant treatment adherence during the screening/prospective observational phase was assessed using the PAQ. Missing 24 days of antidepressant medication in the prior 2-week period was considered as inadequate adherence.
  • Antidepressant treatment compliance during the double-blind induction phase was assessed by performing pill counts (i.e., compliance check) and drug accountability.
  • All antidepressant treatment(s), including adjunctive treatment for MDD, taken during the current depressive episode (i.e., including those taken more than 30 days prior to the start of the screening/prospective observational phase) were recorded at the start of the screening/prospective observational phase.
  • information was also obtained regarding any history of intolerance to any of the 4 antidepressant choices i.e., duloxetine, escitalopram, sertraline, and venlafaxine XR).
  • Subjects receiving psychotherapy could continue receiving psychotherapy provided this therapy had been stable in terms of frequency for the last 6 months prior to the start of the screening/prospective observational phase and remained unchanged until after completion of the double-blind induction phase.
  • Anticonvulsants used for indications other than seizures may be allowed (eg, valproate for migraine)
  • Antidepressants N N Only 1 of the 4 predefined oral Safety and PD (other than the antidepressant treatment interaction specific options are permitted antidepressant If a subject is taking a started in the monoamine oxidase inhibitor induction phase of (MAOI) during the the study) screening/prospective observational phase, there must be a minimum washout interval of 2 weeks prior to the first dose of intranasal study medication.
  • MAOI monoamine oxidase inhibitor induction phase of
  • Antipsychotics N N PD interaction Benzodiazepines Y Y Benzodiazepines are prohibited Safety and PD and non- within 12 hours prior to the start interaction benzodiazepine of each intranasal treatment sleeping session or cognition testing medication
  • Non-benzodiazepine sleeping including: medications are prohibited zolpidem, within 12 hours prior to the start zaleplon, of cognition testing but are eszopiclone, and permitted the night before ramelteon) dosing if no cognitive testing is scheduled.
  • CYP3A4 inhibitors N N Subjects may not take a known PK Potent potent inhibitor of hepatic CYP3A activity within 1 week or within a period less than 5 times the drug's half-life, whichever is longer, before the first administration of study medication until at least 24 hours after the last intranasal dose of study medication Examples (not all-inclusive): Indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, and telithromycin CYP3A4 inducers N N Subjects may not take a known PK Potent potent inducer of hepatic CYP3A activity within 2 weeks of the first administration of intranasal study medication until at least 24 hours after the last intranasal dose of study medication.
  • Efavirenz Efavirenz, nevirapine, barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St.
  • the Time and Events Schedule was as presented in Table 10 and Table 11 below, summarizes the frequency and timing of efficacy, PK, biomarker, pharmacogenomic, medical resource utilization, health economic, and safety measurements applicable to this study.
  • c Pre-dose (if/when performed on intranasal dosing days). With the exception of post-dose assessments, subject-reported outcome assessments were administered before all other study-related procedures during a clinic visit.
  • d Performed only for subjects requiring a taper period during the screening/prospective observational phase; the result was considered as the subject's baseline MADRS for the double-blind induction phase. For all other subjects, the baseline MADRS for the double-blind induction phase was the MADRS performed at the end of Week 4 of the screening/prospective observational phase.
  • Post-dose vital signs were performed at 40 minutes, 1 hour, and 1.5 hours post-dose.
  • the BPRS+ and CADSS were performed pre-dose and at 40 minutes and 1.5 hours post-dose.
  • i CGADR was performed at 1 hour and 1.5 hour post-dose; if the response is not “Yes” at 1.5 hour post-dose, the assessment was repeated every 15 minutes until a “Yes” response was achieved or until the subject was referred for appropriate medical care if clinically indicated. A subject was not to be discharged prior to the 1.5 hour time point.
  • j PWC-20 was performed only if the subject was not continuing into Study ESKETINTRD3003.
  • k Nasal symptom questionnaire was performed pre-dose and at 1 hour post-dose.
  • m Blood samples were collected prior to dosing. It was preferred that subjects adhere to a low fat diet on the day of sample collection.
  • the approximate total blood volume to be collected from each subject was 123.5 mL (See Table 12, below). Repeat or unscheduled samples could be taken for safety reasons or for technical issues with the samples. Additional serum or urine pregnancy tests could be performed, as determined necessary by the investigator or required by local regulation, to establish the absence of pregnancy at any time during the subject's participation in the study.
  • Serum chemistry includes serum ⁇ -hCG pregnancy tests (for women of childbearing potential) and lipid panel.
  • HbA1c will be measured from the sample collected for hematology.
  • Blood volume listed under protein biomarkers represents the combined volume of several different collection tubes. An indwelling IV cannula may be used for blood sample collection. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
  • the investigator Prior to conducting any study procedure, the investigator (or designated study personnel) reviewed and explained the written ICF to each subject. After signing the ICF, subjects who were 18 (or older if the minimum legal age of consent in the country in which the study is taking place is >18) to 64 years of age (inclusive) were screened to determine eligibility for study participation.
  • Subjects had to meet DSM-5 diagnostic criteria for single-episode MDD (if single-episode MDD, the duration must be ⁇ 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI. In addition, at the start of the screening/prospective observational phase, the subject must have had an IDS-C 30 total score ⁇ 34.
  • the subject's current major depressive episode and antidepressant treatment response to antidepressant therapies used during the current depressive episode were confirmed using the Site Independent Qualification Assessment.
  • An independent, blinded rater performed remote MADRS assessments to assess depressive symptoms during this phase.
  • the investigator and study site were blinded to specific details regarding the response criteria for entry into the double-blind induction phase.
  • Eligible non-responders (determined by remote blinded rater) discontinued their current antidepressant medication(s) and any other prohibited psychotropic medications, including adjunctive atypical antipsychotics.
  • Benzodiazepines or nonbenzodiazepine sleep medications were allowed to continue but had specific restrictions regarding the administration time relative to the intranasal treatment sessions.
  • the taper period did not start until after the completion of 4 weeks of prospective antidepressant treatment and assessment of the antidepressant treatment response.
  • subjects self-administered double-blind intranasal treatment with esketamine (56 mg or 84 mg) or placebo twice per week for 4 weeks as a flexible dose regimen.
  • subjects simultaneously initiated a new, open-label oral antidepressant.
  • Study subjects were randomly assigned to 1 of the following 2 double-blind treatment groups at a 1:1 ratio (approximately 98 subjects per group): 1. Intranasal placebo or 2. Intranasal esketamine (56 mg or 84 mg). On the same day (i.e., Day 1), subjects were switched to a new, open-label oral antidepressant treatment.
  • the oral antidepressant was 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR).
  • the antidepressant medication was assigned by the investigator (based on review of the MGH-ATRQ and relevant prior antidepressant treatment information) and was one that the subject had not previously had a nonresponse to in the current depressive episode, had not been previously intolerant to (lifetime), and was available in the participating country.
  • Dosing of the oral antidepressant began on Day 1 and followed the local prescribing information for the respective product, with a forced titration to the maximally tolerated dose.
  • the titration schedule for the selected oral antidepressant was as presented in Table 5, above.
  • the Early Withdrawal visit was conducted within 1 week of the date of discontinuation, followed by the follow up phase. If the Early Withdrawal visit occurred on the same day as a scheduled visit, the early withdrawal visit was performed on the same day and duplicate assessments were not required.
  • the primary efficacy evaluation was the MADRS total score.
  • the MADRS was performed by independent remote raters during the study.
  • the 10-item clinician-administered, clinician-rated scale MADRS was designed to be used in subjects with MDD to measure the overall severity of depressive symptoms, including depression severity and to detect changes due to antidepressant treatment.
  • the MADRS scale was used as the primary efficacy measure for this study because it is validated, reliable, and acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression.
  • the MADRS scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.
  • the MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test exhibits high inter-rater reliability.
  • the primary efficacy endpoint was a change in the MADRS total score from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction phase.
  • subjects in any of the 2 treatment groups who responded to the study medication were defined as subjects who met the criterion for response defined as ⁇ 50% reduction in the MADRS total score from baseline (Day 1 pre-randomization) to the end of the 4-week double-blind induction phase.
  • the MADRS was also used to evaluate the key secondary efficacy endpoint of onset of clinical response (i.e., antidepressant effect) by Day 2 that was maintained for the duration of the double-blind induction phase.
  • Onset of clinical response was defined as ⁇ 50% improvement in MADRS total score by Day 2 (i.e., the day after taking the first dose of double-blind intranasal medication) that continued through the end of the double-blind phase.
  • MADRS was also used to evaluate a secondary objective assessing proportion of subjects with response and those in remission (defined as subjects with a MADRS total score ⁇ 12) at the end of the 4-week double-blind induction phase.
  • the MADRS was administered using a modified recall period of 24 hours for the key secondary efficacy evaluation related to onset of clinical response by Day 2 that was maintained for the duration of the double-blind induction phase.
  • the MADRS with a 24-hour recall period was used on Day 2. The feasibility of this shortened recall period has been confirmed with patients, and physicians, and there are data supporting the psychometric properties of this shortened recall period.
  • the MADRS with a 7-day recall was used for all subsequent MADRS assessments used for the key secondary efficacy evaluation (maintenance of clinical response achieved on Day 2 for duration of double-blind induction phase).
  • the Patient Health Questionnaire (PHQ-9) is a 9-item, subject-reported outcome measure that was used to assess depressive symptoms.
  • the scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and has been used both as a screening tool and a measure of response to treatment for depression.
  • the subject's item responses were summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms.
  • the recall period was 2 weeks.
  • the Sheehan Disability Scale was used to assess the secondary objective of functional impact and associated disability.
  • the SDS is a subject-reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability.
  • the first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale.
  • the score for the first three items were summed to create a total score of 0-30 where a higher score indicated greater impairment.
  • the SDS also has one item on days lost from school or work and one item on days when underproductive. The recall period for this study was 7 days.
  • the Clinical Global Impression—Severity provides an overall clinician-determined summary measure of the severity of the subject's illness that takes into account all available information, including knowledge of the subject's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the subject's ability to function.
  • the CGI-S permits a global evaluation of the subject's condition at a given time.
  • the 7-item subject-reported Generalized Anxiety Disorder 7-item Scale was used to measure the secondary objective of symptoms of anxiety.
  • the Euro-Qol-5 Dimention-5 Level (EQ-5D-5L) is a standardized instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS).
  • the EQ-5D-5L descriptive system comprises the following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).
  • the subject selected an answer for each of the 5 dimensions considering the response that best matches his or her health “today.”
  • the descriptive system was used to represent a health state.
  • the EQ-VAS self-rating recorded the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 to 100.
  • the primary efficacy endpoint was the change in the MADRS total score as measured by the change from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction phase.
  • a serial gatekeeping (fixed sequence) approach was applied to adjust for multiplicity and to strongly control type I error across the primary and the 3 key secondary efficacy endpoints (onset of clinical response, change in SDS total score, and change in PHQ-9 total score).
  • the 3 key secondary endpoints were analyzed sequentially and were considered statistically significant at the 1-sided 0.025 level only if the endpoint was individually significant at the 1-sided 0.025 level and previous endpoints in the hierarchy were significant at the 1-sided 0.025 level, including the primary endpoint. If the primary endpoint was statistically significant, the selected secondary endpoints were assessed in the following order: onset of clinical response, change in SDS total score, change in PHQ-9 total score.
  • the primary efficacy endpoint was the change in MADRS total score from baseline to Day 28.
  • MADRS total scores range from 0 to 60.
  • the primary efficacy analysis was performed on the full analysis set, which included all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant study medication. As shown in Table 13 below, results for the change in MADRS total score favored intranasal esketamine+oral AD over oral AD+intranasal placebo. ( FIG.
  • ⁇ SE least-square mean changes
  • the mean change from baseline (SD) at Day 28 was ⁇ 21.4 (12.32) for esketamine+oral AD and ⁇ 17.0 (13.88) for the active comparator.
  • the least-square mean difference (SE) between esketamine+oral AD and active comparator was ⁇ 4.0 (1.69).
  • the MMRM analysis was considered the primary analysis for all dossiers except the EU.
  • SE east-square mean difference
  • Test for treatment effect is based on mixed model for repeated measures (MMRM) with change from baseline as the response variable and the fixed effect model terms for treatment (intranasal esk + oral AD, oral AD + intranasal placebo), day, country, class of oral antidepressant (SNRI or SSRI), and treatment-by-day, and baseline value as a covariate.
  • MMRM mixed model for repeated measures
  • a negative difference favors esketamine.
  • MADRS Total score ranges from 0 to 60; a higher score indicates a more severe condition. Negative change in score indicates improvement.
  • the first key secondary endpoint was the change from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction phase in subject-reported depressive symptoms, using the PHQ-9 total score.
  • the second key secondary endpoint was the proportion of subjects showing onset of clinical response by Day 2 that was maintained through the end of the 4-week double-blind induction phase. Onset of clinical response was defined as ⁇ 50% reduction in the MADRS total score by the day after taking the first dose of double-blind medication [Day 2] that continued through the end of the 4-week double-blind induction phase). Subjects who discontinued the study prior to the end of the double-blind induction phase were not considered to have maintained clinical response.
  • the third key secondary endpoint was the change in SDS total score as measured by the change from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction phase.
  • a subject was defined as having a clinical response if there was at least 50% improvement from baseline in the MADRS total score with onset by Day 2 that was maintained to Day 28 at each visit. Subjects were allowed one excursion (non-response) on Days 8, 15 or 22, however the score must have shown at least 25% improvement. Subjects who do not meet such criterion, or discontinue during the study before Day 28 for any reason were considered as non-responders and were assigned the value of no, meaning they did not meet the criteria for Onset of Clinical Response.
  • the SDS is a subject-reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability.
  • the first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale.
  • the score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment.
  • results for the change in SDS total score favored intranasal esketamine+oral AD over oral AD+intranasal placebo.
  • the mean change from baseline (SD) at Day 28 was ⁇ 13.3 (8.22) for esketamine+oral AD and ⁇ 9.5 (8.38) for the active comparator.
  • the least-square mean difference (SE) between esketamine+oral AD and active comparator was ⁇ 3.6 (1.18).
  • SE least-square mean difference
  • Adverse events were reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for the duration of the study. Adverse events were followed by the investigator. TEAEs of special interest were examined separately.
  • Urinalysis Dipstick Sediment (if dipstick result is abnormal) specific gravity red blood cells pH white blood cells glucose epithelial cells protein crystals blood casts ketones bacteria bilirubin urobilinogen nitrite leukocyte esterase If dipstick result was abnormal, flow cytometry or microscopy was used to measure sediment. In case of discordance between the dipstick results and the flow cytometric results, the sediment was examined microscopically.
  • subjects should be in a quiet setting without distractions (e.g., television, cell phones). Subjects should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs.
  • distractions e.g., television, cell phones.
  • ECG tracings were sent to a central ECG laboratory.
  • the ECGs were read at the scheduled time points and summarized by a central ECG laboratory.
  • the investigator or sub-investigator was required to review all ECGs at the study visit to assess for any potential safety concerns or evidence of exclusionary conditions.
  • Blood pressure and pulse/heart rate measurements were assessed supine with a completely automated device. Manual techniques were used only if an automated device is not available. Blood pressure and pulse/heart rate measurements were preceded by at least 5 minutes of rest in a quiet setting without distractions (e.g., television, cell phones).
  • Tympanic temperature was recommended.
  • An automated device was used for measurement of respiratory rate.
  • Pulse oximetry was used to measure arterial oxygen saturation. On each dosing day, the device was attached to the finger, toe, or ear before the first nasal spray and then, after the first spray it was monitored and documented. Any arterial blood oxygen saturation (SpO 2 ) ⁇ 93% and lasting for more than 2 minutes, and confirmed by an additional manual measurement on another part of the body, was reported as an adverse event.
  • SpO 2 arterial blood oxygen saturation
  • body mass index was calculated and neck circumference measured as part of the information required for the STOP-Bang questionnaire.
  • Nasal examinations were conducted by a qualified healthcare practitioner.
  • the objective of the examination at screening was to rule out any subjects with anatomical or medical conditions that may impede drug delivery or absorption.
  • Subsequent examinations consisted of a visual inspection of the nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption, and epistaxis, and were graded as absent, mild, moderate, or severe. Any treatment-emergent change or worsening from the baseline examination was recorded as an adverse event.
  • the nasal symptom questionnaire was developed to assess nasal tolerability following intranasal administration of study drug.
  • the questionnaire asks about nasal symptoms, which were rated by the subject as none, mild, moderate, or severe, based on how he or she feels at the time of the assessment.
  • the C-SSRS was performed to assess potential suicidal ideation and behavior.
  • the C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both suicidal ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present.
  • the C-SSRS can also be used during treatment to monitor for clinical worsening.
  • the Baseline/Screening version of the C-SSRS was used in the screening/prospective observational phase. In this version, suicidal ideation was assessed at 2 time points (“lifetime” and “in the past 6 months”) and suicidal behavior was assessed at 2 time points (“lifetime” and “in the past year”).
  • the CADSS is an instrument for the measurement of present-state dissociative symptoms, and was administered to assess treatment-emergent dissociative symptoms.
  • the BPRS is an 18-item rating scale that is used to assess a range of psychotic and affective symptoms, rated from both observation of the subject and the subject's own report. It reportedly provides a rapid and efficient evaluation of treatment response in clinic drug studies and in clinical settings. Only the 4-item positive symptom subscale BPRS+(i.e., suspiciousness, hallucinations, unusual thought content, and conceptual disorganization) were used in this study. It is highly sensitive to change, and excellent inter-rater reliability can be achieved with training and a standard interview procedure.
  • the MOANS was used to measure treatment-emergent sedation, with correlation to levels of sedation defined by the American Society of Anesthesiologists (ASA) continuum.
  • the CGADR was used to measure the subject's current clinical status and was the clinician's assessment of the readiness to be discharged from the study site. The clinician answered “Yes” or “No” to the question “Is the subject considered ready to be discharged based on their overall clinical status (e.g., sedation, blood pressure, and other adverse events)?”
  • the CGADR was performed at 1 hour and 1.5 hours post-dose; if the response was not “Yes” at 1.5 hours post-dose, the assessment was repeated every 15 minutes until a “Yes” response was achieved or until the subject was referred for appropriate medical care, if clinically indicated. A subject was not discharged prior to the 1.5-hour time point. On all intranasal treatment session days, subjects remained at the clinical site until study procedures were completed and the subject was ready for discharge.
  • the PWC-20 was administered to assess potential withdrawal symptoms following cessation of intranasal esketamine treatment. An assessment was performed on Day 25 to establish a baseline prior to discontinuation of intranasal esketamine treatment. In order to better assess potential withdrawal symptoms from the intranasal medication it was recommended that the oral antidepressant medication be continued for at least the first 2 weeks of the follow up phase unless determined as not clinically appropriate.
  • the PWC-20 is a 20-item simple and accurate method to assess potential development of discontinuation symptoms after stopping of study drug.
  • the PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms.
  • the BPIC-SS is a subject-reported outcome measure that was developed to identify an appropriate bladder pain syndrome/interstitial cystitis population for clinical studies evaluating new treatments for bladder pain syndrome.
  • the BPIC-SS was used to monitor subjects for potential symptoms of cystitis, bladder pain, and interstitial cystitis.
  • the BPIC-SS includes 8 questions with a recall period of the past 7 days, and addresses key symptoms identified by subjects with BPS including symptom concepts of pain and/or pressure of the bladder and urinary frequency.
  • Question 8 records the worst bladder pain in the last 7 days using a 0-10 numerical rating scale.
  • a total score was calculated by adding up the numbers beside the response options chosen by the subject.
  • the range of possible scores for the scale is 0 to 38.
  • a total score of 19 or more demonstrated good sensitivity/specificity and was considered a relevant cut-off to distinguish those with significant bladder symptoms or cystitis.
  • the computerized cognitive battery provides assessment of multiple cognitive domains, including attention, visual learning and memory, and executive function.
  • the tests use culture-neutral stimuli, enabling use in multilingual/multicultural settings.
  • the computerized battery includes:
  • the HVLT-R a measure of verbal learning and memory, is a 12-item word list recall test. Administration includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), and a delayed recall (20-minute) trial. Administration is computer-assisted; instructions and word lists appear on-screen. The test administrator records each word correctly recalled, and scores for learning, short-term, and delayed recall are generated via the test software.
  • the HVLT-R is a well-validated and widely used measure of verbal episodic memory.
  • the tests were administered in the following order HVLT-R, computerized cognitive test battery, and HVLT-R Delayed.
  • olfactory function was qualitatively and quantitatively assessed using validated standardized olfactory tests prior to and at specified time points during the study.
  • the 2 tests administered were:
  • the UPSIT assesses a subject's ability to identify odors. This standardized test, the most widely used olfactory test in the world, is derived from basic psychological test measurement theory and focuses on the comparative ability of subjects to identify odorants at the suprathreshold level.
  • the UPSIT consists of 4 envelope-sized booklets, each containing 10 “scratch and sniff” odorants embedded in 10- to 50-pm polymer microcapsules positioned on brown strips at the bottom of the pages of the booklets.
  • the internal consistency and test-retest reliability coefficients of this instrument are >0.90. Numerous studies have shown this and related tests to be sensitive to subtle changes in smell function associated with multiple etiologies, including those due to viruses, head trauma, and a number of neurodegenerative diseases.
  • the Smell Threshold Test assesses the smell threshold using a forced-choice single staircase threshold procedure. This test quantifies a detection threshold for the rose-like smelling odorant phenyl ethyl alcohol (PEA). This odorant is used because it has little propensity to stimulate the trigeminal nerve within the nose. This test is sensitive to olfactory deficits from a wide range of disorders.
  • PDA phenyl ethyl alcohol
  • Subjects underwent MINI (a brief, structured diagnostic interview) to confirm the diagnosis of MDD and to determine if there are other psychiatric conditions present. It has an administration time of approximately 15 minutes.
  • the MGH-ATRQ was used to determine treatment resistance in MDD.
  • the MGH-ATRQ evaluates the adequacy of duration and dosage of all antidepressant medications used for the current major depressive episode.
  • the MGH-ATRQ assesses the degree of improvement on a scale from 0% (not improved at all) to 100% (completely improved).
  • the MGH-ATRQ was completed by the clinician in collaboration with the subject.
  • the STOP-Bang Questionnaire is a concise, easy-to-use, validated, and sensitive screening tool for obstructive sleep apnea (OSA).
  • This questionnaire has 8 items which address key risk factors for obstructive sleep apnea: snoring, tiredness, observed breathing interruption during sleep, high blood pressure, body mass index, age, neck size, and gender.
  • the STOP-Bang questions do not specify a recall period.
  • the total STOP-BANG score was calculated by summing the number of positive responses, yielding a score range of 0 to 8. A score of ⁇ 5 on the STOP-Bang indicates a moderate to severe risk for Obstructive Sleep Apnea (apnea hypopnea index of >30).
  • the 30-item IDS-Cao is designed to assess the severity of depressive symptoms.
  • the IDS assesses all the criterion symptom domains designated by the DSM-5 to diagnose a major depressive episode. These assessments can be used to screen for depression, although they have been used predominantly as measures of symptom severity.
  • the 7-day period prior to assessment is the usual time frame for assessing symptom severity.
  • the psychometric properties of the IDS-Cao have been established in various study samples.
  • the MGH-Female RLHQ Module I (childbearing potential, menopausal status, and menstrual cycle) is a brief questionnaire aimed at standardizing the minimal collection of relevant information about reproductive hormones and status. It was completed by a clinician. This information may facilitate exploratory analyses of the impact of endogenous and exogenous reproductive hormones on the course of treatment of MDD and potentially inform care of women with MDD in the future.
  • Menstrual cycle tracking (start date of last menstrual period) was documented at the study visits specified in the Time and Events Schedule.
  • a subject was considered to have completed the double-blind induction phase of the study if he or she completed the MADRS assessment at the end of the 4-week double-blind induction phase (i.e., Day 28 MADRS). Subjects who prematurely discontinued study treatment for any reason before completion of the double-blind induction phase were not considered to have completed the double-blind induction phase of the study. Subjects who entered the follow-up phase were considered to have completed this phase of the study if he or she had completed the MADRS assessment at Week 24 of the follow-up phase.
  • Safety data was analyzed for the double-blind induction phase using the safety analysis set.
  • TEAEs of special interest were examined separately. AEs of special interest were listed in the SAP. Subjects who died, who discontinued treatment due to an adverse event, or who experienced a severe or a serious adverse event were summarized separately.
  • Laboratory data were summarized by type of laboratory test. Reference ranges and markedly abnormal results (specified in the Statistical Analysis Plan) were used in the summary of laboratory data. Descriptive statistics were calculated for each laboratory analyte at baseline and at each scheduled time point in each phase of the study. Changes from baseline results were presented. Frequency tabulations of the abnormalities were provided. Listings of subjects with laboratory results outside the reference ranges and markedly abnormal results were provided.
  • cardiovascular variables were evaluated by means of descriptive statistics and frequency tabulations. These tables include observed values and change from baseline values.
  • Electrocardiogram data was summarized by ECG parameter. Descriptive statistics were calculated at baseline and for observed values and changes from baseline at each scheduled time point. Frequency tabulations of the abnormalities were made.
  • the ECG variables that were analyzed were heart rate, PR interval, QRS interval, QT interval, and QTc interval using the following correction methods: QT corrected according to Bazett's formula (QTcB) and QTcF.
  • Descriptive statistics of QTc intervals and changes from double-blind baseline were summarized at each scheduled time point.
  • the percentage of subjects with QTc interval >450 msec, >480 msec, or >500 msec were summarized, as will the percentage of subjects with QTc interval increases from baseline ⁇ 30 msec, 30-60 msec, or >60 msec.
  • Scoring from the nasal symptom questionnaire was summarized descriptively for each scheduled time point by treatment group.
  • Suicide-related thoughts and behaviors based on the C-SSRS were summarized by treatment group in incidence and shift tables. Separate endpoints for suicidal ideation and suicidal behavior were defined and summarized descriptively by treatment group. Missing scores were not imputed.
  • An adverse event is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non-investigational) product.
  • An adverse event does not necessarily have a causal relationship with the treatment.
  • An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product (definition per International Conference on Harmonisation [ICH]).
  • the expectedness of an adverse event was determined by whether or not it is listed in the SmPC or US prescribing information.
  • Doubtful An adverse event for which an alternative explanation was more likely, e.g., concomitant drug(s), concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
  • Probable An adverse event that might be due to the use of the drug.
  • the relationship in time was suggestive (e.g., confirmed by dechallenge).
  • An alternative explanation was less likely, e.g., concomitant drug(s), concomitant disease(s).
  • Severe Extreme distress, causing significant impairment of functioning or incapacitation. Prevented normal everyday activities.
  • the investigator used clinical judgment in assessing the severity of events not directly experienced by the subject (e.g., laboratory abnormalities).
  • Safety events of interest on a sponsor study drug that may require expedited reporting and/or safety evaluation included, but were not limited to:
  • Medication error involving a sponsor product (with or without subject/patient exposure to the sponsor study drug, e.g., name confusion)
  • FIG. 6 shows the percentage of subjects reporting problems at baseline and endpoint as determined by EQ-5D-% L individual dimensions.
  • Treatment-emergent adverse events occurring during the double-blind phase are summarized by treatment group for the safety analysis set in Table 19, below.
  • the most common ( ⁇ 20%) TEAEs in the esketamine+oral AD group during the double-blind phase were nausea (26.1%), vertigo (26.1%), dysgeusia (24.3%), and dizziness (20.9%).
  • the most common TEAE in the active comparator group was headache (17.4%).
  • Transient blood pressure increases peaked for the esketamine group at approximately 40 minutes post dose and returned to normal range at 90 minutes.
  • the maximum mean increases (across all dosing days) in systolic BP was 11.6 in the esketamine+oral AD group and 5.0 in the active comparator group.
  • the maximum mean increase (across all dosing days) in diastolic BP were 8.1 in the esketamine group and 4.5 in the active comparator group.
  • FIGS. 7 and 8 present the means for measured blood pressure over time by treatment group in the double-blind phase.
  • CADSS Clinician-Assessed Dissociative Symptom Scale
  • the Clinician Administered Dissociative States Scale was measured prior to the start of each dose, at 40 minutes, and 1.5 hours postdose.
  • the CADSS was used to assess treatment emergent dissociative symptoms and perceptual changes and the total score ranged from 0 to 92 with a higher score representing a more severe condition.
  • the dissociative and perceptual change symptoms measured by the CADSS suggest these symptoms had an onset shortly after the start of the dose and resolved by 1.5 hours postdose (as shown in FIG. 9 ).
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation
  • ASA American Society of Anesthesiologists
  • the MOAA/S scores ranged from 0 (No response to painful stimulus; corresponds to ASA continuum for general anesthesia) to 5 (Readily responds to name spoken in normal tone [awake]; corresponding to ASA continuum for minimal sedation). Sedation as measured by the MOAA/S, suggests that sedation resolved by 1.5 hours postdose (as shown in FIG. 10 ).
  • Venous blood samples of approximately 2 mL were collected for measurement of plasma concentrations of esketamine, noresketamine, and other metabolites (if warranted) at the time points specified in the Time and Events Schedule. The exact dates and times of PK blood sampling were recorded.
  • Plasma samples were analyzed to determine concentrations of esketamine (and noresketamine, if warranted) using a validated, specific, achiral, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method by or under the supervision of the sponsor. If required, some plasma samples were analyzed to document the presence of other analytes (e.g., circulating metabolites or denatonium) using a qualified research method. In addition, plasma PK samples could be stored for future analysis of the metabolite profile.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the plasma concentration-time data of esketamine was analyzed using population PK modeling.
  • Typical population values of basic PK parameters e.g., esketamine clearance distribution volume
  • effects of subject demographics, laboratory parameter values, and other covariates on the PK of esketamine were explored.
  • MADRS total score (and possibly selected adverse events as additional PD parameters) and PK metrics of esketamine were evaluated. If there was any visual trend in graphical analysis, suitable models were applied to describe the exposure-effect relationships.
  • biomarker blood samples were collected prior to dosing. It was preferred that subjects adhere to a low fat diet on the day of sample collection.
  • biomarkers protein, metabolite, and ribonucleic acid [RNA]) related to (but not limited to) the immune system activity, hypothalamus pituitary adrenal (HPA) axis activation, neurotrophic factors, and metabolic factors were investigated. Biomarkers were added or deleted based on scientific information or technical innovations under the condition that the total volume of blood collected was not increased.
  • HPA hypothalamus pituitary adrenal
  • Blood samples for DNA analyses were collected at the time points indicated in the Time and Events Schedule for the assessment of genetic and epigenetic variation in genes in pathways relevant to depression (e.g., HPA axis, inflammation, growth factors, monoamine transporters, ion channels, and circadian rhythm). Genotyping was conducted only on the screening sample; pharmacogenomic and epigenetic evaluations could be performed on any/all collected samples.
  • pathways relevant to depression e.g., HPA axis, inflammation, growth factors, monoamine transporters, ion channels, and circadian rhythm.
  • DNA samples were used for research related to esketamine, oral antidepressants, TRD, or MDD. They could also be used to develop tests/assays related to esketamine, oral antidepressants, TRD, or MDD.
  • Pharmacogenomic research consisted of the analysis of 1 or more candidate genes or of the analysis of genetic markers throughout the genome (as appropriate) in relation to esketamine, oral antidepressants, TRD, or MDD clinical endpoints.
  • Medical resource utilization data associated with medical encounters, were collected during the follow-up phase of the study. Protocol-mandated procedures, tests, and encounters were excluded. The data collected could be used to conduct exploratory economic analyses and include: (a) Number and duration of medical care encounters, including surgeries, and other selected procedures (inpatient and outpatient), (b) Duration of hospitalization (total days length of stay, including duration by wards; e.g., intensive care unit), (c) Number and character of diagnostic and therapeutic tests and procedures, and/or (d) Outpatient medical encounters and treatments (including physician or emergency room visits, tests and procedures, and medications).
  • Plasma esketamine (and noresketamine, if warranted) concentrations were listed for all subjects.
  • the plasma concentration-time data of esketamine (and noresketamine, if warranted) was analyzed using population PK modeling. Data may have been combined with those of other selected studies to support a relevant structural model. Typical population values of basic PK parameters were estimated together with the inter-individual variability. Effects of subject demographics, laboratory parameter values, and other covariates on the PK of esketamine were explored.
  • MADRS total score (and possibly selected adverse events as additional PD parameters) and PK metrics of esketamine were evaluated. If there was any visual trend in graphical analysis, suitable models were applied to describe the exposure-effect relationships.
  • Baseline biomarker values and changes from baseline biomarker values to the time points specified in the Time and Events Schedule were summarized. Exploratory analyses may have included comparison of biomarker measures between the treatment groups and correlation with baseline and change from baseline biomarker values in the efficacy and other measures. Additional exploratory analyses may have also included relationship of baseline and change from baseline in biomarker measures to clinical response, maintenance/stabilization of response, relapse, and non-response.
  • Pharmacogenomic analyses may also have included candidate gene analyses or genome-wide association analyses in relation to treatment response, maintenance/stabilization of response, relapse, non-response, and MDD/TRD.
  • Expression analyses may include testing of known messenger RNA/microRNA (mRNA/miRNA) transcripts or transcriptome-wide analysis in relationship to antidepressant treatment response and MDD/TRD.
  • the maximum sample size planned for this study was calculated assuming a treatment difference for the double-blind induction phase of 6.5 points in MADRS total score between esketamine and the active comparator, a standard deviation of 12, a 1-sided significance level of 0.0125, and a drop-out rate of 25%. A maximum of about 98 subjects would need to be randomized to each treatment group to achieve 90% power using a fixed design with no interim analysis.
  • the treatment difference and standard deviation used in this calculation were based on results of Panel A of the ESKETINTRD2003 study and on clinical judgment.
  • IDMC performed the interim analysis and made recommendations for any sample size adjustment based on the rules defined in the interim SAP. Any changes to sample size were communicated IDMC (or the statistician from the Statistical Support Group) to the IWRS vendor to ensure that the appropriate number of subjects were enrolled in the study. None of the esketamine team members or staff members at the investigational sites conducting the clinical study were informed of the results of the interim analysis and any adjustments that were made to the sample size.
  • the primary efficacy variable change from baseline in MADRS total score at Week 4 in the double-blind induction phase, was analyzed using MMRM.
  • the model included baseline MADRS total score as a covariate, and treatment, country, class of antidepressant (SNRI or SSRI), day, and day-by-treatment interaction as fixed effects, and a random subject effect. Comparison of the esketamine plus oral antidepressant arm versus oral antidepressant plus intranasal placebo was performed using the appropriate contrast.
  • the primary efficacy analysis was based on an analysis of covariance (ANCOVA) model using last observation carried forward (LOCF) data.
  • the model included factors for treatment, country, and class of oral antidepressant (SNRI or SSRI) and baseline MADRS total score as a covariate. Comparison of the esketamine plus oral antidepressant arm versus intranasal placebo plus oral antidepressant was performed using the appropriate contrast.
  • the proportion of subjects showing onset of clinical response by Day 2 that is maintained for the duration of the double-blind induction phase in the esketamine plus oral antidepressant arm was compared with the oral antidepressant plus intranasal placebo arm using a Cochran-Mantel-Haenszel chi-square test adjusting for country and class of antidepressant (SNRI or SSRI).
  • Clinical response was defined as ⁇ 50% improvement in MADRS total score by Day 2 (i.e., the day after taking the first dose of double-blind intranasal medication) that continues through the end of the double-blind phase. Subjects who discontinued the study prior to end of the double-blind induction phase were not considered to have maintained clinical response.
  • the third key secondary efficacy endpoint change from baseline in SDS total score at Week 4 in the double-blind induction phase, was analyzed using ANCOVA.
  • the model included factors for treatment, country, and class of oral antidepressant (SNRI or SSRI) and baseline SDS total score as a covariate. Comparison of each intranasal esketamine plus oral antidepressant arm versus oral antidepressant plus intranasal placebo was performed using the appropriate contrast. Responses to questions H1 to H3 was summarized separately.
  • ESK+AD demonstrated statistically significant and clinically meaningful superiority compared with AD+PBO in primary efficacy endpoint (i.e., change from baseline in the MADRS total score (Montgomery, British Journal of Psychiatry. 1979; 134:382-389)).
  • primary efficacy endpoint i.e., change from baseline in the MADRS total score (Montgomery, British Journal of Psychiatry. 1979; 134:382-389).
  • the efficacy and safety of these treatment groups were analyzed in only US patients and to assess for differences in efficacy and safety between the US population and the overall study population.
  • CGI-S Clinical Global Impressions-Severity
  • Inclusion criteria included adults, aged 18 to 64 years (inclusive), who met DSM-5 diagnostic criteria for MDD confirmed by Mini-International Neuropsychiatric Interview, and Inventory of Depressive Symptomatology-Clinician rated, 30-item total score of ⁇ 34 (moderate to severe depression)
  • the baseline patient demographics and disease characteristics were generally similar between the 2 treatment groups. See, Table 22.
  • the overall mean age was 44.1 year, and approximately two-thirds (61.1%) of patients were women and most (83.3%) patients were Caucasian.
  • the mean age of MDD diagnosis was 27.5 years, indicating on average, a >15-year history of depression.
  • the baseline MADRS, CGI-S and PHQ-9 scores were consistent with a population with TRD.
  • CGI-S score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
  • d PHQ-9 total score ranges from 0 to 27; a higher score indicates greater depression.
  • Efficacy was determined by measuring MADRS total scores, SDS scores, PHQ-9 scores and CGI-S scores.
  • the test for treatment effect was based on mixed model for repeated measures (MMRM) with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, class of oral antidepressant (serotonin and norepinephrine reuptake inhibitor [SNRI] or selective serotonin reuptake inhibitor [SSRI]), treatment-by-day, and baseline value as a covariate.
  • MMRM mixed model for repeated measures
  • the test for treatment effect was based on analysis of covariance (ANCOVA) model last observation carried forward (LOCF) on ranks of change from baseline as the response variable and factors for treatment (ESK+AD, AD+PBO) and class of oral antidepressant (SNRI or SSRI), and baseline value (unranked) as a covariate.
  • ANCOVA covariance
  • LOCF model last observation carried forward
  • ESK+AD, AD+PBO class of oral antidepressant
  • SNRI or SSRI class of oral antidepressant
  • baseline value unranked
  • the treatment effect favored the ESK+AD group at about 24-hours post dose (day 2) and on day 28, with the difference reaching statistical significance at day 28. See, Table 23.
  • the Patient-rated severity of depressive illness decreased in bath treatment groups, but the magnitude of decrease was greater in the ESK+AD group at day 28. See, FIG. 12 .
  • the mean PHQ-9 scores at baseline were 20.2 in the ESK+AD group and 20.9 in the AD+PBO group. On day 28, mean PHQ-9 total scores were 8.0 and 11.7, respectively.
  • TEAEs Treatment emergent adverse events
  • BPRS Brief Psychiatric Rating Scale
  • CADSS Clinician Administered Dissociative States Scale
  • TEAEs were observed in 91.3% of patients in the ESK+AD group and 77.3% of patients in the AD+PBO group. See, Table 25A. There were no deaths.
  • One patient in the ESK+AD group experienced a SAE during the follow-up phase (cerebral hemorrhage on day 98).
  • TEAEs The most common TEAEs ( ⁇ 5% in either treatment group) are shown in Table 4. The incidence of TEAEs was similar between the US patients and the overall study population. AEs observed during the study were mostly mild to moderate in severity and transient in nature.
  • ESK+AD compared with AD+PBO (active comparator) in US patients with TRD provided evidence for clinically meaningful, statistically significant, and rapid reduction of depressive symptoms.
  • Significant improvements in clinician-rated severity of depressive illness were observed as early as 24 hours after dosing in some patients.
  • ESK+AD demonstrated statistically significant and clinically meaningful superiority compared with AD+PBO in primary efficacy endpoint (i.e., change from baseline in the MADRS total score. See, Montgomery cited above.
  • primary efficacy endpoint i.e., change from baseline in the MADRS total score.
  • the response, remission, and safety of these treatment groups were analyzed in only US patients and to assess for differences in efficacy and safety between the US population and the overall study population.
  • CGI-S Clinical Global Impressions-Severity
  • Inclusion criteria included adults, aged 18 to 64 years (inclusive), who met DSM-5 diagnostic criteria for MDD confirmed by Mini-International Neuropsychiatric Interview, and Inventory of Depressive Symptomatology-Clinician rated, 30-item total score of ⁇ 34 (moderate to severe depression).

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