US20230277500A1 - Compositions comprising aticaprant - Google Patents

Compositions comprising aticaprant Download PDF

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US20230277500A1
US20230277500A1 US18/179,093 US202318179093A US2023277500A1 US 20230277500 A1 US20230277500 A1 US 20230277500A1 US 202318179093 A US202318179093 A US 202318179093A US 2023277500 A1 US2023277500 A1 US 2023277500A1
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Prior art keywords
aticaprant
weight
pharmaceutical composition
patient
treatment
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US18/179,093
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Inventor
Nicolaas Martha Felix Goyvaerts
Mark Schmidt
Vanina Popova
Adam Savitz
Rama Melkote
Wayne C. Drevets
Srihari Gopal
Darrel Pemberton
Chakradhar Lagishetty
Iva Kezic
Mahesh N. Samtani
Tom Huybrechts
Geert Van Der Avoort
Matthieu Ravelingien
Laura Martinez Marcos
Tatiana MARCOZZI
Katarina Jokicevic
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Janssen Pharmaceuticals Inc
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Janssen Pharmaceutica NV
Janssen Pharmaceuticals Inc
Janssen Research and Development LLC
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Priority to US18/179,093 priority Critical patent/US20230277500A1/en
Publication of US20230277500A1 publication Critical patent/US20230277500A1/en
Assigned to Janssen Pharmaceuticals, Inc. reassignment Janssen Pharmaceuticals, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JANSSEN PHARMACEUTICA NV
Assigned to JANSSEN RESEARCH & DEVELOPMENT, LLC reassignment JANSSEN RESEARCH & DEVELOPMENT, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAVITZ, Adam, GOPAL, SRIHARI, SAMTANI, MAHESH N., MELKOTE, RAMA, DREVETS, WAYNE, LAGISHETTY, CHARKRADHAR
Assigned to JANSSEN PHARMACEUTICA NV reassignment JANSSEN PHARMACEUTICA NV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: POPOVA, VANINA, MARCOZZI, Tatiana, SCHMIDT, MARK, RAVELINGIEN, Matthieu, GOYVAERTS, NICOLAAS MARTHA FELIX, JOKICEVIC, Katarina, MARCOS, Laura Martinez, PEMBERTON, DARREL, VAN DER AVOORT, Geert, Huybrechts, Tom, KEZIC, IVA
Assigned to Janssen Pharmaceuticals, Inc. reassignment Janssen Pharmaceuticals, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JANSSEN RESEARCH & DEVELOPMENT, LLC
Priority to US18/618,520 priority patent/US12201610B2/en
Priority to US19/023,669 priority patent/US20250228819A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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

  • compositions including oral compositions, comprising aticaprant and methods of using the same.
  • Kappa opioid receptors and their native ligand dynorphin are localized in areas of the brain that effect reward and stress and may play a key role in mood, stress, and addictive disorders.
  • Chronic stress, substance abuse, and acute withdrawal lead to increased dynorphin expression, activating KORs and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to negative affective states.
  • the behavioral pharmacology of KOR antagonism has been tested in animal models of anhedonia, depression, and anxiety and found to have meaningful effects that may translate to therapeutic benefit in humans.
  • KOR antagonists may be effective for the treatment of patients with mood disorders, perhaps by modulating the negative affective state associated with stress response.
  • Anhedonia is one of the core symptoms of depression. At least mild symptoms of anhedonia are present in about 90% of patients suffering from major depressive disorder (MDD). Only about 50% of patients with MDD show a meaningful response (>50% improvement to a first line antidepressant treatment), leaving many patients with substantial persistent impairment. Therapeutic strategies such as switching antidepressants and using adjuvant drug treatments can improve response, however almost 40% of patients remain symptomatic and fail to achieve full remission.
  • MDD major depressive disorder
  • the disclosure provides pharmaceutical compositions comprising about 2 mg to about 20 mg aticaprant and a filler, wherein the composition comprises between about 0.1% to about 90% aticaprant by weight.
  • the disclosure provides oral tablets comprising about 5 mg aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg microcrystalline cellulose, about 30 mg lactose monohydrate, about 2.5 mg croscarmellose sodium, and about 0.5 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 28.5 mg silicified microcrystalline cellulose, about 2.5 mg croscarmellose sodium, about 0.5 mg silica, colloidal anhydrous, and about 0.5 mg magnesium stearate.
  • the disclosure provides oral tablets comprising about 10 mg aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 60 mg microcrystalline cellulose, about 60 mg lactose monohydrate, about 5 mg croscarmellose sodium, and about 1 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 57 mg silicified microcrystalline cellulose, about 5 mg croscarmellose sodium, about 1 mg silica, colloidal anhydrous, and about 1 mg magnesium stearate.
  • the disclosure provides pharmaceutical compositions comprising between about 2 mg and 20 mg aticaprant, wherein the composition has a pharmacokinetic (PK) profile comprising one or more of the following parameters after administration of the composition to a human after at least a 10-hour fast (dose-normalized to 10 mg): (a) a mean C max between about 20 and 45 ng/mL; (b) a mean AUC infinity between about 250 and 450 h*ng/mL; (c) a mean AUC last between about 250 and 450 h*ng/mL; and (d) a median t max between about 1 to 4 hours.
  • PK pharmacokinetic
  • the disclosure provides methods for treating major depressive disorder (MDD) in a human patient, the method comprising administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg aticaprant, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant, and wherein the administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the following PK parameters (dose-normalized to 10 mg) after administration of the composition to a human after at least a 10-hour fast: (a) a mean C max between about 30 and 40 ng/mL; (b) a mean AUC infinity between about 300 and 430 h*ng/mL; (c) a mean AUC last between about 280 and 430 h*ng/mL; and (d) a median t max between about 1 to 4 hours.
  • PK pharmacokinetic
  • the disclosure provides solid pharmaceutical compositions comprising between about 2 mg and 20 mg aticaprant, wherein the composition has a dissolution profile comprising a Q value of between about 60% and 90% at 45 minutes, under the following dissolution operating conditions: Apparatus: Paddle (USP Type 2, Ph. Eur., JP); Dissolution medium: 0.01 M hydrochloric acid; Volume: 900 mL; Temperature: 37+/ ⁇ 0.5° C.; Rotation Speed: 50 rpm; and Analytical Finish: UHPLC with UV detection at 247 nm.
  • Apparatus Paddle (USP Type 2, Ph. Eur., JP); Dissolution medium: 0.01 M hydrochloric acid; Volume: 900 mL; Temperature: 37+/ ⁇ 0.5° C.; Rotation Speed: 50 rpm; and Analytical Finish: UHPLC with UV detection at 247 nm.
  • the disclosure provides methods of treating major depressive disorder (MDD) in a human patient comprising administering to the patient the pharmaceutical composition, oral tablet, or solid pharmaceutical composition described herein.
  • MDD major depressive disorder
  • FIG. 1 is the x-ray powder diffraction (XRPD) pattern of polymorph Form III of aticaprant (transmission mode).
  • FIG. 2 is the differential scanning calorimetry (DSC) thermogram of polymorph Form III of aticaprant.
  • FIG. 3 is the mDSC thermogram of polymorph Form III of aticaprant.
  • FIG. 4 is the trial design of Example 1.
  • FIG. 5 is a line graph showing the MADRS (Montgomery- ⁇ sberg Depression Rating Scale) total score: least squares mean changes from baseline ( ⁇ SE) during the treatment period for the enriched intent-to-treat (eITT) analysis set.
  • MADRS Monitoring- ⁇ sberg Depression Rating Scale
  • FIG. 6 is a plot showing MADRS total score changes at treatment week 6 for enriched and full population: MMRM results—estimated LS means and comparison versus placebo.
  • FIG. 7 is a line graph showing SHAPS (Snaith-Hamilton Pleasure Scale) total score: least squares mean changes from baseline ( ⁇ SE) during the treatment period for the eITT analysis set.
  • SHAPS Snaith-Hamilton Pleasure Scale
  • FIG. 8 is a plot showing SHAPS total score changes at treatment week 6 for enriched and full population: MMRM (Mixed-effects Model for Repeated Measures) Results—estimated LSMeans and comparison versus placebo
  • FIG. 9 is a line graph showing MADRS total score: mean values ( ⁇ SE) over time for the eITT analysis set.
  • FIG. 10 -A is a line graph showing MADRS total score: mean values ( ⁇ SE) over time for the full intent-to-treat (fITT) analysis set.
  • FIG. 10 -B is an excerpt from FIG. 10 -A for treatment weeks 0-6.
  • FIG. 11 is a line graph showing MADRS total score: percentage of subjects with remission of depressive symptoms (total score ⁇ 10) during the treatment period for the eITT analysis set.
  • FIG. 12 is a line graph showing MADRS total score: percentage of subjects with remission of depressive symptoms (total score ⁇ 10) during the treatment period for the fITT analysis set.
  • FIG. 13 is a line graph showing MADRS total score: percentage of responders ( ⁇ 30% improvement from baseline) during the treatment period for the eITT analysis set.
  • FIG. 14 is a line graph showing MADRS total score: percentage of responders ( ⁇ 30% improvement from baseline) during the treatment period for the fITT analysis set.
  • FIG. 15 is a line graph showing MADRS total score: percentage of responders ( ⁇ 50% improvement from baseline) during the treatment period for the eITT analysis set.
  • FIG. 16 is a line graph showing MADRS total score: percentage of responders ( ⁇ 50% improvement from baseline) during the treatment period for the fITT analysis set.
  • FIG. 17 is a line graph showing SHAPS total score: mean values ( ⁇ SE) over time for the eITT analysis set.
  • FIG. 18 is a line graph showing SHAPS total score: mean values ( ⁇ SE) over time for the fITT analysis set.
  • FIG. 19 illustrates the MADRS change from baseline by anhedonia severity.
  • FIG. 20 -A is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS ⁇ 38.
  • FIG. 20 -B is a line graph showing MADRS change from baseline for patients with low anhedonia, i.e., SHAPS ⁇ 38.
  • FIG. 21 is bar graph showing the comparison of MADRS in patients having low and high anhedonia.
  • FIG. 22 is a line graph showing the ASEX total score mean change from baseline.
  • FIG. 23 is a bar graph showing ASEX item level change total score mean change from baseline.
  • FIG. 24 is the flow chart for the process for preparing tablets containing aticaprant.
  • a refers to microfine, i.e., milled aticaprant.
  • FIG. 25 is the schematic overview of part 1 of the study.
  • FIG. 26 is the schematic overview of part 2 of the study.
  • a) Day 1 of a treatment period is the first day of the washout period.
  • Treatment E 2 ⁇ 5 mg oral capsule administered in the morning, after at least 10-hour overnight fasting.
  • Treatment F 1 ⁇ 10 mg Formulation Concept 2 administered in the morning, after at least 10-hour overnight fasting.
  • Treatment G 1 ⁇ 5 mg Formulation Concept 2 administered in the morning, after at least 10-hour overnight fasting.
  • Treatment H 1 ⁇ 10 mg Formulation Concept 2 administered in the morning approximately 30 minutes after the start of a standardized high-fat breakfast following at least 10-hour overnight fasting
  • FIGS. 27 and 28 show the relative bioavailability results for aticaprant PK profiles relative to BA.
  • FIGS. 29 and 30 show the relative bioavailability results for aticaprant PK profile, dose-proportionality.
  • FIGS. 31 - 33 show the relative bioavailability results for aticaprant PK profile, food effect.
  • FIG. 34 is the study scheme for Example 7. All patients will continue their oral antidepressant SSRI/SNRI during the entire study. Approximately an additional 34 elderly participants will be randomized.
  • FIG. 35 is the study scheme for Example 8. All patients will continue their oral antidepressant SSRI/SNRI during the entire study. Approximately an additional 68 elderly participants will be randomized.
  • FIG. 36 is a bar graph showing the SHAPS items: LS means for change from baseline at week 6 by baseline SHAPS total score for the fITT analysis set.
  • the bars alternatively refer to placebo or aticaprant.
  • the first bar refers to aticaprant
  • the second bar refers to placebo
  • the third bar refers to aticaprant, etc.
  • FIG. 37 is a plot showing MADRS total score: difference of LSMeans (60% at Weeks 6 by different subgroups for the fITT analysis set. In this plot, ⁇ 17 indicates mild severity; 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe.
  • compositions comprising pure crystalline Form of III aticaprant that are anhydrous and stable in the solid form.
  • crystalline refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure.
  • polymorph refers to a crystalline form of a molecule having one specific crystal structure.
  • a crystalline compound may have one crystal form or may have two or more crystal forms, i.e., polymorphs.
  • polymorphs of a chemical compound may distinguished from each other by compared physicochemical properties such as solubility, dissolution rate, stability, bioavailability, among others.
  • Polymorphs also may have different spectra selected from, without limitation, x-ray powder diffraction (XRPD), single crystal x-ray diffraction, thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, solid state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), polarized light microscopy (PLM), hot stage microscopy, or dynamic solvent sorption.
  • XRPD x-ray powder diffraction
  • TGA thermogravimetric analysis
  • infrared spectroscopy Raman spectroscopy
  • NMR solid state nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • PLM polarized light microscopy
  • hot stage microscopy or dynamic solvent sorption.
  • crystalline refers to solid state form of a chemical moiety wherein the atoms, molecules, or ions are assembled in a highly ordered structure that extends in all directions.
  • crystalline includes all crystalline forms of Compound I, including salts thereof. Characterization of crystalline forms may be performed by those skilled in the art including, without limitation, XRPD or DSC. Typically, the XRPD pattern contains sharp intensity peaks. This contrasts to the XRPD pattern of an amorphous form that often contains a broad, peak, without no identifying peaks.
  • a crystalline form may be completely crystalline or partially crystalline. In some aspects, a crystalline sample may be 100% w/w crystalline. A crystalline sample may also contain solids that are amorphous.
  • a crystalline form may contain solids such that the sample is at least about 99% w/w crystalline, at least about 95% w/w amorphous, at least about 90% w/w crystalline, at least about 85% w/w crystalline, at least about 80% w/w crystalline, or the like.
  • anhydrous or “anhydrate” as used herein refers to a crystalline as described herein that substantially lacks water.
  • an anhydrous form contains less than about 1% w/w of water.
  • an anhydrous form contains less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w/w of water.
  • temperatures noted herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°.
  • 2 ⁇ values obtained from the XRPD patterns also may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, sample (including particle size, impurities, etc.), and/or laboratory conditions. Unless otherwise defined, the XRPD patterns and/or the 2 ⁇ peak values may vary. In certain aspects, the 2 ⁇ peak values vary (higher or lower) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more of the 2 ⁇ peak values are higher by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In further aspects, one or more of the 2 ⁇ peak values are lower by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.
  • the term “corresponds to” may be used in reference to certain spectra.
  • “corresponds to” includes a spectrum that is identical or substantially similar to another spectrum.
  • One skilled in the art would be able to compare such spectra and determine if a spectrum corresponds to another.
  • the term “corresponds to” is used herein to compare XRPD patterns, DSC thermograms, among others.
  • one XRPD pattern corresponds to another XRPD pattern when their 2 ⁇ values are within the margin of error as described above.
  • one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 2 ⁇ peak value, but one or more peaks have a different height (intensity).
  • one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 2 ⁇ peak value, but one or more peaks have a different peak area.
  • one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 2 ⁇ peak value, but one or more peak is obscured. Such obscured peaks may be due to impurities, excipients, or the like. Such obscured peaks typically do not prevent characterization of the crystalline form.
  • aticaprant refers to 3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, i.e., the following compound:
  • aticaprant refers to the (S)-enantiomer of aticaprant, i.e., the following compound:
  • the aticaprant used in the methods described herein is substantially free of the (R)-enantiomer, i.e., (R)-aticaprant or (R)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide having the following structure:
  • the aticaprant contains less than about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In further embodiments, aticaprant contains less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, about 0.5, about 0.1, about 0.005, or about 0.001% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In yet other embodiments, the aticaprant contains about 0.001 to about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant.
  • the aticaprant 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 aticaprant.
  • compositions of aticaprant are also contemplated by the present invention, which may be readily selected by those skilled in the art.
  • a “pharmaceutically acceptable salt” refers a salt of aticaprant 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. Berge, “Pharmaceutical Salts”, J. Pharm.
  • salts examples include those that are pharmacologically effective and suitable for administration to patients without undue toxicity, irritation, or allergic response.
  • Examples of 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, xylenesulf
  • the aticaprant is crystalline Form III of aticaprant.
  • Crystalline Form III of aticaprant may be characterized by a number of techniques including, without limitation, x-ray diffraction and differential scanning calorimetry.
  • crystalline Form III of aticaprant is characterized by x-ray diffraction.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 8.2°, 9.7°, 12.0°, 13.5°, 15.1°, 16.4°, 19.4°, 28.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, 28.8°, and 30.0°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 3.1°, 19.0°, 24.0°, 24.3°, or 26.2 and one or more additional peaks of Table 1.
  • crystalline Form III of aticaprant is characterized the x-ray diffraction pattern peaks in Table 2.
  • crystalline Form III of aticaprant is characterized the x-ray diffraction pattern peaks in Table 3.
  • crystalline Form III of aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 1 .
  • Crystalline Form III of aticaprant may also be characterized by differential scanning calorimetry.
  • the differential scanning calorimetry thermogram comprises a peak temperature (T m ) at about 121° C.
  • crystalline Form III of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 2 .
  • composition comprising aticaprant and one or more pharmaceutically acceptable excipient.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the preferred pharmaceutical composition contains crystalline Form III of aticaprant as the active ingredient intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • 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.
  • the amount of aticaprant present in the compositions is about 2 mg to about 60 mg. In some embodiments, the composition contains about 2 mg to about 20 mg of aticaprant. In some embodiments, the composition contains about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of aticaprant. In other embodiments, the composition contains about 5 to about 20 mg, about 10 to about 20 mg, about 15 to about 20 mg, about 1 to about 15 mg, about 2 to about 15 mg, about 5 to about 15 mg, about 10 to about 15 mg, about 1 to about 10 mg, about 2 to about 10 mg, or about 5 to about 10 mg of aticaprant.
  • the effective amount of aticaprant is about 5 to about 15 mg. In further embodiments, the amount of aticaprant is about 5 or 10 mg. In other embodiments, the amount of aticaprant is about 5 mg. In still further embodiments, the amount of aticaprant is about 10 mg.
  • the composition contains about 0.1% to about 90% by weight of aticaprant. In some embodiments, the composition contains about 0.1, about 0.5, about 1, 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90% by weight, based on the weight of the composition, of aticaprant.
  • the composition contains about 0.1 to about 80, about 0.1 to about 70, about 0.1 to about 60, about 0.1 to about 50, about 0.1 to about 40, about 0.1 to about 30, about 0.1 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 0.5, about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 90, about 20 to about 80, about 20 to about 20 to about
  • the composition contains about 5% by weight of aticaprant. In yet other embodiments, the composition contains about 6% by weight of aticaprant. In still further embodiments, the composition contains about 7% by weight of aticaprant. In other embodiments, the composition contains about 8% by weight of aticaprant. In further embodiments, the composition contains about 9% by weight of aticaprant. In still other embodiments, the composition contains about 10% by weight of aticaprant.
  • the amount of aticaprant for administration according to the methods described herein may be determined by one skill in the art and, unless otherwise noted, are set forth on an aticaprant free base basis. That is, the amounts indicate that amount of the aticaprant molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).
  • the pharmaceutical compositions have a particular pharmacokinetic (PK) profile at a specific dose.
  • the pharmaceutical compositions have a PK profile that is dose-proportional.
  • the pharmaceutical compositions have a PK profile comprising parameters, e.g., exposure parameters such as C max or AUC, that are dose-proportional.
  • the pharmaceutical compositions have a PK profile or PK parameter that is dose-proportional between about 1 mg to 60 mg aticaprant, between about 2 mg to 60 mg aticaprant, between about 2 mg to 40 mg aticaprant, between about 2 mg to 20 mg aticaprant, between about 2 mg to 15 mg aticaprant, between about 2 mg to 10 mg aticaprant, and between about 5 mg to 10 mg aticaprant.
  • compositions comprising aticaprant that are bioequivalent to any one of the pharmaceutical compositions described herein.
  • the pharmaceutical composition comprises between about 2 mg and about 60 mg, between about 2 mg and about 20 mg aticaprant, between about 5 mg and about 10 mg aticaprant, or about 5 mg or about 10 mg aticaprant, wherein the composition is bioequivalent to a pharmaceutical composition comprising aticaprant which when administered to a human after at least a 10-hour fast yields a PK profile that includes one or more of: a mean Cmax of between about 30 and 35 ng/mL, a mean AUCinfinity of between about 300 and 320 ng/mL, and a median t max of about 1.5 hour (dose-normalized to 10 mg).
  • Bioequivalence may be demonstrated by any method known to one skilled in the art, for example, as described in Example 9 herein, or as described in Chow, Bioavailability and Bioequivalence in Drug Development, Wiley interdisciplinary reviews, Computational statistics, 6, 4 (2014): 304-312. doi:10.1002/wics.1310.
  • the pharmaceutical composition comprises between about 2 mg and about 20 mg aticaprant, about 5 mg aticaprant, or about 10 mg aticaprant, wherein when the pharmaceutical composition is compared to a reference composition, the 90% confidence interval of the ratio of geometric means of one or more PK parameters of the pharmaceutical composition and reference composition is within the bioequivalence limits of 80% and 125%.
  • the reference composition is a composition comprising aticaprant which when administered to a human after at least a 10-hour fast yields a PK profile that includes one or more of: a mean Cmax of between about 30 and 35 ng/mL, a mean AUCinfinity of between about 300 and 320 ng/mL, and a median t max of about 1.5 hour (dose-normalized to 10 mg).
  • the reference composition has a PK profile of any one of Treatment A, Treatment B, Treatment C, or Treatment D described in Table 69.
  • the PK profile is based on administration of the composition, containing about 2 mg to about 60 mg aticaprant, to a human after at least a 10-hour fast. In some other embodiments, the PK profile is based on administration of the composition, containing about 2 mg to about 60 mg aticaprant, to a human about 30 minutes after the start of a high-fat meal following at least a 10-hour fast. As another example, the PK profile is based on administration of the composition, containing about 2 mg to about 20 mg aticaprant, to a human after at least a 10-hour fast.
  • the PK profile is based on administration of a composition containing about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of aticaprant to a human.
  • the PK profile is based on administration of a composition containing about 2 to about 19, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 4 to about 20, about 4 to about 18, about 4 to about 16, about 4 to about 14, about 4 to about 12, about 4 to about 10, about 4 to about 8, about 4 to about 6, about 6 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12, about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to about 18, about 8 to about 16, about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18, or about 18 to about 20 mg of aticaprant to a
  • the PK profile is determined after an at least 10-hour food fast.
  • the food fast is at least about 1, about 2, about 4, about 5, about 10, about 12, about 15, about 18, about 20, about 22, 24, about 28, or about 32 hours.
  • the PK profile may include a C max ranging between about 1 and about 100, about 5 and about 70, about 5 and about 65, about 5 and about 60, about 5 and about 55, about 5 and about 50, about 5 and about 45, about 10 and about 70, about 10 and about 65, about 10 and about 60, about 10 and about 55, about 10 and about 50, about 10 and about 45, about 13 and about 60, about 13 and about 55, about 13 and about 50, about 20 and about 70, about 20 and about 65, or about 20 and about 63 ng/mL (dose-normalized to 10 mg).
  • C max ranging between about 1 and about 100, about 5 and about 70, about 5 and about 65, about 5 and about 60, about 5 and about 55, about 5 and about 50, about 5 and about 45, about 10 and about 70, about 10 and about 65, about 10 and about 60, about 10 and about 55, about 10 and about 50, about 10 and about 45, about 13 and about 60, about 13 and about 55, about 13 and about 50, about 20 and about 70, about 20 and
  • the PK profile includes a C max ranging between about 20 and about 45, about 22 and about 45, about 23 and about 45, or about 24 and about 44 ng/mL (dose-normalized to 10 mg) when administered after at least a 10-hour fast. In some embodiments, the PK profile includes a C max ranging between about 25 and about 50, about 27 and about 38, about 25 and about 40, or about 28 and about 38 ng/mL (dose-normalized to 10 mg) when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the PK profile includes an AUC infinity ranging between about 50 and about 800, about 100 and about 500, about 100 and about 480, about 100 and about 450, about 100 and about 400, about 110 and about 500, about 110 and about 480, about 110 and about 450, about 110 and about 400, about 150 and about 700, about 200 and about 700, about 200 and about 650, about 250 and about 450, about 280 and about 420, about 290 and about 410, or about 210 and about 650 h*ng/mL (dose-normalized to 10 mg).
  • the PK profile includes an AUC infinity ranging between about 200 and about 400, about 210 and about 400, about 210 and about 398, about 220 and about 400, or about 220 and about 398 h*ng/mL (dose-normalized to 10 mg) when administered after at least a 10-hour fast.
  • the PK profile includes an AUC infinity ranging between about 300 and about 600, about 300 and 550, or about 320 and about 530 h*ng/mL (dose-normalized to 10 mg) when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the PK profile includes an AUC last ranging between about 50 and about 800, about 100 and about 500, about 100 and about 480, about 100 and about 450, about 100 and about 400, about 110 and about 500, about 110 and about 480, about 110 and about 450, about 110 and about 400, about 150 and about 700, about 200 and about 700, about 200 and about 650, about 250 and about 450, about 280 and about 420, about 290 and about 410, or about 210 and about 650 h*ng/mL (dose-normalized to 10 mg).
  • the PK profile includes an AUC last ranging between about 300 and about 400 (dose-normalized to 10 mg).
  • the PK profile incudes a t max ranging between about 0.5 and about 5, between about 1 and about 4.5, about 1 and about 4, about 1 and about 3, about 1 and about 2.5, or about 1 and about 2 hours. In some embodiments, the PK profile includes a t max that ranges between about 1 and about 2.5, about 1 and about 2, or about 1 and about 3 hours when administered after at least a 10-hour fast. In some embodiments, the PK profile includes a t max that ranges between about 1 and about 4 hours when administered after about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the PK profile incudes a t 1/2 ranging between about 5 and about 60, about 5 and about 55, about 5 and about 50, about 5 and about 45, about 5 and about 40, about 9 and about 60, about 9 and about 55, about 9 and about 50, about 9 and about 45, or about 9 and about 40 hours.
  • the PK profile includes a ⁇ z ranging between about 0.010 and about 0.080, about 0.010 and about 0.075, about 0.010 and about 0.070, about 0.015 and about 0.080, about 0.015 and about 0.075, about 0.015 and about 0.070, about 0.015 and about 0.065, about 0.015 and about 0.060, about 0.015 and about 0.055, or about 0.015 and about 0.050 l/hour.
  • the PK profile includes a CL/F ranging between about 10 and about 90, about 10 and about 85, about 10 and about 80, about 10 and about 75, about 10 and about 70, about 10 and about 60, about 10 and about 50, about 15 and about 90, about 15 and about 80, about 15 and about 70, about 15 and about 60, about 15 and about 50, about 20 and about 90, about 20 and about 80, about 20 and about 75, about 20 and about 70, about 20 and about 60, or about 20 and about 50 L/h.
  • the PK profile includes a Vd/F ranging between about 400 and about 6000, about 400 and about 5500, about 400 and about 5000, about 400 and about 4000, about 400 and about 3500, about 400 and about 3400, about 450 and about 3500, about 450 and about 3000, about 500 and about 3500, about 500 and about 3000, about 400 and about 2000, about 400 and about 1500, about 400 and about 1200, about 550 and about 3500, about 550 and about 3000, about 600 and about 3500, about 600 and about 3000, about 600 and about 2500, or about 450 and about 1200 L.
  • the PK profile may include a mean C max between about 20 and 45 ng/mL when dose-normalized to 10 mg.
  • the mean C max is about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, or about 55 ng/mL (dose-normalized to 10 mg).
  • the mean C max is about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 45, about 35 to about 40, or about 40 to about 45 ng/mL (dose-normalized to 10 mg).
  • the mean C max is between about 30 and 35 ng/mL, about 31 and 35 ng/mL, or about 31 and 34 ng/mL (dose-normalized to 10 mg) when administered after at least a 10-hour fast.
  • the mean C max is between about 35 and 40, about 36 and 39, or about 37 and 38 ng/mL (dose-normalized to 10 mg) when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the PK profile also may have a mean AUC infinity between about 250 and 450 h*ng/mL (dose-normalized to 10 mg).
  • the AUC infinity is 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, or about 450 h*ng/mL (dose-normalized to 10 mg).
  • the mean AUC infinity is about 250 to about 400, about 250 to about 375, about 250 to about 350, about 250 to about 325, about 250 to about 300, about 250 to about 275, about 275 to about 450, about 275 to about 425, about 275 to about 400, about 275 to about 375, about 275 to about 350, about 275 to about 325, about 275 to about 300, about 300 to about 450, about 300 to about 425, about 300 to about 400, about 300 to about 390, about 300 to about 380, about 300 to about 370, about 300 to about 360, about 300 to about 350, about 300 to about 340, about 300 to about 330, about 300 to about 320, about 300 to about 310, about 325 to about 450, about 325 to about 425, about 325 to about 400, about 325 to about 375, about 325 to about 350, about 350 to about 450, about 350 to about 425, about 400, about 350 to about 375, about 375 to about 375 to about 325 to
  • the mean AUC infinity is between about 300 and 320 h*ng/mL (dose-normalized to 10 mg) when administered after at least a 10-hour fast. In further embodiments, the mean AUC infinity is between about 320 and 530 h*ng/mL (dose-normalized to 10 mg) when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the pharmaceutical composition has a PK profile comprising a mean AUC last between about 250 and 450 h*ng/mL (dose-normalized to 10 mg).
  • the AUC last is 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, or about 450 h*ng/mL.
  • the mean AUC last is about 250 to about 400, about 250 to about 375, about 250 to about 350, about 250 to about 325, about 250 to about 300, about 250 to about 275, about 275 to about 450, about 275 to about 425, about 275 to about 400, about 275 to about 375, about 275 to about 350, about 275 to about 325, about 275 to about 300, about 300 to about 450, about 300 to about 425, about 300 to about 400, about 300 to about 390, about 300 to about 380, about 300 to about 370, about 300 to about 360, about 300 to about 350, about 300 to about 340, about 300 to about 330, about 300 to about 320, about 300 to about 310, about 325 to about 450, about 325 to about 425, about 325 to about 400, about 325 to about 375, about 325 to about 350, about 350 to about 450, about 350 to about 425, about 400, about 350 to about 375, about 375 to about 375 to about 325 to about
  • the pharmaceutical composition has a PK profile comprising a median t max between about 1 to 4 hours.
  • the median t max is about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4 hours.
  • the median t max is about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 4, about 3 to about 3.5, or about 3.5 to about 4 hours. In further embodiments, the median t max is about 1.5 hours.
  • the pharmaceutical composition comprises a PK profile of Treatment A, Treatment B, Treatment C, or Treatment D, as shown in Table 69.
  • the pharmaceutical composition has a PK profile including a mean C max of about 30, about 31, about 32, about 33, about 34, or about 35 ng/mL when administered after at least a 10-hour fast (dose-normalized to 10 mg).
  • the pharmaceutical composition comprises has a PK profile including a mean C max of about 31.2 ng/mL with standard deviation of about 6.9 ng/mL (dose-normalized to 10 mg).
  • the pharmaceutical composition comprises about 10 mg aticaprant and has a PK profile including a mean C max of about 34.1 ng/mL with standard deviation of about 10.0 ng/mL when administered after at least a 10-hour fast.
  • the pharmaceutical composition comprises about 5 mg aticaprant and has a PK profile including a mean Cmax of about 17.0 ng/mL with standard deviation of about 4.48 ng/mL when administered after at least a 10-hour fast.
  • the pharmaceutical composition has a PK profile including a mean Cmax of about 36, about 37, about 38, about 39, or about 35 ng/mL when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast (dose-normalized to 10 mg).
  • the pharmaceutical composition comprises about 10 mg aticaprant and has a PK profile including a mean Cmax of about 37.7 ng/mL with a standard deviation of about 9.18 ng/mL when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the pharmaceutical composition has a PK profile comprising a mean AUCinfinity of about 300, about 305, about 310, about 315, or about 320 h*ng/mL when administered after a least a 10-hour fast (dose-normalized to 10 mg).
  • the pharmaceutical composition has a PK profile comprising a mean AUCinfinity of about 400, about 420, about 425, about 430, about 440, or about 450 h*ng/mL when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast (dose-normalized to 10 mg).
  • the pharmaceutical composition has a PK profile comprising a median t max of about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 hours when administered after at least a 10-hour fast. In some embodiments, the pharmaceutical composition has a PK profile comprising a median t max of about 1.5 hours when administered after at least a 10-hour fast.
  • the pharmaceutical composition has a PK profile comprising a median t of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9 or about 3.0 hour when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast. In some embodiments, the pharmaceutical composition has a PK profile comprising a median t max of about 2.75 hours when administered about 30 minutes after the start of a high-fat meal following at least a 10-hour fast.
  • the compositions contain a pharmaceutically acceptable excipient, one of which may be a filler.
  • the filler is the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose, or a combination thereof.
  • the filler is microcrystalline cellulose.
  • the filler is lactose monohydrate.
  • the filler is silicified microcrystalline cellulose.
  • the composition comprises between about 10% to about 99.9% filler by weight, based on the weight of the composition.
  • the composition contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 99.9% by weight, based on the weight of the composition, of a filler
  • the composition comprises about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 99.9, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 99.9, about 30
  • the aticaprant to filler ratio is between about 0.005 and about 9 by weight. In some embodiments, the aticaprant to filler ratio is about 0.008 and 0.8 about by weight. In other embodiments, the aticaprant to filler ratio is about 0.005 to about 8, about 0.005 to about 7, about 0.005 to about 6, about 0.005 to about 5, about 0.005 to about 4, about 0.005 to about 3, about 0.005 to about 2, about 0.005 to about 1, about 0.005 to about 0.5, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 9, about 0.01 to about 8, about 0.01 to about 7, about 0.01 to about 6, about 0.01 to about 5, about 0.01 to about 4, about 0.01 to about 3, about 0.01 to about 2, about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 9, about 0.05 to
  • the composition may further comprise one or more of a filler, disintegrant, glidant, lubricant, solvent, coloring agent, binder. buffers, preservatives, penetration agents, wetting agents, surfactants, solubilizing agents, thickening agents, colorants, antioxidants, emulsifying agents, isotonizing agents, suspending agents, and/or viscosity increasing agents.
  • the composition further comprises one or more of a disintegrant.
  • disintegrants useful in the compositions include, e.g., the disintegrant is croscarmellose sodium.
  • the composition comprises between about 0.5% to about 50% by weight, based on the weight of the composition, of the disintegrant. In some embodiments, the composition comprises about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% by weight, based on the weight of the composition, of the disintegrant.
  • the composition comprises about 0.5 to about 40%, about 0.5 to about 30%, about 0.5 to about 20%, about 0.5 to about 10%, about 0.5 to about 5%, about 0.5 to about 4%, about 0.5 to about 3%, about 0.5 to about 2%, about 0.5 to about 1%, about 5 to about 50%, about 5 to about 40%, about 5 to about 30%, about 5 to about 20%, about 5 to about 10%, about 10 to about 50%, about 10 to about 40%, about 10 to about 30%, about 10 to about 20%, about 20 to about 50%, about 20 to about 40%, about 20 to about 30%, about 30 to about 50%, about 30 to about 40%, or about 40 to about 50% by weight, based on the weight of the composition of the disintegrant.
  • the composition comprises about 5% by weight, based on the weight of the composition, of the disintegrant.
  • the aticaprant to disintegrant ratio is between about 0.1 and 10 by weight. In some embodiments, the aticaprant to disintegrant ratio is about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 by weight.
  • the aticaprant to disintegrant ratio is about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 6, about 3 to about 5, about 3 to about 4, about 4 to to to about 4 to to about
  • the composition further comprises one or more of a glidant.
  • glidants useful in the compositions include, e.g., silica, colloidal anhydrous.
  • the composition comprises between about 0.1% to about 10% glidant by weight, based on the weight of the composition. In some embodiment, the composition contains about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10% by weight, based on the weight of the composition, of the glidant.
  • the composition contains about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3, to about 3 to about 6, about 3 to about 6, about 3 to about 5, about 3 to about 4, about
  • the composition contains about 1% by weight, based on the weight of the composition, of the glidant.
  • the aticaprant to glidant ratio is between 0.5 and 50 by weight. In some embodiments, the aticaprant to glidant ratio is about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 by weight.
  • the aticaprant to glidant ratio is about 0.5 to about 50, about 0.5 to about 45, about 0.5 to about 40, about 0.5 to about 35, about 0.5 to about 30, about 0.5 to about 25, about 0.5 to about 20, about 0.5 to about 15, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 50, about 1 to about 45, about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 50, about 5 to about 45, about 5 to about 40, about 5 to about 35, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 50, about 10 to about 45, about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about about
  • the composition further comprises one or more of a lubricant.
  • lubricants useful in the compositions include, e.g., the lubricant is magnesium stearate.
  • the composition comprises between about 0.05% to about 5% lubricant by weight, based on the weight of the composition. In some embodiments, the composition comprises about 0.05, about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5 or about 5% by weight, based on the weight of the composition, of lubricant.
  • the composition comprises about 0.05 to about 4.5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5% by weight, based on the weight of the composition, of lubricant.
  • the composition comprises about 0.5% by weight, based on the weight of the composition, of the lubricant.
  • the aticaprant to lubricant ratio is between about 1 and about 100 by weight. In some embodiments, the aticaprant to lubricant ratio is about 1, about 5, 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 by weight.
  • the aticaprant to lubricant ratio is 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 100, about 20 to about 90,
  • the composition comprises one or more of an aticaprant to filler ratio between 0.005 and 9 by weight; an aticaprant to disintegrant ratio between 0.1 and 10 by weight; an aticaprant to glidant ratio between 0.5 and 50 by weight; and an aticaprant to lubricant ratio between 1 and 100 by weight.
  • the composition comprises one or more of an aticaprant to filler ratio of about 0.06 by weight; an aticaprant to disintegrant ratio of about 1 by weight; an aticaprant to glidant ratio of about 5 by weight; and an aticaprant to lubricant ratio of about 10 by weight.
  • the composition comprises about 5% by weight of aticaprant, about 88.5% by weight of filler, about 5% by weight of disintegrant by weight, about 1% by weight of glidant, and about 0.5% by weight of lubricant, based on the weight of the composition.
  • the composition is formulated as a solid composition.
  • the solid composition is a tablet, capsule, or caplet.
  • the solid composition is a tablet such as an oral tablet.
  • the solid composition is a capsule such as an oral capsule.
  • the solid composition is a caplet such as an oral caplet.
  • the solid compositions are coated.
  • the coating is an enteric coating. By doing so, the coating provides a film coat on the solid composition.
  • the film coat comprises a coating powder.
  • the film coat comprises Opadry II Orange.
  • the coating powder is Opadry II Orange.
  • the tablet may comprise one or more layers.
  • the tablet comprises a core tablet and a film coat to provide a film coated tablet.
  • the ratio of the film coat to core tablet is between about 0.03 to 10 by weight. In some embodiments, the ratio of the film coat to core tablet is about 0.03, 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 by weight, based on the weigh of the composition.
  • the ratio of the film coat to core tablet is about 0.03 to about 9, about 0.03 to about 8, about 0.03 to about 7, about 0.03 to about 6, about 0.03 to about 6, about 0.03 to about 5, about 0.03 to about 4, about 0.03 to about 3, about 0.03 to about 2, about 0.03 to about 1, about 0.03 to about 0.5, about 0.03 to about 0.1, about 0.05 to about 10, 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 10, 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, 0.05 to about 0.1, about 0.1 to about 10,
  • the core tablet may contain one or more phases.
  • the core tablet comprises a first phase such as an intragranular phase.
  • the core tablet comprises a second phase such as an extragranular phase.
  • the core tablet comprises intragranular and extragranular phases.
  • the ratio of the intragranular phase to extragranular phase in the core tablet is between about 1.5 and about 3 by weight. In some embodiments, the ratio of the intragranular phase to extragranular phase in the core tablet is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, or about 3 by weight.
  • the ratio of the intragranular phase to extragranular phase in the core tablet is about 1.5 to about 2.8, about 1.5 to about 2.5, about 1.5 to about 2.3, about 1.5 to about 2, about 1.5 to about 1.8, about 1.8 to about 3, about 1.8 to about 2.8, about 1.8 to about 2.5, about 1.8 to about 2.3, about 2 to about 3, about 2 to about 2.8, about 2 to about 2.5, about 2 to about 2.3, about 2 to about 2.1, about 2.1 to about 3, about 2.1 to about 2.8, about 2.1 to about 2.5, about 2.1 to about 2.3, about 2.3 to about 3, about 2.3 to about 2.8, about 2.3 to about 2.5 to about 2.5 to about 3, about 2.5 to about 2.8, and about 2.8 to about 3 by weight.
  • the ratio of the intragranular phase to extragranular phase in the core tablet is about 2.1 by weight.
  • the solid composition contains aticaprant and one or more pharmaceutically acceptable excipients.
  • the intragranular phase comprises aticaprant, a filler, a disintegrant, and a glidant.
  • the intragranular phase comprises one filler.
  • the intragranular phase comprises two fillers.
  • the intragranular phase comprises about 10 to about 120 mg of the filler. In some embodiments, the intragranular phase comprises about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 mg of the filler.
  • the intragranular phase comprises about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 100, about 50 to about 90, about
  • the intragranular phase contains about 60 mg of filler. In yet other embodiments, the intragranular phase contains about 30 mg of microcrystalline cellulose. In still further embodiments, the intragranular phase contains about 30 mg of lactose monohydrate. In other embodiments, the intragranular phase contains about 60 mg of microcrystalline cellulose. In further embodiments, the intragranular phase contains about 60 mg of lactose monohydrate.
  • the intragranular phase comprises an aticaprant to filler ratio of between about 0.008 and 0.8 by weight.
  • the intragranular phase contains an aticaprant to filler ratio of about 0.008, about 0.005, about 0.001, about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 by weight.
  • the intragranular phase comprises an aticaprant to filler ratio of about 0.008 to about 0.7, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.4, about 0.008 to about 0.3, about 0.008 to about 0.2, about 0.008 to about 0.1, about 0.008 to about 0.05, about 0.008 to about 0.01, about 0.01 to about 0.8, about 0.01 to about 0.7, 0.01 to about 0.6, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.3, about 0.01 to about 0.2, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 0.8, about 0.05 to about 0.9, about 0.05 to about 0.8, about 0.05 to about 0.7, about 0.05 to about 0.6, about 0.05 to about 0.6, about 0.05 to
  • the intragranular phase also may contain a disintegrant.
  • the intragranular phase contains about 1 to about 10 mg of the disintegrant.
  • the intragranular phase contains about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 mg of the disintegrant.
  • the intragranular phase contains about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 9, about 7 to
  • the intragranular phase contains about 2.5 mg of the disintegrant. In still further embodiments, the intragranular phase contains about 5 mg of the disintegrant. In other embodiments, the intragranular phase contains about 2.5 mg of croscarmellose sodium. In further embodiments, the intragranular phase contains about 5 mg of croscarmellose sodium.
  • the intragranular phase may further contain a glidant.
  • the intragranular phase contains about 0.1 to about 5 mg of a glidant.
  • the intragranular phase contains about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg of a glidant.
  • the intragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a glidant.
  • the intragranular phase contains about 0.5 mg of the glidant.
  • the intragranular phase contains about 1 mg of the glidant.
  • the intragranular phase contains about 0.5 mg of silica, colloidal anhydrous.
  • the intragranular phase contains about 1 mg of silica, colloidal anhydrous.
  • the intragranular phase has an aticaprant to disintegrant ratio of between about 0.2 and 20 by weight; In some embodiments, the intragranular phase has an aticaprant to disintegrant ratio of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 by weight.
  • the intragranular phase comprises an aticaprant to disintegrant ratio of about 0.2 to about 18, about 0.2 to about 16, about 0.2 to about 14, about 0.2 to about 12, about 0.2 to about 10, about 0.2 to about 8, about 0.2 to about 6, about 0.2 to about 4, about 0.2 to about 3, about 0.2 to about 2, about 0.2 to about 1, about 0.2 to about 0.5, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 1 to about 1.5, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 10, about
  • the intragranular phase comprises an aticaprant to glidant ratio of between about 1 and 100 by weight. In some embodiments, the intragranular phase comprises an aticaprant to glidant ratio of about 1, about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 by weight.
  • the intragranular phase comprises an aticaprant to glidant ratio of about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 15, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 80, about 40 to about 60, or about 60 to about 80 by weight.
  • the intragranular phase comprises an aticaprant to glidant ratio of 10 by weight.
  • the extragranular phase comprises one or more of a filler, a disintegrant, a glidant, and a lubricant.
  • the extragranular phase comprises a filler.
  • the extragranular phase comprises a disintegrant.
  • the extragranular phase comprises a glidant.
  • the extragranular phase comprises a lubricant.
  • the extragranular phase may comprise a filler.
  • the extragranular phase contains one filler.
  • the extragranular phase contains about 10 to about 80 mg of a filler.
  • the extragranular phase contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, or about 80 mg of a filler.
  • the extragranular phase contains about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 10 to about 15, about 15 to about 80, about 15 to about 70, about 15 to about 60, about 15 to about 50, about 15 to about 40, about 15 to about 30, about 15 to about 20, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 25 to about 80, about 25 to about 70, about 25 to about 60, about 25 to about 50, about 25 to about 40, about 25 to about 30, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 35 to about 80, about 35 to about 70, about 35 to about 60, about 35 to about 50, about 35 to about 40, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 40 to about 80, about 40 to about 70, about 40 to
  • the extragranular phase contains about 28.5 mg of the filler. In other embodiments, the extragranular phase contains about 28.5 of silicified microcrystalline cellulose. In further embodiments, the extragranular phase contains about 57 mg of the filler. In still other embodiments, the extragranular phase contains about 57 mg of silicified microcrystalline cellulose.
  • the extragranular phase may additionally contain a disintegrant.
  • the disintegrant is croscarmellose sodium.
  • the extragranular phase contains about 1 to about 10 mg of a disintegrant.
  • the extragranular phase contains about 1, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 7.5, about 8, about 9, or about 10 mg of a disintegrant.
  • the extragranular phase contains about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 6 to about 10, about 9, about 6 to about 8, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 about 7 about
  • the extragranular phase contains about 2.5 mg of a disintegrant. In other embodiments, the extragranular phase contains about 5 mg of a disintegrant. In further embodiments, the extragranular phase contains about 2.5 mg of croscarmellose sodium. In still other embodiments, the extragranular phase contains about 5 mg of croscarmellose sodium.
  • the extragranular phase comprises a filler to disintegrant ratio of between about 1 and 100 by weight. In some embodiments, the extragranular phase comprises a filler to disintegrant ratio of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 by weight.
  • the extragranular phase comprises a filler to disintegrant ratio of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 10 to about 15, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 by weight.
  • the extragranular phase comprises a filler to disintegrant ratio of about 11.4.
  • the extragranular phase further may contain a glidant.
  • the glidant is silica, colloidal anhydrous.
  • the extragranular phase contains about 0.1 to about 5 mg of the glidant.
  • the extragranular phase contains about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, or 5 mg of a glidant.
  • the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a glidant.
  • the extragranular phase contains about 0.5 mg of a glidant.
  • the extragranular phase contains about 1 mg of a glidant.
  • the extragranular phase contains about 0.5 mg of silica, colloidal anhydrous.
  • the extragranular phase contains about 1 mg of silica, colloidal anhydrous.
  • the extragranular phase comprises a filler to glidant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to glidant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500.
  • the extragranular phase comprises a filler to glidant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500 by weight.
  • the extragranular phase comprises a filler to glidant ratio of about 57
  • the extragranular phase may also contain a lubricant.
  • the lubricant is magnesium stearate.
  • the extragranular phase contains about 0.1 to about 5 mg of the lubricant.
  • the extragranular phase contains about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, or 5 mg of a lubricant.
  • the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a lubricant.
  • the extragranular phase contains about 0.5 mg of a lubricant.
  • the extragranular phase contains about 1 mg of a lubricant.
  • the extragranular phase contains about 0.5 mg of magnesium stearate.
  • the extragranular phase contains about 1 mg of magnesium stearate.
  • the extragranular phase comprises a filler to lubricant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to lubricant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500.
  • the extragranular phase comprises a filler to lubricant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500 by weight.
  • the extragranular phase comprises a filler to lubricant ratio of about 57
  • the intragranular phase comprises one or more of: an aticaprant to filler ratio of between about 0.008 and 0.8 by weight; an aticaprant to disintegrant ratio of between about 0.2 and 20 by weight; and an aticaprant to glidant ratio of between about 1 and 100 by weight.
  • the extragranular phase comprises one or more of: a filler to disintegrant ratio of between about 1 and 100 by weight; a filler to glidant ratio of between about 5 and 500 by weight; and a filler to lubricant ratio of between about 5 and 500 by weight.
  • the extragranular phase comprises a filler to disintegrant ratio of about 11.4 by weight.
  • the extragranular phase comprises a filler to glidant ratio of about 57 by weight.
  • the extragranular phase comprises a filler to lubricant ratio of about 57 by weight.
  • the core tablet comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% glidant by weight, and about 0.5% lubricant by weight.
  • the oral tablet may be of weight that is suitable for administration by a patient.
  • the oral tablet has a core tablet of about 10 to about 1000 mg.
  • the core tablet is about 10, about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg.
  • the core tablet is about 10 to about 900, about 10 to about 800, about 10 to about 700, about 10 to about 600, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 1000, about 25 to about 900, about 25 to about 800, about 25 to about 700, about 25 to about 600, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 50 to about 1000, about 50 to about 900, about 50 to about 800, about 50 to about 700, about 50 to about 600, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 700, about 100 to about 600, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200, about 50 to
  • the core tablet contains a disintegrant.
  • the core tablet contains about 5 to about 100 mg of a disintegrant.
  • the core tablet contains about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a disintegrant.
  • the core tablet contains about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a disintegrant.
  • the core tablet contains about 5 mg of the disintegrant.
  • the core tablet contains about 10 mg of the disintegrant.
  • the core tablet contains a glidant.
  • the core tablet contains about 1 to about 100 mg of a glidant.
  • the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a glidant.
  • the core tablet contains about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a glidant. In further embodiments, the core tablet contains about 1 mg of the glidant. In yet other embodiments, the core tablet contains about 2 mg of the glid
  • the core tablet contains a lubricant.
  • the core tablet contains about 0.5 to about 100 mg of a lubricant.
  • the core tablet contains about 0.5, about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a lubricant.
  • the core tablet contains about 0.5 to about 80, about 0.5 to about 60, about 0.5 to about 40, about 0.5 to about 20, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg
  • the core tablet contains a filler.
  • the core tablet contains about 1 to about 200 mg of a filler.
  • the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg of a filler.
  • the core tablet contains about 1 to about 180, about 1 to about 160, about 1 to about 140, about 1 to about 120, 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 200, about 2 to about 180, about 2 to about 160, about 2 to about 140, about 2 to about 120, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 200 m, about 5 to about 180, about 5 to about 160, about 5 to about 140, about 5 to about 120, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 200, about 10 to about 180, about 10 to about 160, about 10 to about 140, about 10 to about 120, about 10 to about 100, about 10 to about 80, about 10 to about 10 to
  • the oral tablet comprises a core tablet of about 100 mg and comprising about 5 mg aticaprant, about 5 mg disintegrant, about 88.5 mg filler, about 1 mg glidant, and about 0.5 mg lubricant.
  • oral tablet comprising a core tablet of about 200 mg, the core tablet comprising about 10 mg aticparant, about 10 mg disintegrant, about 177 mg filler, about 2 mg glidant, and about 1 mg lubricant.
  • the core tablet may be coated with a film coat.
  • the oral tablet comprises about 3 mg of film coat. In other embodiments, the oral tablet comprises about 6 mg of film coat.
  • the film coated oral tablet comprises about 80 to about 99.9% by weight of the core tablet and about 0.1 to about 20% by weight, based on the weight of the film coated oral tablet, of the core tablet.
  • the film coated oral tablet comprises about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or 99.9% by weight, based on the weight of the film coated oral tablet.
  • the film coated oral tablet comprises about 80 to about 99, about 80 to about 96, about 80 to about 94, about 80 to about 92, about 80 to about 90, about 80 to about 88, about 80 to about 86, about 80 to about 84, about 80 to about 82, about 82 to about 99, about 82 to about 96, about 82 to about 94, about 82 to about 92, about 82 to about 90, about 82 to about 88, about 82 to about 86, about 82 to about 84, about 84 to about 99, about 84 to about 99, about 84 to about 96, about 84 to about 94, about 84 to about 92, about 84 to about 90, about 84 to about 88, about 84 to about 86, about 86 to about 99, about 86 to about 96, about 86 to about 94, about 86 to about 92, about 86 to about 90, about 86 to about 92, about 86 to about 90, about 86 to about 88, about 88
  • the film coated oral tablet comprises about 97% core tablet by weight, based on the weight of the film coated oral tablet. In yet other embodiments, the film coated oral tablet comprises about 0.1 to about 20% by weight, based on the weight of the film coated oral tablet, of film coat. In still further embodiments, film coated oral tablet comprises about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% by weight, based on the weight of the film coated oral tablet, of the film coat.
  • the film coated oral tablet comprises about 0.1 to about 18, about 0.1 to about 16, about 0.1 to about 14, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 8, about 0.1 to about 6, about 0.1 to about 4, about 0.1 to about 2, about 0.1 to about 1, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 2, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 8, about 2 to about 8, about 2 to about 6, about 2, about 4 to about 20, about 4 to about 18, about 18, about 4 to about 16, about 4 to about 12, about 4 to about 18, about 18, about 16,
  • the film coated oral tablet comprises about 3% by weight, based on the weight of the film coated oral tablet, of the film coat. In yet other embodiments, the film coated oral tablet comprises about 97% core tablet by weight and about 3% film coat by weight, based on the weight of the film coated oral tablet.
  • the disclosure provides oral tablets comprising about 5 mg aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg microcrystalline cellulose, about 30 mg lactose monohydrate, about 2.5 mg croscarmellose sodium, and about 0.5 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 28.5 mg silicified microcrystalline cellulose, about 2.5 mg croscarmellose sodium, about 0.5 mg silica, colloidal anhydrous, and about 0.5 mg magnesium stearate.
  • the disclosure provides oral tablets comprising about 10 mg aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 60 mg microcrystalline cellulose, about 60 mg lactose monohydrate, about 5 mg croscarmellose sodium, and about 1 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 57 mg silicified microcrystalline cellulose, about 5 mg croscarmellose sodium, about 1 mg silica, colloidal anhydrous, and about 1 mg magnesium stearate.
  • the solid compositions may also have a desirable dissolution profile that provide the desired release of aticaprant.
  • the solid composition contains about 2 mg and 20 mg of aticaprant and has a dissolution profile comprising a Q value of between about 60% and 90% at 45 minutes, under the dissolution operating conditions of (i) apparatus: Paddle (USP Type 2, Ph. Eur., JP), (ii) dissolution medium: 0.01 M hydrochloric acid, (iii) volume: 900 mL, (iv) temperature: 37 ⁇ 0.5° C., (v) rotation speed: 50 rpm, and (vi) analytical finish: UHPLC with UV detection at 247 nm.
  • the Q value is about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, or about 95% at 45 minutes.
  • the Q value is about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 90, about 80 to about 85, or about 85 to about 90% at 45 minutes.
  • the Q value is between about 70% and 80% at 45 minutes. In other aspects, the Q value is about 75% at 45 minutes.
  • Aticaprant may be administered once daily, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the composition containing aticaprant is administered once daily.
  • the oral tablet containing aticaprant is administered once daily.
  • the solid pharmaceutical composition containing anticaprant is administered once daily.
  • the disclosure relates to aticaprant, for use as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant.
  • the disclosure also relates to the use of aticaprant in the manufacture of a medicament, as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with of aticaprant.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant.
  • antidepressant therapy can be in particular selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
  • Aticaprant may be used as adjunctive treatment, or in other words, in conjunction, as an add-on, or in combination with one or more antidepressants, for example, the patient may be already, or also, administered one or more antidepressants.
  • the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, in combination with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of aticaprant, in the manufacture of a medicament, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, in combination with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct administration of an effective amount of aticaprant, in combination with an effective amount of one or more antidepressants.
  • one or more antidepressants can be selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
  • the disclosure relates to aticaprant, for use as described herein.
  • aticaprant is S-aticaprant.
  • aticaprant, in particular S-aticaprant, for use as described herein is to be administered in an amount of about 2 to about 35 mg, more in particular, of about 10 mg.
  • aticaprant, in particular S-aticaprant, for use as described herein is administered orally.
  • the disclosure relates to aticaprant, in particular S-aticaprant, for use as described herein, administered once daily.
  • the disclosure also relates to the use of aticaprant, in the manufacture of a medicament, as described herein.
  • Aticaprant is S-aticaprant.
  • about 2 to about 35 mg aticaprant is to be administered, more in particular, about 10 mg.
  • aticaprant is to be administered orally.
  • aticaprant in particular S-aticaprant is to be administered once daily.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein aticaprant is in particular S-aticaprant.
  • the instructions for treatment direct administration of about 2 to about 35 mg aticaprant, more in particular, about 10 mg.
  • the instructions for treatment direct aticaprant in particular S-aticaprant
  • the instructions for treatment direct aticaprant, in particular S-aticaprant is for once daily administration.
  • administration of aticaprant does not result in weight gain during treatment, including clinically relevant weight gain.
  • the disclosure relates to aticaprant, for use as described herein, wherein the patient does not experience weight gain during the treatment with aticaprant.
  • the disclosure relates to a use as defined herein, wherein the patient does not experience weight gain during the treatment with aticaprant.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during the treatment with aticaprant.
  • the body weight of the patient can in particular be assessed at the time of the initial administration of aticaprant.
  • the disclosure relates to aticaprant, for use as described herein, wherein the patient does not experience a decrease in sexual functioning during the treatment with aticaprant.
  • the disclosure relates to a use as described herein, wherein the patient does not experience a decrease in sexual functioning during the treatment with aticaprant.
  • the disclosure relates to a package or pharmaceutical product as described herein, wherein the patient does not experience a decrease in sexual functioning during the treatment with aticaprant.
  • Such term “sexual functioning” comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.
  • Sexual satisfaction can be assessed by methods known to the skilled person, for example, by applying the Arizona Sexual Experience Scale (ASEX).
  • the patient has anhedonia.
  • the anhedonia is moderate.
  • the anhedonia is severe.
  • Anhedonia can be measured, through an anhedonia scale, for example, the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Hamilton Pleasure Scale
  • the disclosure relates to aticaprant, for use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Snaith Hamilton Pleasure Scale
  • the disclosure relates to the use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • the disclosure relates to the package or pharmaceutical product as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • methods are provided for treating patients having a more severe type of depression, i.e., major depressive disorder, using the compounds, compositions, e.g., solid compositions, and tablets, e.g., oral tablets, described herein.
  • the patient also may be experiencing anhedonia.
  • MDD alone is difficult to treat, treatment patients having anhedonia are even more problematic since their ability to gauge pleasure is impaired.
  • antidepressants are known to have a variety of side effects such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among others.
  • patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side-effects.
  • the methods described herein are effective in managing the patient's depression and anhedonia using aticaprant. Desirably, the methods successfully permit the patient to manage their depression while simultaneously reducing anhedonia.
  • the patients treated according to the described methods have moderate to severe anhedonia.
  • the term “anhedonia” as used herein refers to the lack of or decreased ability to experience pleasure in daily activities.
  • the term anhedonia includes loss of pleasure in sensory experiences (i.e., touch, taste, smell), as well as social interactions.
  • anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD.
  • Anhedonia also describes deficits in one or more components of reward-related behavior, also known as the pleasure cycle, such as wanting, liking, and learning.
  • the pleasure cycle can be divided into three phases: the appetitive phase (dominated by wanting), the consummatory phase (dominated by liking), and the satiety phase (dominated by learning).
  • the appetitive phase is characterized by the initial energy expenditure to attain a reward; the consummatory phase is enjoyment of the reward; and the satiety phase is characterized by learning and feedback integration.
  • an anhedonia scale may be used.
  • the Snaith-Hamilton Pleasure Scale (SHAPS) analysis is a validated scale for the measurement of anhedonia.
  • the SHAPS is a subject completed scale in which subjects score whether or not they experience pleasure in performing a list of activities or experiences.
  • the SHAPS is a self-reported 14-item instrument, developed for the assessment of hedonic capacity. Subjects score whether they experience pleasure in performing a list of activities or experiences. Subjects can rate the answers as 1-4 where 1 indicates “Nonetheless agree”, 2 indicates “Agree”, 3 indicates “Disagree” and 4 indicates “Nonetheless disagree”.
  • the subject's item responses are summed to provide a total score ranging from 14 to 56.
  • a higher total SHAPS score indicates higher levels of current anhedonia.
  • Physician/clinical judgment can be used to assess anhedonia separately or in conjunction with an anhedonia scale.
  • the patient has moderate anhedonia. In other embodiments, the patient has severe anhedonia.
  • An assessment of moderate or severe anhedonia is typically determined physician/clinical judgment and/or by one or more tests that provide insight into whether a patient has anhedonia.
  • the severity of the anhedonia may be determined using the SHAPS method.
  • a patient with moderate or severe anhedonia is considered to have a high level of anhedonia.
  • a patient with a SHAPS score of 38 or greater is considered to have moderate to severe anhedonia that can be considered a high level of anhedonia.
  • a high level of anhedonia is reflected by a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58, or higher.
  • a patient with mild or no anhedonia would be considered to have a low level of anhedonia that is assessed by physician/clinical judgment and/or one or more tests.
  • a patient with a SHAPS score of less than 38 is considered to have low anhedonia.
  • a patient with mild anhedonia may have a SHAPS score of 20 to less than 38, for example, a SHAPS score of 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 36, about 30, to about 36, about 32 to about 36, about 34 to about 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 36, about 30 to about 34, about 30 to about 32, about 32 to about 36, about 32 to about 34, or about 34 to about 36.
  • a SHAPS score of less than 20 can be considered to correspond to normal hedonic functioning, and for purposes of this disclosure, would fall into the low category of anhedonia, e.g.
  • the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
  • the patient's anhedonia is reduced by about 40 to about 90%, about 50 to about 90%, about 60 to about 90%, about 70 to about 90%, about 80 to about 90%, about 40 to about 80%, about 50 to about 80%, about 60 to about 80%, about 70 to about 80%, about 40 to about 70%, about 50 to about 70%, about 60 to about 70%, about 40 to about 60%, about 50 to about 60%, or about 50 to about 60%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
  • the patient's anhedonia is ameliorated, i.e., reduced by 100%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
  • Reduction of anhedonia after initiating treatment with aticaprant may be measured relative to the anhedonia of the patient as measured before treatment with aticaprant, i.e., a baseline anhedonia measurement.
  • the treating clinician is able to calculate the change of anhedonia from the baseline to the real time anhedonia measurement at any point after treatment with aticaprant.
  • standard methods for measuring anhedonia may be used, such as an anhedonia scale, e.g., SHAPS.
  • a baseline anhedonia measurement is obtained no more than about 1 week before initiating treatment with aticaprant.
  • a baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day before treatment with aticaprant.
  • a baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hours, about 30 minutes, or about 15 minutes before initiating treatment with aticaprant.
  • the patient's change of anhedonia will depend on several factors including, without limitation, anhedonia severity, patient's sensitivity to aticaprant, other pharmaceutical agents being administered, among others.
  • the patient's anhedonia is reduced after about 3 weeks of treatment with aticaprant. In other embodiments, the patient's anhedonia is reduced after about 3 weeks of treatment with aticaprant. In further embodiments, the patient's anhedonia is reduced after about 3 weeks to about 6 weeks, and, in certain embodiments, through week 6, of treatment with aticaprant.
  • the patient's anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following about 6 weeks of the treatment with aticaprant.
  • the anhedonia of the patient is reduced within about 3 weeks, and in some embodiments within about 3 weeks to about 6 weeks, as measured by the change from baseline in total score in an anhedonia scale and/or by physician/clinical judgement.
  • the methods described herein were found to not only improve the patient's depression and anhedonia symptoms, but resulted in fewer antidepressant side effects. Doing so resulted in less absenteeism (i.e., more visits or interactions with physicians), greater cognitive functioning, improvements in health-related quality of life, more interest and engagement in everyday activities, improvement in family and inter-personal relationships, ability to function in the workplace, fewer hospitalizations, among others.
  • the disclosure provides methods for treating MDD in a human patient by administering to the patient a pharmaceutical composition comprising between about 2 mg and 20 mg aticaprant, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant.
  • administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the PK parameters noted above (dose-normalized to 10 mg) after administration of the composition to a human after at least a 10-hour fast.
  • PK pharmacokinetic
  • the terms “subject” and “patient” refer to a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the patient is an adult. As used herein, the term “adult” as used herein refers to a human that is about 18 years of age or older. In certain aspects, the patient is an elderly adult, i.e., greater than or equal to 65 years of age.
  • 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 described herein to prevent the onset of the symptoms or complications, alleviate one or more of the symptoms or complications, or eliminate the disease, condition, or disorder.
  • depression also referred to as depressive disorder
  • depression includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholic, mid-life depression, late-life depression, bipolar 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.
  • the depression is major depressive disorder with suicidal ideation.
  • a patient is considered to have major depressive disorder if exhibiting five or more symptoms during the same two week period that are a change from previous functioning; depressed mood and/or loss of interest/pleasure must be present; excluding symptoms clearly attributable to another medical condition. See, e.g., Table 4.
  • Depressed mood Most of the day, nearly every day; may be subjective (e.g., feels sad, empty, hopeless) or observed by others (e.g., appears tearful); in children and adolescents, can be irritable mood 2.
  • Loss of interest/pleasure Markedly diminished interest/pleasure in all (or almost all) activities most of the day, nearly every day; may be subjective or observed by others 3.
  • Weight loss or gain Significant weight loss (without dieting) or gain (change of >5% body weight in a month), or decrease or increase in appetite nearly every day; in children, may be failure to gain weight as expected 4.
  • Insomnia or hypersomnia Nearly every day 5.
  • the following criteria also are met:
  • Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning 2. Episode not attributable to physiological effects of a substance or another medical condition 3. Episode not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders 4. No history of manic or hypomanic episode
  • Major depressive disorder may be categorized as mild, moderate, or severe.
  • the MDD is mild.
  • the MDD is moderate.
  • the MDD is severe.
  • “mild MDD” applies to a patient having few, if any, symptoms in excess of those required to make the diagnosis, the intensity of the symptoms is distressing but manageable, and the symptoms result in minor impairment in social or occupational functioning.
  • the mild MDD may be a single episode (ICD-10 F32.0) or a recurrent episode (ICD-10 F33.0).
  • Mode MDD applies to a patient having a number of symptoms, intensity of symptoms, and/or functional impairment are between those specified for “mild” and “severe.”
  • the moderate MDD may be a single episode (ICD-10 F32.1) or a recurrent episode (ICD-10 F33.1).
  • severe MDD applies to a patient where the number of symptoms is substantially in excess of that required to make the diagnosis, the intensity of symptoms is seriously distressing and unmanageable, and the symptoms markedly interfere with social and occupational functioning, and urgent symptom control is necessary.
  • the severe MDD may be a single episode (ICD-10 F32.2) or a recurrent episode (ICD-10 F33.2).
  • MDD is classified according to the DSM-5 definition of Table 5.
  • MGH Multiple- ⁇ sberg Depression Rating Scale
  • CGI-S Clinical Global Impression—Severity
  • SATE Self-Assessment of Treatment Experience
  • MGH Massachusetts General Hospital
  • ATRQ Antidepressant Treatment Response Questionnaire
  • MADRS is utilized to diagnose and/or monitor the patient.
  • MADRS is a 10-item rating scale that is used in antidepressant studies. It is clinician-administered and designed to be used in subjects with MDD to measure the overall severity of depressive symptoms.
  • the MADRS scale is validated, reliable, and acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression.
  • MADRS is administered using the Structured Interview Guide for the MADRS (SIGMA).
  • the 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), summed 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, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • CGI-S is utilized to diagnose and/or monitor the patient's depression.
  • CGI-S is a scale that rates the severity of the subject's illness at the time of assessment, relative to the clinician's past experience with subjects who have the same diagnosis and improvement with treatment.
  • CGI-S provides an overall clinician-determined summary measure of severity of subject's illness that considers all available information, including knowledge of subject's history, psychosocial circumstances, symptoms, behavior, and impact of symptoms on subject's ability to function.
  • CGI-S evaluates severity of psychopathology on scale of 0 to 7.
  • SMDDS is utilized to diagnose and/or monitor the patient's depression.
  • SMDDS is a subjective rating of the patient.
  • the SMDDS is a 16-item PRO measure. Each item is rated by the subject according to a 5-point Likert scale. Subjects respond to each question using a rating scale between 0 (“Not at all” or “Never”) to 4 (“Extremely” or “Always”). The total score ranges from 0 to 60.
  • the SMDDS uses a 7-day recall period and verbal rating scales. Higher score indicates more severe depressive symptomatology.
  • SATE is utilized to diagnose and/or monitor the patient's depression.
  • SATE is a one to three questionnaire administered when the subject is unable to complete other evaluations, i.e., away from the clinical setting such as at home.
  • SATE is useful to evaluate improvement or deterioration of depressive symptoms of the subjects over a short period of time. For rating overall depression, subject selected one option out of Improved, not changed or got worse; for depression improvement, subject selected one option out of slightly improved, much improved, very much improved and for depression worsen subject selected slightly worse, much worse, very much worse. See, Table 6.
  • the MGH-ATRQ is a self-rated scale used to determine treatment resistance in patient's having MDD. This questionnaire examines the antidepressant treatment history, using specific anchor points to define the adequacy of both dose and duration of each antidepressant trial, and the degree of symptomatic improvement.
  • the MGH-ATRQ permits determining treatment resistance in depression and is known to those skilled in the art.
  • the patient had an inadequate response to other antidepressant therapy.
  • “Inadequate response” as used herein refers to a patient experiencing a less than about 50% reduction in depressive symptom severity from the start of initiating treatment. Typically, the inadequate response is during a current/active episode of the depression. In some embodiments, an inadequate response refers to a patient experiencing about 26 to less than about 50% reduction in depressive symptom severity from the start of initiating treatment.
  • an inadequate response refers to a patient experiencing about 26 to about 49, about 26 to about 45, about 26 to about 40, about 26 to about 35, about 26 to about 30, about 30 to about 49, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 49, about 35 to about 45, about 35 to about 40, about 40 to about 49, or about 40 to about 45% reduction in depressive symptom severity from the start of initiating treatment.
  • a patient's response may be measured by one or more scales described herein and/or by physician/clinical judgment.
  • an inadequate response is measured by MGH-ATRQ, MADRS, or SHAPS.
  • an inadequate response is measured by MGH-ATRQ.
  • a patient is said to have a partial response to treatment, this refers to some minor to moderate symptomatic improvement since the initiation of treatment, but some of the initial symptoms are still present and troubling to the patient and these persistent symptoms still affect behavior and function. For instance, the patient's motivation, productivity, and interest in his or her usual activities may still be impaired.
  • other antidepressant therapy refers to an antidepressant medication or non-pharmacological treatment that is used to treat patients having depression.
  • the other antidepressant therapy is an antidepressant medication.
  • the other antidepressant therapy is a non-pharmacological treatment.
  • the other antidepressant therapy is an antidepressant medication other than aticaprant.
  • the antidepressant medication is any pharmaceutical agent which can be used to treat depression. Suitable examples include, without limitation, mono-amine oxidase inhibitors, tricyclics, tetracyclics, non-cyclics, triazolopyridines, selective serotonin reuptake inhibitors (SSRI), serotonin receptor antagonists, serotonin noradrenergic reuptake inhibitors (SNRI), noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics).
  • mono-amine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, and the like.
  • Examples of tricyclics include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, and the like.
  • Examples of tetracyclics includes maprotiline, and the like.
  • Examples of non-cyclics include nomifensine, and the like.
  • Examples of triazolopyridines include trazodone, and the like.
  • Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, citalopram, escitalopram, fluvoxamine, and the like.
  • Examples of serotonin receptor antagonists include nefazadone, and the like.
  • Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levomilnacipran and the like.
  • Examples of noradrenergic and specific serotonergic agents include mirtazapine, and the like.
  • Examples of noradrenaline reuptake inhibitors include reboxetine, edivoxetine and the like.
  • Typical antipsychotics include 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), and the like.
  • phenothiazines e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin
  • thioxanthenes e.g., thiothixene, flupentixol
  • antidepressant medication includes natural products such as Kava-Kava, St.
  • the antidepressant medication includes neuropeptides such as thyrotropin-releasing hormone and the like or compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like.
  • the antidepressant medication is a hormone such as triiodothyronine, and the like.
  • the antidepressant medication is SSRI, SNRI, or a combination thereof.
  • the antidepressant is a SSRI that is escitalopram, sertraline, paroxetine, fluoxetine or citalopram.
  • the antidepressant medication is a SNRI that is venlafaxine, duloxetine, vortioxeine or desvenlafaxine.
  • the non-pharmacologic treatment for use herein may be selected by one skilled in the art.
  • the non-pharmacologic treatment is psychotherapy, transcranial magnetic stimulation, or the like.
  • Therapeutically effective amounts/dosage levels and dosage regimens for the other antidepressant therapy 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.
  • other antidepressant therapy may include one antidepressant medication.
  • other antidepressant therapy includes two or more antidepressant medications.
  • other antidepressant therapy includes two antidepressant medications.
  • other antidepressant therapy includes three antidepressant medications. The attending physician would be able to select suitable antidepressant therapies for use as described herein.
  • the patient was receiving treatment with other antidepressant therapy prior to receiving aticaprant. In some embodiments, the patient was receiving treatment with other antidepressant therapy that comprised a SSRI, SNRT, or a combination thereof. In other embodiments, the patient stopped treatment with other antidepressant therapy before initiating treatment with aticaprant.
  • adjunctive treatment with an effective amount of one or more antidepressants.
  • adjuctive treatment and “adjunctive therapy” shall mean treatment of a patient in need thereof by administering aticaprant in combination with one or more antidepressant(s), wherein aticaprant and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.
  • Aticaprant is administered adjunctively with other antidepressant(s) currently being administered to the patient, including current antidepressant(s) to which the patient had an inadequate response, i.e., the antidepressant failed to treat the patient's depression.
  • aticaprant is administered adjunctively with an antidepressant(s) not previously administered to the patient, i.e., a new antidepressant.
  • aticaprant is administered in a regimen with an antidepressant(s) previously administered to the patient.
  • the number of dosages administered per day for each active 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 aticaprant is dosed as described herein.
  • a patient is under concurrent treatment with both an antidepressant and aticaprant, where both are administered by their prescribed dosing regimens.
  • the aticaprant and antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • Aticaprant 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.
  • aticaprant is administered orally.
  • the patient does not experience many of the side effects that are associated with other antidepressants, i.e., antidepressants other than aticaprant.
  • the patient does not experience weight gain during the treatment with aticaprant.
  • weight gain refers to an increase in the weight of patient, relative to the weight of the patient before taking aticaprant or the weight of the patient that is assessed at the time of the initial administration of aticaprant.
  • the patient may actually see a decrease in overall weight, relative to the weight of the patient before taking aticaprant.
  • the patient's weight is stable, i.e., does not increase or decrease.
  • the patient does not experience a clinically relevant weight gain which is characterized as a weight increase of ⁇ 7%.
  • the patient does not experience a decrease in sexual functioning during the treatment with aticaprant.
  • the term “decrease in sexual functioning” refers to reducing or lessening of one or more components of the human sex drive, i.e., sexual functioning.
  • the sexual functioning comprises one or more of sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.
  • the sexual functioning comprises sexual drive.
  • the sexual functioning comprises vaginal lubrication satisfaction.
  • the sexual functioning comprises orgasm achievement.
  • the sexual functioning comprises orgasm satisfaction.
  • the patient's sexual functioning is assessed at the time of initial administration of aticaprant.
  • the patient's sexual functioning while taking aticaprant can be compared to the patient's sexual functioning before administration of aticaprant.
  • Sexual functioning may be assessed by using standard scales and techniques such as the Arizona Sexual Experience Scale (ASEX).
  • ASEX Arizona Sexual Experience Scale
  • the ASEX is used to investigate whether aticaprant has a further positive or negative effect on sexual function.
  • the ASEX is 5 item rating scale administered to patients that quantifies sexual drive, sexual arousal, vaginal lubrication or penile erection, ability to reach orgasm and satisfaction. Scores range from 5 to 30, and two different versions of the scale are available (males and females).
  • CPFQ Cognitive and Physical Functioning Questionnaire
  • KSS Karolinska Sleepiness Scale
  • TEPS Temporal Experience of Pleasure Scale
  • the CPFQ is a brief self-report scale that provides additional information regarding the impact of adjunctive treatment on aspects of cognitive and executive function including attention, memory and mental acuity. Subjects with MDD are often reported to have difficulties with functioning in this area.
  • the KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from “extremely alert” (1) to “very sleepy, great effort to keep awake, fighting sleep” (9).
  • the TEPS includes 18 items, 2 subscales designed to distinguish between anticipatory and consummatory pleasure.
  • the methods described herein include administering an effective amount of aticaprant to the patient.
  • effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated.
  • aticaprant is utilized in an effective amount as determined by the attending physician.
  • other antidepressant(s) is utilized in an effective amount either separately or in combination with aticaprant.
  • XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu K ⁇ radiation (40 kV, 40 mA) and a ⁇ -2 ⁇ goniometer fitted with a Ge monochromator.
  • the incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge.
  • the diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector.
  • the software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.
  • Samples were run under ambient conditions as flat plate specimens using powder as received.
  • the sample was prepared on a polished, zero-background ( 510 ) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.
  • XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu K ⁇ radiation (45 kV, 40 mA) in transmission geometry.
  • a 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam.
  • a PIXcel 3D detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Soller slits.
  • the software used for data collection was X'Pert Data Collector using X'Pert Operator Interface. The data were analyzed and presented using Diffrac Plus EVA or HighScore Plus.
  • Samples were prepared and analyzed in either a metal or Millipore 96 well-plate in transmission mode. X-ray transparent film was used between the metalsheets on the metal well-plate and powders (approximately 1-2 mg) were used as received.
  • the Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.
  • the scan mode for the metal plate used the gonio scan axis, whereas a 2 ⁇ scan was utilized for the Millipore plate.
  • the software used for data collection was X'Pert Data Collector and the data analyzed and presented using Diffrac Plus EVA.
  • DSC Differential Scanning calorimetry
  • DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10° C./min from 25° C. to 275° C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
  • Modulated temperature DSC was carried out using an underlying heating rate of 2° C./min and temperature modulation parameters of ⁇ 0.636° C. (amplitude) every 60 seconds.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
  • DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10° C./min from 25° C. to 275° C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.
  • Aqueous sodium hydroxide was added to compound 1 in 2-methyltetrahydrofuran.
  • compound 2 i.e., the free base of compound 1 in 2-MeTHF was solvent switched to tetrahydrofuran (THF).
  • Reductive amination of compound 3 using compound 2 was carried out by adding sodium triacetoxyborohydride and THF. Upon reaction completion, the reaction mixture was washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing crude compound 4 was concentrated and ethanol and water were added. The product was crystallized using THF, ethanol, and water to produce compound 4 as a solid.
  • Form III of aticaprant was found to be crystalline by XRPD.
  • 1 H NMR showed that the material was consistent with the proposed structure, with the presence of residual ethyl acetate.
  • Ion chromatography showed that there were no cations/anions present, and HPLC showed 99.8% purity.
  • the DSC (heating from 20 to 131° C. at 10° C./min) showed a peak temperature at 121° C. See, FIG. 3 .
  • Tablets containing aticaprant were prepared according to the scheme in FIG. 24 containing the components in Table 10.
  • Example 3 The tablets of Example 3 are tested to determine dissolution properties and chemical stability. See, Table 11 for dissolution conditions and Tables 12-13 for results.
  • Dissolution Medium 0.01M hydrochloric acid Volume 900 mL Temperature 37 ⁇ 0.5° C. Rotation Speed 50 rpm Analytical Finish UHPLC with UV detection at 247 nm
  • the chemical stability of the tablets is evaluated over a 28-day period using a Risk Based Predictive Stability (RiBPS) study.
  • the stability protocols for the studies are provided in Tables 14-15.
  • the primary objective was to evaluate the efficacy of aticaprant compared to placebo when administered as adjunctive treatment in subjects with MDD partially responsive to SSRI/SNRI treatment in terms of reduction of symptoms of depression, as assessed by the change from baseline on the MADRS in non-responders during the placebo lead-in period.
  • the secondary objectives are:
  • Secondary exploratory objectives include:
  • the study consisted of two phases: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. See, FIG. 4 .
  • Subjects with MDD who have had treatment initiated with a permitted SSRI/SNRI and have had an inadequate or only partial response to this treatment were screened.
  • Assessments include the MINI, Antidepressant Treatment History Questionnaire (TRQ), and MADRS.
  • the treatment phase consisted of 3 periods. A placebo lead-in period of concealed duration, after which subjects entered the double-blind treatment period when they were randomly assigned to 10 mg aticaprant (two 5 mg capsules) or continue placebo for 6 weeks. Each capsule contained aticaprant (5 mg), microcrystalline cellulose (94.95 mg), and magnesium stearate (0.05 mg) in a hard gelatin capsule. Subjects who completed the treatment period, entered the withdrawal period and were treated with placebo for the remaining time of the treatment phase. The total duration for each subject was approximately 16 weeks. There were 11 scheduled visits, including screening. An overall flow diagram is shown in FIG. 4 .
  • Subjects were screened within 35 to 2 days prior to Day 1 to ascertain their eligibility per the inclusion and exclusion criteria.
  • the symptoms of depression were assessed using the structured interview guide for the MADRS.
  • the duration of the double-blind treatment phase was 11 weeks divided into 3 periods.
  • the subject received medication after completion of the visit on Day 1.
  • the first dose was taken at home on Day 2. All medication was taken in fasting condition.
  • Visits 3, 4 and 5 the subjects were re-randomized to blind subjects the duration of the placebo lead-in period.
  • the subjects visited the center for out-patient visits every 1 to 2 weeks. See, Table 17.
  • EW visit should be completed.
  • d At home In fasting condition.
  • At clinic visit days Use blisters dispensed at the previous visit. In fasting condition after completion of predose assessments.
  • j During the first screening visit and by telephone up to 4 days before Visit 2, if 2 weeks or more elapse between the MADRS rating at screening and Visit 2.
  • k Using Q1.6-app on subjects' smartphone. l Breakfast, lunch or dinner after drug intake at site.
  • Lead-in period Subjects who successfully complete the baseline examination visit at the clinical site/unit, were treated with placebo for the entire duration of the lead-in period.
  • Treatment period At the end of the lead-in period both placebo lead-in responders and placebo lead-in non-responders were randomized to receive either placebo or 10 mg aticaprant in a 1:1 ratio for 6 weeks. Subjects remained blinded to exact timing of the randomization, response criterion and drug treatment assignment for each subject.
  • Aticaprant was supplied as 5-mg capsules. Placebo was supplied as matching capsules. All subjects took 2 capsules QD. The capsules were taken daily from Day 2 to Day 78 in fasting condition with some water (fasting for at least 4 hours before dosing). Medication was taken before breakfast. If the subject has forgotten to take the medication before breakfast, this was done before the next following meal, at the latest at dinner of the same day. If the subject remembered later than dinner, the dose of that day was omitted, and the subject took the dose before breakfast on the next day.
  • Visit 11 was planned up to 3 days later, the subject continued medication until Visit 11.
  • the capsules were swallowed whole and not chewed, divided, dissolved or crushed. After having taken the medication, subjects did not to eat or drink for at least 30 minutes.
  • the first dose was taken in fasting condition on Day 2 of the double-blind phase.
  • the dose of the medication was:
  • Medication dose was adjusted as needed to 5 mg QD based on the results of a blinded review of the safety data. When a dose reduction has been decided on, this only applied to new subjects and the dose of medication was:
  • the Enriched ITT Analysis Set (eITT) is defined as all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least one dose of study medication in the treatment period and have at least one post-baseline MADRS assessment during the treatment period.
  • the Full ITT Analysis Set (fITT) is defined as all enrolled subjects who were randomized into a treatment period, received at least one dose of study medication in the treatment period and have at least one post-treatment baseline assessment of MADRS during the treatment period.
  • Standard safety assessments including physical and neurological examination, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis was performed. Based on observations of GI complaints in previous studies, a panel including PGI, PGII, G17 and Hp IgG was added to the clinical laboratory test panel to test for stomach mucosa status.
  • response status of the subjects was assessed according to the double-blind response criteria based on reduction in MADRS relative to lead-in baseline.
  • Both lead-in placebo responders and lead-in placebo non-responders were randomly assigned in a 1:1 ratio to either aticaprant or placebo in the treatment period. The randomization was stratified by lead-in response status (non-responders: ⁇ 30% reduction from baseline in MADRS total score at the end of the lead-in period vs responders: ⁇ 30% reduction from baseline at the end of the lead-in period) and presence/absence of anhedonia (presence defined as SHAPS total score ⁇ 20).
  • Treatment duration The study consisted of two periods: a screening phase of up to 5 weeks and a double-blind treatment phase of 11 weeks.
  • the first period was a placebo lead-in of 3 weeks, after which subjects entered the treatment period when they were randomly assigned to aticaprant or continuation on placebo for 6 weeks.
  • Subjects who successfully completed the treatment period were treated with placebo during a 2-week withdrawal period, i.e., Period 3.
  • the total duration for each subject was approximately 16 weeks.
  • the efficacy analysis is based on the eITT set defined as all enrolled lead-in placebo non-responders who were randomized into the treatment period, received at least one dose of medication, and have at least one post-baseline MADRS assessment during the treatment period.
  • the primary analysis set is used for all efficacy endpoints.
  • a secondary analysis set is the fITT set defined as all enrolled subjects who were randomized into the treatment period, received at least one dose of medication, and have at least one post-baseline MADRS assessment during the treatment period.
  • the secondary analysis set is used for all efficacy endpoints to examine the effect in the general population, which may be useful for designing subsequent studies in the development program.
  • the safety analysis is based on the full safety analysis set, defined as all enrolled subjects who received at least one dose of medication in the treatment period.
  • the mean (SD) MADRS total score at treatment baseline was 29.0 (4.61), ranging from 19 to 41. See, FIG. 5 .
  • the mean change from treatment baseline (SD) in MADRS total score at treatment week 6 was ⁇ 10.2 (8.44) for aticaprant and ⁇ 8.2 (8.53) for placebo.
  • the observed effect size was 0.23. See, Tables 20-22 and FIG. 8 .
  • the mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), ranging from 0 to 41. See, FIGS. 7 A and 7 B .
  • the mean changes from treatment baseline in MADRS total score at Treatment Week 6 for fITT were smaller than for eITT: ⁇ 9.7 (8.02) for aticaprant and ⁇ 6.6 (8.57) for placebo.
  • the observed effect size was 0.36.
  • the percentage of subjects with ⁇ 50% improvement in MADRS total score at treatment week 6 in the eITT population was 35.6% for aticaprant and 22.0% for placebo.
  • Treatment week 6 response rates in fITT population were 38.2% for aticaprant and 23.5% for placebo.
  • the mean (SD) SHAPS total score at treatment baseline was 36.6 (5.45), ranging from 20 to 50.
  • the mean change from treatment baseline (SD) in SHAPS total score at treatment week 6 was ⁇ 4.6 (6.23) for aticaprant and ⁇ 4.2 (5.04) for placebo.
  • the observed effect size was 0.07. See, Table 27 and FIGS. 17 and 37 .
  • the estimated LS mean differences with 80% 2-sided CI at treatment week 6 between aticaprant and placebo was ⁇ 0.8 [ ⁇ 1.79, 0.10].
  • the corresponding p-value was 0.250. See, FIGS. 7 and 8 .
  • the observed effect size was 0.38 and 0.11, respectively.
  • C max is defined as maximum plasma concentration of aticaprant.
  • the eITT population included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period.
  • N number of subjects analyzed
  • n number analyzed
  • the most common TEAEs during the treatment period were headache (experienced by 10/85 subjects—11.8% in the aticaprant group and by 6/84 subjects—7.1% in the placebo group) and diarrhea (experienced by 7/85 subjects—8.2% in the aticaprant group and by 2/84 subjects—2.4% in the placebo group). See, Table 40.
  • Subjects with Adverse 4 (4.8) 13 (15.3) 17 (10.1) Events of Special Interest Gastrointestinal Disorders 4 (4.8) 9 (10.6) 13 (7.7) deaths causally related to treatment/all Diarrhea 2 (2.4) 7 (8.2) 9 (5.3) Abdominal Pain Upper 2 (2.4) 0 2 (1.2) Dyspepsia 1 (1.2) 1 (1.2) 2 (1.2) Abdominal Pain 0 1 (1.2) 1 (0.6) Skin And Subcutaneous Tissue 0 5 (5.9) 5 (3.0) Disorders Pruritus 0 5 (5.9) 5 (3.0) Percentages calculated with the number of subjects in each group as denominator. Reported dictionary version: MedDRA 22.1. Subjects are presented by the treatment received during the Treatment period.
  • the results illustrate that the treatment effect is larger in patients with more anhedonia at baseline. See, FIGS. 20 -A and 20 -B.
  • the placebo+oral antidepressant group shows less placebo response as compared to the low anhedonia group in FIGS. 7 - 8 .
  • the treatment effect of the aticaprant+oral antidepressant group is higher in the high anhedonia group as compared to the low anhedonia group.
  • Overall the effect size is larger at every single time point (from week 1 onwards) in the high anhedonia group.
  • the LSMD in the high anhedonia group is more than double that of the low anhedonia group at week 6. Further, when looking at the symptom level, greater improvement in items related to anhedonia and dysphoria in subgroup with high anhedonia vs low anhedonia. See, FIG. 21 .
  • the mean weight for subjects in the placebo group was 76.17 kg compared to 78.66 in the aticaprant group.
  • the mean weight in the placebo group was 75.75 kg compared to 78.57 kg in the aticaprant group. This indicates that the weight in both groups remained relatively stable over the 6-week double blind treatment period. This is unexpected because other adjunctive treatments for MDD result in a mean weight increase. See, Thase M, et al. J Clin Psych. 2015: 76(9), 1224-1231; Thase, J Clin Psych. 2015, 76(9):1232-1240; El Khalili, Int J Neuropsychopharmacol.
  • Impairments in sexual functioning is a common side effect of antidepressant treatment and can be very upsetting to patients and their sexual partners.
  • Major depression itself is associated with increased sexual dysfunction, and many of the pharmacological treatments are known to worsen sexual functioning even further.
  • MDD In a large survey of nearly 5000 patients in France, it was estimated that in untreated patients with MDD, the prevalence of sexual dysfunction was 65%. The prevalence of sexual dysfunction increased to 71% for patients treated with antidepressant therapy.
  • the brain reward circuitry is controlled by several areas: nucleus accumbens, ventral tegmental area and the amygdala. It is hypothesized that treatment with kappa opioid receptors may restore the normal homeostatic balance in patients with overactivation. Treatment with aticaprant could potentially improve symptoms of anhedonia. Other symptoms associated with the reward circuitry includes: sexual pleasure, lack of interest and lack of enjoyment.
  • the mean change from treatment baseline (SD) in ASEX total score to week 6 was ⁇ 1.5 (4.02) points for aticaprant compared to ⁇ 0.7 (2.98) points for placebo.
  • a lower score on the ASEX indicates improvement.
  • the score reduction at week 6 was greater in the aticaprant group compared to placebo. This is unexpected because adjunctive treatments with other agents are expected to worsen sexual functioning, i.e., increase in ASEX score over time. See, FIG. 22 .
  • FIG. 10 -B depicts the least squares mean change from baseline. A significant treatment effect favoring aticaprant was seen as early as week 3. At this point, aticaprant showed a statistically superior effect compared to placebo.
  • Study Design A 6-week, multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy, safety, and tolerability of aticaprant in adult and elderly subjects (18 to 74 years) who have MDD with prominent anhedonia (MDD ANH+), and who have had an inadequate response to a SSRI or a serotonin and SNRI in the current depressive episode. See, FIG. 34 .
  • this study will consist of 3 phases: an eligibility screening phase (up to 4 weeks prior to first dose administration), a double-blind treatment phase of 6 weeks, and a follow-up of 1-2 weeks. Subjects who have completed the double-blind phase may participate in an open-label long-term safety study.
  • MDD ANH+ Approximately 544 subjects with MDD with prominent anhedonia (MDD ANH+) and without prominent anhedonia (MDD ANH ⁇ ) will be randomized in a 1:1 ratio to adjunctive placebo or aticaprant to achieve a minimum of 314 adult subjects meeting predefined criteria for MDD ANH+ eligible to be included in the primary analysis. Randomization will be stratified by study site, age group (adults [ ⁇ 65 years], elderly [ ⁇ 65 years]), baseline anhedonia, and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI/SNRT) during the entire study.
  • SSRI/SNRT baseline antidepressant
  • Inclusion Criteria 1. Age of 18 to 74 years (inclusive). 2. Be medically stable on the basis of physical examination (including a brief neurological examination), medical history, vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their significance must be determined. 3. Be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, retesting of an abnormal lab values that may lead to exclusion will be allowed once during the screening phase. 4.
  • An adequate trial is defined as an antidepressant treatment for at least 6 weeks (and no greater than 12 months in the current episode) at or above the stable therapeutic dose specified in the MGH-ATRQ, must include the subject's current antidepressant treatment. If the subject has received 2 SSRI/SNRI treatments of sufficient dose and duration in the current episode, and has shown ⁇ 25% improvement to both, then the subject would not qualify based on exclusion criterion (first exclusion criterion). 6. Current major depressive episode, depression symptom severity, presence of anhedonia and antidepressant treatment response in the current depressive episode must be confirmed.
  • SSRI or SNRI for depressive symptoms, in any formulation and available in the participating country: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine at a stable dose (at therapeutic dose level) for at least 6 weeks, and for no greater than 12 months in the current episode, at screening.
  • the above SSRI/SNRI needs to be approved for the treatment of MDD. Subjects using fluvoxamine as baseline SSRI and have normal renal and hepatic function are admitted. 7.
  • MDE symptoms Item 2 positive response for anhedonia
  • BMI between 18 and 40 kg/m 2 (inclusive).
  • a woman of childbearing potential must have a negative highly sensitive serum ( ⁇ - hCG) pregnancy test at screening and a negative urine pregnancy test predose on Day 1 of the double-blind phase prior to randomization. 12.
  • Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects in clinical studies. 13.
  • a woman must be either: Postmenopausal Permanently sterile Of childbearing potential and practicing a highly effective method of contraception (failure rate of ⁇ 1% per year when used consistently and correctly).
  • a woman must not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of at least 1 month after receiving the last dose of study medication. 15.
  • spermatogenesis cycle (defined as approximately 3 months) after receiving the last dose of study medication, a man: who is sexually active with a woman of childbearing potential must use a barrier method of contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) and his female partner must use a highly effective method of contraception.
  • a barrier method of contraception e.g., condom with spermicidal foam/gel/film/cream/suppository
  • his female partner must use a highly effective method of contraception.
  • who is sexually active with a woman who is pregnant must use a condom. must not to donate sperm.
  • Exclusion Criteria 1. History of treatment-resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no or minimal improvement ( ⁇ 25% improvement) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6 weeks). 2. Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the SCID-CT), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, narcissistic personality disorders or somatoform disorders. 3.
  • History of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening or positive test results for alcohol and/or drugs of abuse (e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, CBD, barbiturates, MDMA) at screening or at baseline.
  • drugs of abuse e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, CBD, barbiturates, MDMA
  • One retest during screening is allowed.
  • Tobacco and caffeine use are not exclusionary. 7.
  • Subjects reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the double-blind treatment phase should be excluded.
  • Cognitive impairment that would render the informed consent invalid or limit the ability of the subject to comply with the study requirements.
  • Subject has neurodegenerative disorder (e.g., Alzheimer's disease, vascular dementia, Parkinson's disease with clinical evidence of cognitive impairment) or evidence of MCI.
  • Current or history of seizures uncomplicated childhood febrile seizures with no sequelae are not exclusionary). 11.
  • liver cirrhosis e.g., esophageal varices, ascites, and increased prothrombin time
  • ALT or AST values >3 ⁇ the ULN or total bilirubin >1.5 ⁇ the ULN in the screening phase. Repeat of screening test for abnormal ALT and AST is permitted during the screening period there is an alternative explanation for the out of range value. 13.
  • the subject may participate. 14.
  • Positive test result for drugs of abuse e.g., barbiturates, methadone, opiates, cocaine, PCP, MDMA, and amphetamine/methamphetamine
  • Subjects who have a positive test result at screening due to prescribed psychostimulants taken for any indication must discontinue the medication at least 2 weeks before Day 1 of the double-blind treatment phase (prior to randomization).
  • the result of the Day 1 (prior to randomization) test for drugs of abuse must be negative for the subject to be randomized.
  • Subjects who have a positive test result at screening due to prescribed/over-the-counter opiates or barbiturates may be permitted to continue in the screening phase if the medication is discontinued at least 1 week or 5 half-lives, whichever is longer, before Day 1 of the double-blind treatment phase (prior to randomization).
  • the result of the Day 1 (prior to randomization) test for drugs of abuse must be negative for the subject to be randomized. Intermittent use of cannabinoids prior to the start of the screening phase is not exclusionary as long as the subject does not meet the criteria for substance use disorder.
  • a positive test for cannabinoids at the start of the screening phase is not exclusionary; however, a positive test result for cannabinoids predose on Day 1 of the double-blind treatment phase is exclusionary. 16. Taking a total daily dose of benzodiazepines greater than the equivalent of 6 mg/day of lorazepam at the start of the screening phase. 17. Recent (last 3 months) history of, or current signs and symptoms of: Severe renal insufficiency (creatinine clearance ⁇ 30 mL/min) Clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders. Uncontrolled Type 1 or Type 2 diabetes mellitus.
  • Subjects with Type 1 or Type 2 diabetes mellitus who are controlled may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose-lowering medications for at least 2 months prior to screening). 18.
  • Current signs/symptoms of hypothyroidism or hyperthyroidism For subjects with a history of thyroid disease and for subjects who, regardless of thyroid history have the TSH value out of range, a FT 4 test will be conducted. If the FT4 value is abnormal and considered to be clinically significant the subject is not eligible. 19.
  • Subjects with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones need to be on a stable dosage for 3 months prior to the start of the screening phase.
  • Subjects taking thyroid supplementation for antidepressant purposes are not allowed.
  • Ongoing psychological treatments e.g., Cognitive Behavior Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy etc.
  • a subject who has been receiving ongoing psychological treatment for a period of greater than 6 weeks is eligible, if psychological treatment to be of stable duration and frequency.
  • an investigational drug including investigational vaccines
  • used an invasive investigational medical device within 60 days before the start of the screening phase, or has participated in 2 or more MDD or other psychiatric condition clinical interventional studies (with different investigational medication) in the previous 1 year before the start of the screening phase, or is currently enrolled in an investigational interventional study.
  • 29. A woman who is pregnant, breastfeeding, or planning to become pregnant while enrolled or within 6 weeks after the last dose of the study medication.
  • 30. Plans to father a child while enrolled or within 90 days after the last dose of study intervention.
  • 31. Diagnosis of acquired immunodeficiency syndrome. Human immunodeficiency virus testing is not required.
  • Any condition or situation/circumstance for which participation would not be in the best interest of the subject e.g., compromise the well-being) or that could prevent, limit, or confound the protocol specified assessments.
  • the assessment of primary and secondary (key and other) endpoints will be conducted on the FAS which includes adult (not elderly) subjects with MDD ANH+ who took at least 1 dose of study medication.
  • Safety Objectives (All): The following safety endpoints will be assessed separately for the adult and elderly subjects; the safety analysis set for each age group will include all randomized subjects who have received at least one dose of study medication:
  • Prohibited therapies Subjects must not use the following medications or food supplements prior to or during the study, as indicated, except to treat an AE or breakthrough symptoms, preferably after the EOT visit:
  • Example 8 a Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Aticaprant 5 mg and 10 mg as Adjunctive Therapy in Adult and Elderly Subjects with MDD with Prominent Anhedonia and Inadequate Response to Current Antidepressant Therapy
  • Study Design An 8-week, multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy, safety, and tolerability of aticaprant in adult and elderly subjects (18 to 74 years) who have MDD with prominent anhedonia and who have had an inadequate response to a SSRI or a SNRI in the current depressive episode. See, FIG. 35 .
  • Subjects who have completed the double-blind treatment phase may participate in an open-label long-term safety study.
  • Sample Size and Randomization Approximately 624 adult ( ⁇ 65 years) and elderly ( ⁇ 65 years) subjects with MDD with prominent anhedonia will be randomized in a 2:1:1 ratio to adjunctive placebo, 5-mg aticaprant, or 10-mg aticaprant to achieve a minimum of 556 adult subjects meeting predefined criteria for MDD with prominent anhedonia eligible to be included in the primary efficacy analysis set. Randomization will be stratified by study site, age group (adult, elderly) and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI/SNRI) during the entire study.
  • SSRI/SNRI baseline antidepressant
  • Inclusion Criteria 1. Age of 18 to 74 years (inclusive). 2. Medically stable on the basis of physical examination (including a brief neurological examination), medical history, vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline. 3. Medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, retesting of an abnormal lab values that may lead to exclusion will be allowed once during the screening phase. 4. Meet DSM-5 diagnostic criteria for recurrent or single episode MDD, without psychotic features (DSM-5 296.22, 296.23, 296.32, or 296.33), based upon clinical assessment and confirmed by the SCID-CT.
  • SSRI/SNRI antidepressants
  • An inadequate response is defined as 26% to ⁇ 50% reduction in depressive symptom severity and overall good tolerability, as assessed by the MGH-ATRQ.
  • An adequate trial is defined as an antidepressant treatment for at least 6 weeks (and no greater than 12 months in the current episode) at or above the stable therapeutic dose specified in the MGH-ATRQ, must include the subject's current antidepressant treatment. If the subject has received 2 SSRI/SNRI treatments of sufficient dose and duration in the current episode, and has shown ⁇ 25% improvement to both, then the subject would not qualify based on exclusion criterion (first exclusion criterion). 8. The current major depressive episode, depression symptom severity, presence of anhedonia and antidepressant treatment response in the current depressive episode, must be confirmed.
  • any one of the following SSRI or SNRI for depressive symptoms in any formulation and available in the participating country citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine at a stable dose (at therapeutic dose level) for at least 6 weeks, and for no greater than 12 months in the current episode, at screening.
  • the SSRI/SNRI needs to be approved for the treatment of MDD. 9.
  • BMI between 18 and 40 kg/m 2 (inclusive).
  • Postmenopausal A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
  • a high FSH level in the postmenopausal range based on the reference range of the central laboratory may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
  • Permanently sterile Of childbearing potential and practicing a highly effective method of contraception (failure rate of ⁇ 1% per year when used consistently and correctly). Remains on a highly effective method and for at least 1 month after the last dose of study medication.
  • a woman must not donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of at least 1 month after receiving the last dose of study medication.
  • a man (a) who is sexually active with a woman of childbearing potential must use a barrier method of contraception and his female partner must use a highly effective method of contraception; (b) who is sexually active with a woman who is pregnant must use a condom; (c) must not donate sperm.
  • Exclusion Criteria 1. History of treatment-resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no or minimal improvement ( ⁇ 25% improvement) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6 weeks). 2. Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the SCID-CT), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, narcissistic personality disorders or somatoform disorders. 3.
  • History of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening or positive test results for alcohol and/or drugs of abuse (e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, CBD, barbiturates, MDMA) at screening or at baseline.
  • drugs of abuse e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, CBD, barbiturates, MDMA
  • One retest during screening is allowed.
  • Tobacco and caffeine use are not exclusionary. 7.
  • Subjects reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the double-blind treatment phase should be excluded.
  • Cognitive impairment that would render the informed consent invalid or limit the ability of the subject to comply with the study requirements.
  • Subject has neurodegenerative disorder (e.g., Alzheimer's disease, vascular dementia, Parkinson's disease with clinical evidence of cognitive impairment) or evidence of MCI.
  • Current or history of seizures uncomplicated childhood febrile seizures with no sequelae are not exclusionary). 11.
  • ECG electrocardiogram
  • liver cirrhosis e.g., esophageal varices, ascites, and increased prothrombin time
  • ALT or AST values ⁇ 3 ⁇ the ULN or total bilirubin >1.5 ⁇ the ULN in the screening phase. Repeat of screening test for abnormal ALT and AST is permitted during the screening period provided there is an alternative explanation for the out of range value. 13.
  • the subject may participate in the study. 14.
  • Positive test results for drugs of abuse e.g., barbiturates, methadone, opiates, cocaine, PCP, MDMA, and amphetamine/methamphetamine
  • Subjects who have a positive test result at screening due to prescribed psychostimulants taken for any indication must discontinue the medication at least 2 weeks before Day 1 of the double-blind treatment phase (prior to randomization).
  • the result of the Day 1 (prior to randomization) test for drugs of abuse must be negative for the subject to be randomized.
  • subjects who have a positive test result at screening due to prescribed/over-the-counter opiates or barbiturates may be permitted to continue in the screening phase if the medication is discontinued at least 1 week or 5 half-lives, whichever is longer, before Day 1 of the double-blind treatment phase (prior to randomization).
  • the result of the Day 1 (prior to randomization) test for drugs of abuse must be negative for the subject to be randomized. 16.
  • Intermittent use of cannabinoids prior to the start of the screening phase is not exclusionary as long as the subject does not meet the criteria for substance use disorder.
  • a positive test for cannabinoids at the start of the screening phase is not exclusionary; however, a positive test result for cannabinoids predose on Day 1 of the double-blind treatment phase is exclusionary. 17. Taking a total daily dose of benzodiazepines greater than the equivalent of 6 mg/day of lorazepam at the start of the screening phase. 18. Recent (last 3 months) history of, or current signs and symptoms of: Severe renal insufficiency (creatinine clearance ⁇ 30mL/min) Clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders. Uncontrolled Type 1 or Type 2 diabetes mellitus.
  • Subjects with Type 1 or Type 2 diabetes mellitus who are controlled may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose- lowering medications for at least 2 months prior to screening). 19. Current signs/symptoms of hypothyroidism or hyperthyroidism. For subjects with a history of thyroid disease and for subjects who, regardless of thyroid history have the TSH value out of range, a FT 4 test will be conducted. If the FT4 value is abnormal and considered to be clinically significant the subject is not eligible. 20.
  • Subjects with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones need to be on a stable dosage for 3 months prior to the start of the screening phase. Subjects taking thyroid supplementation for antidepressant purposes are not allowed. 21. Cushing's Disease, Addison's Disease, primary amenorrhea, or other evidence of significant medical disorders of the hypothalamic-pituitary-adrenal axis. 22. Significant medical illness, particularly unstable medical problem 23. Ongoing psychological treatments (e.g., Cognitive Behavior Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 6 weeks prior to start of screening. A subject who has been receiving ongoing psychological treatment for a period of greater than 6 weeks is eligible. 24. Significant medical illness, particularly unstable medical problem. 25.
  • Clinically-relevant GI complaints (unless symptoms of Axis I disorder) at screening or baseline or history of gastric disease (including but not limited to documented peptic ulcer disease, gastritis [including atrophic gastritis], upper GI bleeding, Barret's esophagus, Crohn's disease, ulcerative colitis, GI precancerous conditions or any other clinically-relevant GI disease irritable bowel syndrome).
  • gastric disease including but not limited to documented peptic ulcer disease, gastritis [including atrophic gastritis], upper GI bleeding, Barret's esophagus, Crohn's disease, ulcerative colitis, GI precancerous conditions or any other clinically-relevant GI disease irritable bowel syndrome).
  • gastric disease including but not limited to documented peptic ulcer disease, gastritis [including atrophic gastritis], upper GI bleeding, Barret's esophagus, Crohn's disease, ulcerative colitis, GI pre
  • an investigational drug including investigational vaccines
  • used an invasive investigational medical device within 60 days before the start of the screening phase, or has participated in 2 or more MDD or other psychiatric condition clinical interventional studies (with different investigational medication) in the previous 1 year before the start of the screening phase, or is currently enrolled in an investigational interventional study.
  • 32. A woman who is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 weeks after the last dose of the study medication.
  • 33. Plans to father a child while enrolled in this study or within 90 days after the last dose of study intervention.
  • 34. Diagnosis of acquired immunodeficiency syndrome. Human immunodeficiency virus testing is not required for this study.
  • Any condition or situation/circumstance for which participation would not be in the best interest of the subject e.g., compromise the well-being) or that could prevent, limit, or confound the protocol specified assessments.
  • FAS full analysis set
  • Safety Objectives (All): The following safety endpoints will be assessed separately for the adult and elderly subjects; the safety analysis set for each age group will include all randomized subjects who have received at least one dose of study medication:
  • Subjects must not use the following medications or food supplements prior to or during the study, as indicated, except to treat an AE or breakthrough symptoms, preferably after the EOT visit:
  • a total of approximately 80 qualified healthy adult participants are planned to be enrolled in this study: 24 participants each are to be enrolled to ensure at least 20 participants in each part complete all required PK assessments. Eligible participants can be enrolled in more than one part of the study if sufficient wash-out period is completed between periods by participants.
  • PK sampling will be done up to 120 hours (Day 6).
  • Each dosed participant will have a safety follow-up on Day 10 to Day 14 after last dose of the study intervention.
  • Part 1 of the study involves determination of relative bioavailability for tablet (Formulation Concept 1, i.e., unmilled aticaprant formulation, see Table 10) and capsule formulations (see Example 6, study design, for description of capsule formulation) and dose proportionality and food effect for tablet formulation (Formulation Concept 1) in healthy adult participants ( FIG. 25 ).
  • Part 1 will consist of Subpart 1A and Subpart 1B consisting of a total of 4 periods.
  • Subpart 1A is a randomized, open label, 3-way crossover, 3-period study to be conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg aticaprant administered as 1 ⁇ 10 mg oral tablet (Formulation Concept 1) under fasted conditions (Treatment B) compared to 10 mg aticaprant administered as 2 ⁇ 5 mg oral capsules under fasted conditions (Treatment A) and to evaluate the dose proportionality of a single dose of 5 mg aticaprant administered as 1 ⁇ 5 mg oral tablet (Formulation Concept 1) under fasted conditions (Treatment C) compared to the potential Phase 3 oral tablet (Formulation Concept 1) under fasted conditions (1 ⁇ 10 mg, Treatment B; Table 49).
  • Subpart 1B consists of a fourth period to evaluate the food effect of a single dose of 10 mg aticaprant administered as 1 ⁇ 10 mg oral tablet (Formulation Concept 1) under fed conditions (Treatment D; Table 50 and Table 52).
  • a preliminary PK analysis will be conducted at the end of the food effect part (Subpart 1B) for all the periods from Part 1 and will include the food effect data.
  • Treatment Formulation Dose Food D Formulation Concept 1 10 mg Fed (10 mg oral tablet) (1 ⁇ 10 mg) Treatment D: 1 ⁇ 10 mg Formulation Concept 1 administered in the morning approximately 30 minutes after the start of a standardized high-fat breakfast following at least 10-hour overnight fasting
  • Treatment D 1 ⁇ 10 mg Formulation Concept 1 administered in the morning approximately 30 minutes after the start of a standardized high-fat breakfast following at least 10-hour overnight fasting
  • Part 2 of the study involves determination of relative bioavailability for tablet (Formulation Concept 2, i.e., milled (microfine) aticaprant formulation; see Table 10) and capsule formulations (see Example 6, study design, for description of capsule formulation) and dose proportionality and food effect for tablet formulation (Formulation Concept 2) in healthy adult participants ( FIG. 26 ).
  • Part 2 will consist of Subpart 2A and Subpart 2B consisting of a total of 4 periods.
  • Subpart 2A is a randomized, open label, 3-way crossover, 3-period study to be conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg aticaprant administered as 1 ⁇ 10 mg oral tablet (Formulation Concept 2) under fasted conditions (Treatment F) compared to 10 mg aticaprant administered as 2 ⁇ 5 mg oral capsules under fasted conditions (Treatment E) and to evaluate the dose proportionality of a single dose of 5 mg aticaprant administered as 1 ⁇ 5 mg oral tablet (Formulation Concept 2) under fasted conditions (Treatment G) compared to the potential Phase 3 oral tablet (Formulation Concept 2) under fasted conditions (1 ⁇ 10 mg, Treatment F; Table 53).
  • Subpart 2B consists of a fourth period to evaluate the food effect of a single dose of 10 mg aticaprant administered as 1 ⁇ 10 mg oral tablet (Formulation Concept 2) under fed conditions (Treatment H; Tables 54 and 56).
  • a preliminary PK analysis will be conducted at the end of the food effect part (Subpart 2B) for all the periods from Part 2 and will include the food effect data.
  • Treatment Formulation Dose Food H Formulation Concept 2 10 mg Fed (10 mg oral tablet) (1 ⁇ 10 mg) Treatment H: 1 ⁇ 10 mg Formulation Concept 2 administered in the morning approximately 30 minutes after the start of a standardized high-fat breakfast following at least 10-hour overnight fasting
  • Treatment H 1 ⁇ 10 mg Formulation Concept 2 administered in the morning approximately 30 minutes after the start of a standardized high-fat breakfast following at least 10-hour overnight fasting
  • Day 1 of a treatment period is the first day of the washout period (also in between the study parts, if applicable).
  • Participants will be fasting in Part 1A and Part 2A. Participants will have been fed in Parts 1B and 2B. For a fasted condition, participants will fast (nothing to eat or drink except noncarbonated water) overnight for at least 10 hours before and until 4 hours after study intervention administration during each fasted treatment period. Approximately, 4 hours post-dose and after the 4-hour PK sampling, a standard lunch will be served at the study-site. Intake of water is allowed until 2 hours before the intake of the study intervention. Thereafter, water intake is only allowed for study intervention intake and for breakfast, if applicable. Drinking of water is allowed ad libitum from approximately 2 hours after dosing.
  • participant will consume, after an overnight fast (at least 10 hours), a standardized high-fat breakfast within a 20-minute period.
  • a high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended for food effect bioavailability studies (e.g., 2 strips of fried bacon, 2 eggs fried in butter, 4 ounces [120 gram] hash brown potatoes fried in butter, 2 buttered pieces of whole wheat bread, and 240 mL whole milk). Study intervention will be administered approximately 30 minutes after the start of the breakfast.
  • Plasma concentrations will be determined for aticaprant. Blood samples for determination of plasma concentrations of aticaprant will be collected predose and at the postdose time points starting on Day 1 as indicated in the Tables 57-58.
  • Parts 1 and 2 of the study will start at any time, irrespective of other parts of the study.
  • the study will consist of a screening phase (within 28 days before study intervention administration), an open-label treatment phase (Day ⁇ 1 until Day 5, with single-dose treatment on Day 1 and at least 96 hours of PK for Part 1 and 120 hours of PK (Day 6) for Part 2).
  • a total of approximately 80 qualified healthy adult participants are planned to be enrolled in this study: 24 participants each are to be enrolled in Parts 1 and 2 to ensure at least 20 participants in each part complete all required PK assessments. Eligible participants can be enrolled in more than one part of study if sufficient wash-out period is completed between periods by participants.
  • Type of Participant and Disease Characteristic Healthy on the basis of physical examination, medical history (screening only), vital signs, and 12-lead ECG performed at screening and admission to the clinical unit on Day ⁇ 1 of the first treatment period. Minor abnormalities in ECG, which are not considered to be of clinical significance are acceptable. Healthy on the basis of clinical laboratory tests performed at screening and at admission to the study center. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included.
  • retesting of an abnormal lab value(s) that may lead to exclusion will be allowed once during the screening phase.
  • ALT, AST, alkaline phosphatase and bilirubin must be within 1.5 times of upper limit of normal range and not clinically significant.
  • Weight BMI weight [kg]/height 2 [m] 2 ) between 18 and 29.9 kg/m 2 (inclusive), and body weight not less than 50 kg.
  • Sex and Contraceptive/Barrier Requirements Male or female All women participants must have a negative highly sensitive serum ⁇ -hCG pregnancy test at screening and all women participants must have a negative urine pregnancy test on Day ⁇ 1 of each treatment period. A woman must be a. Not of childbearing potential b. Of childbearing potential and Practicing a highly effective method of contraception (failure rate of ⁇ 1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and until 90 days after last dose - the end of relevant systemic exposure. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of at least 90 days after receiving the last dose of study intervention.
  • a male participant must agree to use a barrier method of contraception (e.g., condom) when engaging in any activity that allows for passage of ejaculate to another person.
  • a barrier method of contraception e.g., condom
  • a male participant who is sexually active with a woman who is pregnant must use a condom.
  • Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak.
  • a male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 3 months) after receiving the last dose of study intervention.
  • Blood pressure (after the participant is [supine] for 5 minutes) between 90 mmHg and 140 mmHg systolic, inclusive, and no higher than 90 mmHg diastolic at screening and Day ⁇ 1 of each treatment period.
  • a 12-lead ECG consistent with normal cardiac conduction and function, at screening and Day ⁇ 1 of each treatment period, including: Sinus rhythm Heart rate between 40 and 100 beats per minute, extremes included QTc interval ⁇ 450 ms for males, ⁇ 470 for females (corrected cf. Fridericia 1920; ICH E14 2005) QRS interval of ⁇ 120 ms PR interval ⁇ 210 ms Morphology consistent with healthy cardiac conduction and function
  • Medical Conditions History of or current significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematological disease, lipid abnormalities, bronchospastic respiratory disease, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, neurologic or psychiatric disease, seizure disorder (uncomplicated childhood febrile seizures with no sequelae are not exclusionary) Parkinson's disease, infection, hypertension, vascular disorder, significant pulmonary disease, or any other illness. History of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence).
  • GI complaints per clinical judgment at screening or baseline or history of documented gastric disease (including but not limited to documented peptic ulcer disease, gastritis [including atrophic gastritis], upper GI bleeding, Barret's esophagus, Crohn disease, ulcerative colitis, GI precancerous conditions or any other clinically relevant GI disease irritable bowel syndrome).
  • Participant has current or past homicidal ideation/intent within the last 6 months, or has current or past suicidal ideation with some intent to act within 6 months prior to the start of the screening phase, corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior within the past year prior to the start of the screening phase. Participants reporting suicidal ideation with intent to act or suicidal behavior on Day ⁇ 1 prior to the start of the treatment should be excluded. Serology positive for HbsAg, HCV antibodies or HIV antibodies at screening.
  • any prescription or nonprescription medication including vitamins, herbal supplements, and mineral supplements
  • Prior/Concurrent Clinical Study Experience Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within at least 1 month, before the planned first dose of study intervention or is currently enrolled in an investigational study. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 1 month after the last dose of study intervention. Plans to father a child while enrolled in this study or within 3 months after the last dose of study intervention. Diagnostic Assessments Had major surgery, (e.g., requiring general anesthesia) within 12 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.
  • major surgery e.g., requiring general anesthesia
  • Study intervention will be taken in the morning on Day 1 of each treatment period with 240 mL of noncarbonated water. Study intervention must be swallowed whole and not chewed, divided, dissolved, or crushed.
  • Participants receiving study intervention in the fed condition will fast overnight (at least 10 hours) followed by the consumption of a high-fat breakfast within a 20-minute period.
  • the high-fat breakfast will be the same on the day of dosing in the fed period (Period 4 for Part 1 and Part 2).
  • Study intervention will be administered approximately 30 minutes after the start of the breakfast.
  • Noncarbonated water will be allowed up to 2 hours before study intervention administration. Participants will continue fasting until at least 4 hours after study intervention administration. At approximately 2 hours after dosing (but not earlier), drinking of water is allowed ad-libitum onwards. A standardized lunch will be served on Day 1 for all participants after collection of the 4-hour PK blood sample. Participant can resume their normal diet after 4 hours.
  • the exact composition of breakfast and the lunch will be recorded.
  • the lunch will be the same in all intervention periods.
  • the exact start and end time of breakfast, as well as the start time of lunch will be recorded, together with any deviation regarding the timing of the meals.
  • Aticaprant will be supplied for this study as 5 mg capsule and 5 mg and 10 mg tablet formulation.
  • All therapies prescription or over-the-counter medications, including vaccines, vitamins, herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special diets, exercise regimens, or other specific categories of interest
  • Recorded information will include a description of the type of therapy, duration of use, dosing regimen, route of administration, and indication. Modification of an effective preexisting therapy should not be made for the explicit purpose of entering a participant into the study.
  • All concomitant therapies that are considered to be a CYP inhibitor or inducer or a transport inhibitor or inducer are disallowed during the study and disallowed for at least 1 month before receiving the first intake of study intervention.
  • Women using hormonal contraceptives as a means of birth control must continue to use the same hormonal contraceptives throughout the study. Women using hormone replacement therapy must continue to use the same hormone replacement therapy throughout the study.
  • Tables 59-60 summarize the frequency and timing of PK measurements applicable to this study.
  • assessments should preferably take place in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse/heart rate), blood/CSF draws for PK or laboratory measurements, and C-SSRS. Blood collections for PK assessments should be kept as close to the specified time as possible. Other measurements may be done earlier than specified timepoints, if needed.
  • the maximum amount of blood drawn from each participant will not exceed 500 mL.
  • the total volume of CSF collected per participant enrolled in CSF PK will not exceed 52.3 mL which is considered to be acceptable considering the daily CSF production rate.
  • Body temperature, pulse/heart rate, respiratory rate, blood pressure will be assessed.
  • Blood pressure and pulse/heart rate measurements will be assessed with a completely automated device consisting of an inflatable cuff and an oscillatory detection system. All values will be registered on a built-in recorder so that measurements are observer-independent. Blood pressure and pulse/heart rate measurements will be recorded after 5 minutes rest in a quiet setting without distractions (e.g., television, cell phones) in a supine position.
  • distractions e.g., television, cell phones
  • participant During the collection of ECGs, participants should be in a quiet setting without distractions (e.g., television, cell phones). Participants should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital sign measurement is scheduled for the same time point as ECG recording, they should preferably take place in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse/heart rate), blood/CSF draws for PK, or laboratory measurements, and C-SSRS.
  • a quiet setting without distractions (e.g., television, cell phones). Participants should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital sign measurement is scheduled for the same time point as ECG recording, they should preferably take place in the following order: 12-lead ECG, vital signs (supine blood pressure, pulse/heart rate), blood/CSF draws for PK, or laboratory measurements, and C-SS
  • the C-SSRS is a measure of the spectrum of suicidal ideation and behavior that was developed to assess severity and track suicidal events through any treatment studies. It is a clinical interview to assess the risk of treatment-emergent suicidal ideation/behavior.
  • a baseline/screening version of the C-SSRS will be completed at screening, and subsequently a since-your-last-visit version of the C-SSRS will be completed predose on Day ⁇ 1, prior to discharge on Day 5 of each treatment period (for Part 1), prior to discharge on Day 6 of each treatment period (for Part 2) and at end-of-study or early withdrawal.
  • Fundoscopy is a form of examination of the fundus of the eye.
  • the WelchAllyn® PanOpticTM Ophthalmoscope (model 11810) is used according to the internal standard operating procedure.
  • Plasma and CSF samples will be used to evaluate the PK of aticaprant.
  • Blood samples (4 mL each) for determination of aticaprant plasma concentrations will be collected at the time points indicated in Tables 59-60.
  • Plasma samples will be analyzed to determine concentrations of aticaprant using a validated, specific, and sensitive Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method.
  • LC-MS/MS Liquid chromatography coupled to tandem mass spectrometry
  • the following plasma PK parameters of aticaprant will be determined.
  • a noncompartmental model with extravascular input will be used for the pharmacokinetic analysis.
  • the intra-participant coefficient of variation (CV) for PK parameters (AUC ⁇ and C max ) is estimated to be between 8.3% and 10.4% for AUC ⁇ and between 14.4% and 24.3% for C max .
  • CV intra-participant coefficient of variation
  • the statistical analysis plan will be finalized prior to DBL and it will include a more technical and detailed description of the statistical analyses described in this section. This section is a summary of the planned statistical analyses of the most important endpoints.
  • Factors that may influence the plasma concentrations e.g., vomiting, high predose concentration
  • Reasons for exclusion of a participant or a sample from the analysis include, but are not limited, to the following:
  • descriptive statistics including arithmetic mean, standard deviation (SD), coefficient of variation (CV), geometric mean, median, minimum, and maximum will be calculated for the aticaprant plasma concentrations at each sampling time and for all PK parameters of aticaprant.
  • the primary objective of the statistical analysis will be to estimate the relative bioavailability of aticaprant test formulations with respect to aticaprant reference formulations, dose proportionality of aticaprant test formulations, and the effect of food on the PK of aticaprant test formulations.
  • the primary parameters of interest for the statistical analysis will be the log-transformed estimated AUCs, AUC last , AUC ⁇ , and C max .
  • the AUC ⁇ will be rejected as primary parameter for a group if more than half of the participants do not have a reliable value. If one of PK parameter of interest is not estimable for a given participant in one or more periods, the participant's data will not be included in the statistical analysis of that particular PK parameter.
  • This study included two parts with similar study design to investigate two different tablet formulation concepts with part 1 (unmilled API tablet) and part 2 (milled API tablet).
  • the evaluations included relative bioavailability of immediate-release tablet formulation (1 ⁇ 10 mg) versus API in capsule formulation (2 ⁇ 5 mg), dose-proportionality between 10 and 5 mg tablet strengths, and food effect assessment at 10 mg of tablet strength.
  • Each part consisted of a subpart A and subpart B with a total of 4 periods.
  • Subpart A was a randomized, open label, 3-way crossover, 3-period study conducted in 24 healthy participants to evaluate the relative bioavailability of a single dose of 10 mg aticaprant administered as 1 ⁇ 10 mg oral tablet under fasted conditions compared to 10 mg aticaprant administered as 2 ⁇ 5 mg oral capsules under fasted conditions and to evaluate the dose proportionality of a single dose of 5 mg aticaprant administered as 1 ⁇ 5 mg oral tablet under fasted conditions compared to the 1 ⁇ 10 mg oral tablet under fasted conditions.
  • the same 24 participants who completed subpart A were enrolled in subpart B which consisted of a fourth period to evaluate the food effect of a single dose of 10 mg aticaprant administered as 1 ⁇ 10 mg oral tablet under fed conditions.
  • the PK analysis results for part 1 including the PK parameters across treatments and statistical comparisons between treatments of interest are shown in Tables 62-65.
  • Table 62 summarizes PK parameters across treatments in Part 1.
  • Table 63 shows the statistical comparison results of the relative bioavailability of a 1 ⁇ 10 mg unmilled API tablet with 2 ⁇ 5 mg API in capsule formulation.
  • Table 64 shows the statistical comparison results of the dose-proportionality between 1 ⁇ 10 mg unmilled API tablet and 1 ⁇ 5 mg unmilled API tablet formulation.
  • Table 65 shows the statistical comparison results of food effect assessment with 1 ⁇ 10 mg unmilled API tablet when administered in the presence of high-fat diet to that of fasted condition.
  • PK parameters were comparable between unmilled API tablet (1 ⁇ 10 mg) and API in capsule (2 ⁇ 5 mg) formulation and the statistical assessment using calculated geometric mean ratios indicated that these two formulations are comparable and within the BE limits of criteria.
  • a dose-proportionality was established between 10 and 5 mg unmilled API tablet formulation strengths based on dose-dependent increase in PK parameters, a comparison of dose-normalized PK parameters and statistical assessment of calculated geometric mean ratios being within BE limits of 0.8 to 1.25.
  • unmilled API tablet formulation showed ⁇ 40% increase in AUC when 10 mg given in the presence of high-fat diet compared to fasted condition administration as evident from geometric mean ratio calculated for AUC.
  • Tables 66-73 The PK analysis results for part 2 (milled API tablet formulation) including the PK parameters across treatments and statistical comparisons between treatments of interest are shown in Tables 66-73.
  • Table 70 summarizes PK parameters across treatments in Part 2.
  • Table 71 shows the statistical comparison results of the relative bioavailability of a 1 ⁇ 10 mg milled API tablet with 2 ⁇ 5 mg API in capsule formulation.
  • Table 72 shows the statistical comparison results of the dose-proportionality between 1 ⁇ 10 mg milled API tablet and 1 ⁇ 5 mg milled API tablet formulation.
  • Table 73 shows the statistical comparison results of food effect assessment with 1 ⁇ 10 mg milled API tablet when administered in the presence of high-fat diet to that of fasted condition.
  • PK parameters were comparable between milled API tablet (1 ⁇ 10 mg) and API in capsule (2 ⁇ 5 mg) formulation and the statistical assessment using calculated geometric mean ratios indicated that these two formulations are comparable and within the BE limits of criteria.
  • a dose-proportionality was established between 10 and 5 mg milled API tablet formulation strengths based on dose-dependent increase in PK parameters, a comparison of dose-normalized PK parameters and statistical assessment of calculated geometric mean ratios being within BE limits of 0.8 to 1.25.
  • milled API tablet formulation showed ⁇ 30% increase in AUC when 10 mg given in the presence of high-fat diet compared to fasted condition administration as evident from geometric mean ratio calculated for AUC.
  • both the milled and unmilled API tablet formulations of 1 ⁇ 10 mg showed similar comparable exposures for aticaprant as those were observed with 10 mg reference API in capsule formulation (2 ⁇ 5 mg API in capsules) and were bioequivalent.
  • a dose-proportionality was observed between 10 and 5 mg tablet formulation strengths of each of the tablet formulation concepts of unmilled and milled API.
  • a modest food effect of ⁇ 30% (milled API tablet) and ⁇ 40% (unmilled API tablet) increase in AUC was observed at 10 mg with a slightly delayed median T max of 2.00 hours (milled API tablet) and 2.75 hours (unmilled API tablet) in presence of high-fat diet vs. 1.5 hours in the fasted condition administration.
  • a 40% food effect is not considered clinically relevant for many drugs given it is part of PK variability and no safety concerns exist at higher aticaprant exposures. Aticaprant can therefore be administered with or without food.
  • 1 ⁇ 10 mg unmilled API tablet concept may show similar exposures for aticaprant as those were observed with 10 mg reference API in capsule formulation (2 ⁇ 5 mg API in capsules)
  • Dose-proportionality may be observed between 1 ⁇ 10 mg unmilled API tablet vs. 1 ⁇ 5 mg unmilled API tablet
  • Treatment F 1 ⁇ 10 mg Formulation Concept 2 administered in the morning, after at least 10-hour overnight fasting (Reference)
  • Treatment G 1 ⁇ 5 mg Formulation Concept 2 administered in the morning, after at least 10-hour overnight fasting (Test)
  • Treatment G Dose Normalized to 10 mg Participants 100029 (incomplete PK profile) and 100031 (vomiting) from treatment F were excluded from the analysis.

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