WO2023170554A1 - Compositions comprising aticaprant - Google Patents

Compositions comprising aticaprant Download PDF

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Publication number
WO2023170554A1
WO2023170554A1 PCT/IB2023/052097 IB2023052097W WO2023170554A1 WO 2023170554 A1 WO2023170554 A1 WO 2023170554A1 IB 2023052097 W IB2023052097 W IB 2023052097W WO 2023170554 A1 WO2023170554 A1 WO 2023170554A1
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WIPO (PCT)
Prior art keywords
aticaprant
treatment
weight
pharmaceutical composition
placebo
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Ceased
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PCT/IB2023/052097
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English (en)
French (fr)
Inventor
Nicolaas Martha Felix Goyvaerts
Mark Schmidt
Vanina Popova
Adam J. SAVITZ
Rama Melkote
Wayne C. Drevets
MD 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 Pharmaceuticals Inc
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Publication date
Priority to JP2024553421A priority Critical patent/JP2025508069A/ja
Priority to CN202380038806.7A priority patent/CN119156202A/zh
Priority to EP23716356.3A priority patent/EP4489730B1/en
Priority to AU2023231767A priority patent/AU2023231767A1/en
Priority to KR1020247033299A priority patent/KR20240152410A/ko
Application filed by Janssen Pharmaceuticals Inc filed Critical Janssen Pharmaceuticals Inc
Priority to IL315415A priority patent/IL315415A/en
Priority to CA3254546A priority patent/CA3254546A1/en
Publication of WO2023170554A1 publication Critical patent/WO2023170554A1/en
Priority to JOJO/P/2024/0196A priority patent/JOP20240196A1/ar
Priority to MX2024010977A priority patent/MX2024010977A/es
Anticipated expiration legal-status Critical
Priority to CONC2024/0012454A priority patent/CO2024012454A2/es
Ceased 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

  • J&J Ref JPI6063WOPCT1 COMPOSITIONS COMPRISING ATICAPRANT CROSS REFERENCE TO RELATED APPLICATION
  • This application claims the benefit of U.S. Provisional Application 63/317,471 filed on March 7, 2022.
  • TECHNICAL FIELD [0002] The present disclosure relates to compositions, including oral compositions, comprising aticaprant and methods of using the same.
  • Kappa opioid receptors (KOR) 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.
  • 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).
  • 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.
  • 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 10mg): (a) a mean Cmax between about 20 and 45 ng/mL; (b) a mean AUCinfinity 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 tmax 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 -2- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1 300 and 430 h*ng/mL; (c) a mean AUC last between about 280 and 430 h*ng/mL; and (d) a median tmax 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.
  • 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.
  • 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.
  • 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. -3- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1
  • 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. In this figure, a refers to microfine, i.e., milled aticaprant. -4- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1
  • 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. In this figure and going from top to bottom, the bars alternatively refer to placebo or aticaprant. For example, 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. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS -5- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1 [0046] All individual features (e.g., particular embodiments or specific preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including particular embodiment or preferred feature) mentioned herein; hence, preferred features may be taken in conjunction with other preferred features, or independently of them (and likewise with particular embodiments).
  • 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.
  • Characterization of crystalline forms may be performed by those skilled in the art including, without limitation, XRPD or DSC.
  • 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.
  • 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.
  • the term “anhydrous” or “anhydrate” as used herein refers to a crystalline as described herein that substantially lacks water. In some aspects, an anhydrous form contains less than about 1% w/w of water.
  • an anhydrous form contains less than about 0.9%, -6- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1 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.
  • all temperature values may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, and/or laboratory conditions. Unless otherwise defined, a recited temperature may vary. In some aspects, the temperatures noted herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°. [0053] Similarly, 2 ⁇ values obtained from the XRPD patterns also may vary.
  • the XRPD patterns and/or the 2 ⁇ peak values may vary.
  • the 2 ⁇ peak values vary (higher or lower) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.
  • one or more of the 2 ⁇ peak values are higher by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.
  • 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.
  • the term “aticaprant” refers to 3-fluoro- 4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, i.e., the following compound: -7- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1 . CERC-501, and LY-2456302.
  • “aticaprant” refers to the (S)-enantiomer of aticaprant, i.e., the following compound: . 2-(3,5-dimethylphenyl)pyrrolidin-1-yl- methylphenoxybenzamide.
  • 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: . contains less than about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant.
  • 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 -8- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1 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.
  • Pharmaceutically acceptable salts 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. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
  • Examples of pharmaceutically acceptable salts are 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, methylbenzo
  • 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°, -9- 4879-5314-2357.1 J&J Ref: JPI6063WOPCT1 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 by an x-ray powder diffraction pattern that corresponds to Fig.1. [0060] Crystalline Form III of aticaprant may also be characterized by differential scanning calorimetry.
  • the differential scanning calorimetry thermogram comprises a peak temperature (Tm) at about 121°C.
  • crystalline Form III of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.2.
  • compositions 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. [0062]
  • 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.
  • 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. In yet other embodiments, 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.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • Some embodiments include pharmaceutical 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).
  • 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 Cmax 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).
  • 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 J&J Ref: JPI63WOPCT1 (dose-normalized to 10 mg) when administered after at least a 10-hour fast.
  • the PK profile includes a Cmax 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 AUCinfinity 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 tmax 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.
  • 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.
  • 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 0.0501/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 Cmax 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 J&J Ref: JPI63WOPCT1 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 AUCinfinity 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 AUCinfinity 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 AUClast 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 AUClast 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 J&J Ref: JPI63WOPCT1 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 425,
  • the PK profile has a mean AUC last of between about 280 and 310 h*ng /mL (dose-normalized to 10 mg).
  • the pharmaceutical composition has a PK profile comprising a median tmax between about 1 to 4 hours.
  • the median tmax 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. [0079] In some embodiments, 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 Cmax 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 J&J Ref: JPI63WOPCT1 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.
  • the pharmaceutical composition has a PK profile comprising a median tmax of about 1.5 hours when administered after at least a 10-hour fast. [0085] In some embodiments, the pharmaceutical composition has a PK profile comprising a median tmax 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 tmax 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. [0086] As noted, 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. In other embodiments, the filler is microcrystalline cellulose. In further embodiments, the filler is lactose monohydrate. In yet other embodiments, the filler is silicified microcrystalline J&J Ref: JPI63WOPCT1 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 composition comprises about 90% by weight, based on the weight of the composition, of the filler. In other embodiments, the composition comprises about 88.5% by weight, based on the weight of the composition, of the filler.
  • 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.
  • 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 7, 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 J&J Ref
  • the aticaprant to filler ratio is about 0.056 by weight.
  • 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. Examples of 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, J&J Ref: JPI63WOPCT1 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 aticaprant to disintegrant ratio is about 5 by weight. In other embodiments, the aticaprant to disintegrant ratio is about 1 by weight.
  • 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 J&J Ref: JPI63WOPCT1 3 to about 9, about 3 to about 8, about 3 to about 7, about 6 about 6 about 3
  • 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 aticaprant to glidant ratio is about 5 by weight.
  • 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 J&J Ref: JPI63WOPCT1 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 aticaprant to lubricant ratio is about 10 by weight.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • 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 1, about 0.1 J&J Ref: JPI63WOPCT1
  • 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 J&J Ref: JPI63WOPCT1 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.
  • 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 10 to about 80,
  • 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. [00101]
  • 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 J&J Ref: JPI63WOPCT1 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
  • the intragranular phase comprises an aticaprant to filler ratio of about 0.08 by weight.
  • 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. [00103]
  • the intragranular phase may further contain a glidant. In some embodiments, the intragranular phase contains about 0.1 to about 5 mg of a glidant. In other embodiments, 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. In further embodiments, the intragranular phase contains about 1 mg of silica, colloidal anhydrous. [00104]
  • 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 J&J Ref: JPI63WOPCT1 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 16, about 2 to about 4, about
  • the intragranular phase comprises an aticaprant to disintegrant ratio of about 2 by weight.
  • 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.
  • J&J Ref JPI63WOPCT1
  • 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. In further embodiments, 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. [00108]
  • the extragranular phase may additionally contain a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In other embodiments, 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 J&J Ref: JPI63WOPCT1 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 10, about 4 to about 9,
  • 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. [00109]
  • 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 J&J Ref: JPI63WOPCT1 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. In further embodiments, the extragranular phase contains about 0.5 mg of silica, colloidal anhydrous. In yet other embodiments, the extragranular phase contains about 1 mg of silica, colloidal anhydrous. [00111]
  • 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 J&J Ref: JPI63WOPCT1 about 0.5 mg of a lubricant.
  • the extragranular phase contains about 1 mg of a lubricant. In further embodiments, the extragranular phase contains about 0.5 mg of magnesium stearate. In yet other embodiments, the extragranular phase contains about 1 mg of magnesium stearate. [00113]
  • 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. In further embodiments, the extragranular phase comprises a filler to glidant ratio of about 57 by weight. In yet other embodiments, 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.
  • J&J Ref JPI63WOPCT1
  • 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. In other embodiments, 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 is about 100 mg. In still further embodiments, the oral tablet comprises a core tablet of about 200 mg. [00118] In some aspects, the core tablet contains a disintegrant. For example, the core tablet contains about 5 to about 100 mg of a disintegrant. In some embodiments, 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.
  • the core tablet contains about 1 mg of the glidant. In yet other embodiments, the core tablet contains about 2 mg of the glidant. [00120] In further aspects, the core tablet contains a lubricant. For example, the core tablet contains about 0.5 to about 100 mg of a lubricant. In some embodiments, 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 about 0.5 mg of the lubricant. In yet other embodiments, the core tablet contains about 1 mg of the lubricant. J&J Ref: JPI63WOPCT1 [00121] In further aspects, the core tablet contains a filler. For example, the core tablet contains about 1 to about 200 mg of a filler. In some embodiments, 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 200m, 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 about
  • the core tablet contains about 88.5 mg of the filler. In yet other embodiments, the core tablet contains about 177 mg of the filler. J&J Ref: JPI63WOPCT1 [00122]
  • 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, J&J Ref: JPI63WOPCT1 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.
  • 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. In some embodiments, 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.
  • J&J Ref JPI63WOPCT1 [00130]
  • 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.
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • 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 J&J Ref: JPI63WOPCT1 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.
  • 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.
  • 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 is for oral administration.
  • the instructions for treatment direct aticaprant, in particular S-aticaprant is for once daily administration.
  • 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).
  • ASEX Arizona Sexual Experience Scale
  • the patient has anhedonia. In certain aspects, the anhedonia is moderate. In other aspects, the anhedonia is severe. Anhedonia can be measured, through an anhedonia scale, for example, the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Snaith 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).
  • J&J Ref: JPI63WOPCT1 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).
  • Treatment 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.
  • 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.
  • 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. In particular embodiments, the patients treated according to the described methods have moderate to severe anhedonia.
  • anhedonia 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 J&J Ref: JPI63WOPCT1 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.
  • 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 J&J Ref: JPI63WOPCT1 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., a SHAPS score of less than 38.
  • the patient’s anhedonia is reduced from a high level of anhedonia to a low level of anhedonia.
  • 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.
  • 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 toa bout 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. In doing so, 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 J&J Ref: JPI63WOPCT1 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.
  • the patient’s anhedonia is reduced after about 3 weeks of treatment with aticaprant.
  • 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 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. J&J Ref: JPI63WOPCT1
  • the patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.
  • the patient is an adult.
  • 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.
  • the terms “treating”, “treatment” and the like 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. Table 4 1.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • Psychomotor agitation or retardation Nearly every day and observable by others (not merely subjectively restless or slow) 6. Fatigue: Or loss of energy, nearly every day 7.
  • 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).
  • “Moderate MDD” applies to a patient having a number of symptoms, intensity of symptoms, and/or functional impairment are between those J&J Ref: JPI63WOPCT1 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.
  • Table 5 DSM-5 Criteria for MDD 1. Depressed Mood At least 1 2. Loss of interest/pleasure (anhedonia) 1. Weight loss or gain At least 5 2. Sleep problems 3. Psychomotor agitation or retardation 4. Guilt or worthlessness 5. Decreased concentration 6. Suicidality 7. Fatigue 1. Symptoms cause significant distress or impairment Must have all 4 2. Not attributable to medical condition 3. Exclude schizophrenia disorders 4.
  • MADRS Montgomery– ⁇ 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 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).
  • SIGMA Structured Interview Guide for the MADRS
  • 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.
  • 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”).
  • 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.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • MGH-ATRQ an inadequate response to MGH-ATRQ.
  • 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).
  • Examples of 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.
  • phenothiazines e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, J&J Ref: JPI63WOPCT1 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
  • 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. In some embodiments, 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.
  • 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.
  • J&J Ref JPI63WOPCT1
  • the patient was receiving treatment with other antidepressant therapy prior to receiving aticaprant.
  • the patient was receiving treatment with other antidepressant therapy that comprised a SSRI, SNRI, or a combination thereof.
  • the patient stopped treatment with other antidepressant therapy before initiating treatment with aticaprant.
  • Also encompassed by the methods described herein include adjunctive treatment with an effective amount of one or more antidepressants.
  • the term “adjunctive 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.
  • 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. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in) intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal. In some embodiments, aticaprant is administered orally.
  • Treatment with aticaprant as described herein has several advantages over the treatments in the art.
  • the patient does not experience many of the J&J Ref: JPI63WOPCT1 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%.
  • 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). 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).
  • Other scales may be utilized to determine the effectiveness of the methods used herein to treat the patient. Examples include the Cognitive and Physical Functioning Questionnaire (CPFQ), Karolinska Sleepiness Scale (KSS), and Temporal Experience of Pleasure Scale (TEPS).
  • CPFQ is a brief self-report scale that provides additional J&J Ref: JPI63WOPCT1 information regarding the impact of adjunctive treatment on aspects of cognitive and executive function including attention, memory and mental acuity.
  • 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.
  • Embodiments are utilized in an effective amount as determined by the attending physician. In other embodiments, other antidepressant(s) is utilized in an effective amount either separately or in combination with aticaprant.
  • Embodiments The invention provides also the following non-limiting embodiments: Embodiment 1 is a pharmaceutical composition 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.
  • Embodiment 2 is the pharmaceutical composition of Embodiment 1, further comprising one or more of: a disintegrant, a glidant, a lubricant, a solvent, a coloring agent, and a binder.
  • Embodiment 3 is the pharmaceutical composition of Embodiment 1 or 2, wherein the composition comprises between about 10% to about 99.9% filler by weight.
  • Embodiment 4 is the pharmaceutical composition of any one of Embodiments 1-3, wherein the composition comprises a disintegrant.
  • Embodiment 5 is the pharmaceutical composition of Embodiment 4, wherein the composition comprises between about 0.5% to about 50% disintegrant by weight.
  • Embodiment 6 is the pharmaceutical composition of any one of Embodiments 1-5, wherein the composition comprises a glidant.
  • Embodiment 7 is the pharmaceutical composition of Embodiment 6, wherein the composition comprises between about 0.1% to about 10% glidant by weight.
  • Embodiment 8 is the pharmaceutical composition of any one of Embodiments 1-7, wherein the composition comprises a lubricant.
  • Embodiment 9 is the pharmaceutical composition of Embodiment 8, wherein the composition comprises between about 0.05% to about 5% lubricant by weight.
  • Embodiment 10 is the pharmaceutical composition of any one of Embodiments 1-9, wherein 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.
  • Embodiment 11 is the pharmaceutical composition of any one of Embodiments 1-10, wherein the composition 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.
  • Embodiment 12 is the pharmaceutical composition of any one of Embodiments 1-11, wherein the composition is an oral tablet.
  • Embodiment 13 is the pharmaceutical composition of Embodiment 12, wherein the oral tablet is a film coated oral tablet comprising (a) a core tablet and (b) a film coat.
  • Embodiment 14 is the pharmaceutical composition of Embodiment 13, wherein the ratio of the film coat to core tablet is between about 0.03 to 10 by weight.
  • Embodiment 15 is the pharmaceutical composition of Embodiment 13 or 14, wherein the film coat comprises a coating powder.
  • Embodiment 16 is the pharmaceutical composition of any one of Embodiments 13-15, wherein the core tablet comprises an intragranular and an extragranular phase.
  • Embodiment 17 is the pharmaceutical composition of Embodiment 16, wherein the ratio of intragranular to extragranular phase in the core tablet is between about 1.5 and 3.
  • Embodiment 18 is the pharmaceutical composition of Embodiment 16, wherein the intragranular phase comprises aticaprant, a filler, a disintegrant, and a glidant.
  • Embodiment 19 is the pharmaceutical composition of Embodiment 18, wherein 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.
  • Embodiment 20 is the pharmaceutical composition of Embodiment 16 or 17, wherein the extragranular phase comprises a filler, a disintegrant, a glidant, and a lubricant.
  • Embodiment 21 is the pharmaceutical composition of Embodiment 20, wherein 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.
  • Embodiment 22 is the pharmaceutical composition of any one of Embodiments 13-21, wherein the film coated oral tablet comprises about 97% core tablet by weight and about 3% film coat by weight and wherein 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.
  • Embodiment 23 is the pharmaceutical composition of any one of Embodiments 1-22, wherein the composition is an oral tablet comprising a core tablet of about 100 mg, the core tablet comprising about 5 mg aticaprant, about 5 mg disintegrant, about 88.5 mg filler, about 1 mg glidant, and about 0.5 mg lubricant.
  • Embodiment 24 is the pharmaceutical composition of Embodiment 23, further comprising about 3 mg of film coat.
  • Embodiment 25 is the pharmaceutical composition of any one of Embodiments 1-24, wherein the composition is an 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.
  • Embodiment 26 is the pharmaceutical composition of Embodiment 25, further comprising about 6 mg of film coat.
  • Embodiment 27 is the pharmaceutical composition of any of Embodiments 1-26, wherein the filler is selected from: microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose.
  • Embodiment 28 is the pharmaceutical composition of any of Embodiments 2-27, wherein the disintegrant is croscarmellose sodium.
  • Embodiment 29 is the pharmaceutical composition of any of Embodiments 2-28, wherein the glidant is silica, colloidal anhydrous.
  • Embodiment 30 is the pharmaceutical composition of any of Embodiments 2-29, the lubricant is magnesium stearate.
  • Embodiment 31 is the pharmaceutical composition of any of Embodiments 15-30, wherein the coating powder is Opadry II Orange.
  • Embodiment 32 is an oral tablet 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.
  • Embodiment 33 is the oral tablet of Embodiment 32, further comprising about 3 mg film coat.
  • Embodiment 34 is the oral tablet of Embodiment 33, wherein the film coat comprises Opadry II Orange.
  • Embodiment 35 is an oral tablet 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.
  • Embodiment 36 is the oral tablet of Embodiment 35, further comprising 3 mg film coat.
  • Embodiment 37 is the oral tablet of Embodiment 36, wherein the film coat comprises Opadry II Orange.
  • Embodiment 38 is a pharmaceutical composition comprising between about 2mg 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 Cmax between about 30 and 40 ng/mL ; b. a mean AUC infinity between about 300 and 430 h*ng/mL; c.
  • PK pharmacokinetic
  • Embodiment 39 is the pharmaceutical composition of Embodiment 38, wherein the mean Cmax is between about 30 and 35 ng/mL.
  • Embodiment 40 is the pharmaceutical composition of Embodiment 38 or 39, wherein the mean AUCinfinity is between about 300 and 320 h*ng/mL.
  • Embodiment 41 is the pharmaceutical composition of any one of Embodiments 38-40, wherein the mean AUClast is between about 280 and 310 h*ng/mL.
  • Embodiment 42 is the pharmaceutical composition of any one of Embodiments 38-41, wherein the median t max is about 1.5 hours.
  • Embodiment 43 is the pharmaceutical composition of any one of Embodiments 38-42, wherein the composition is an oral tablet.
  • Embodiment 44 is the pharmaceutical composition of any one of Embodiments 38-43, wherein the composition further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
  • Embodiment 45 is the pharmaceutical composition of any one of Embodiments 38-44, wherein the composition comprises between about 0.1% and 90% aticaprant by weight.
  • Embodiment 46 is the pharmaceutical composition of any one of Embodiments 38-45, wherein the composition comprises about 5 mg aticaprant or about 10 mg aticaprant.
  • Embodiment 47 is the pharmaceutical composition of any one of Embodiments 38-46, wherein 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.
  • Embodiment 48 is the pharmaceutical composition of any one of Embodiments 38-47, wherein the composition wherein the composition 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.
  • Embodiment 49 is a method 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: e. a mean C max between about 30 and 40 ng/mL; f. a mean AUCinfinity between about 300 and 430 h*ng/mL; g.
  • MDD major depressive disorder
  • Embodiment 50 is the method of Embodiment 49, wherein the mean C max is between about 30 and 35 ng/mL.
  • Embodiment 51 is the method of Embodiment 49 or 50, wherein the mean AUCinfinity is between about 300 and 320 h*ng/mL.
  • Embodiment 52 is the method of any one of Embodiments 49-51, wherein the mean AUClast is between about 280 and 310 h*ng/mL.
  • Embodiment 53 is the method of any one of Embodiments 49-52, wherein the median t max is about 1.5 hours.
  • Embodiment 54 is the method of any one of Embodiments 49-53, wherein the composition is an oral tablet.
  • Embodiment 55 is the method of any one of Embodiments 49-54, wherein the composition further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
  • Embodiment 56 is the method of any one of Embodiments 49-55, wherein the composition comprises between about 0.1% and 90% aticaprant by weight.
  • Embodiment 57 is the method of any one of Embodiments 49-56, wherein the composition comprises between about 10% and 99.9% filler by weight.
  • Embodiment 58 is the method of any one of Embodiments 49-57, wherein 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.
  • Embodiment 59 is the method of any one of Embodiments 49-58, wherein the composition wherein the composition 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.
  • Embodiment 60 is the method of any one of Embodiments 49-59, wherein the patient has anhedonia.
  • Embodiment 61 is the method of any one of Embodiments 49-60, wherein the pharmaceutical composition comprises about 5 mg aticaprant.
  • Embodiment 62 is the method of any one of Embodiments 49-60, wherein the pharmaceutical composition comprises about 10 mg aticaprant.
  • Embodiment 63 is the method of any one of Embodiments 49-60, wherein the other antidepressant therapy comprised one or more antidepressants.
  • Embodiment 64 is the method of Embodiment 63, wherein the one or more antidepressants comprised a SSRI, SNRI, or a combination thereof.
  • Embodiment 65 is the method of any one of Embodiments 49-64, wherein the aticaprant is S- aticaprant.
  • Embodiment 66 is the method of any one of Embodiments 49-65, further comprising treatment with an effective amount of one or more antidepressants.
  • Embodiment 67 is the method of Embodiment 66, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
  • Embodiment 68 is the method of any one of Embodiments 49-67, wherein the pharmaceutical composition comprising aticaprant is administered once daily.
  • Embodiment 69 is a solid pharmaceutical composition 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.
  • Embodiment 70 is the solid pharmaceutical composition of Embodiment 69, wherein the composition comprises about 5 mg or about 10 mg aticaprant.
  • Embodiment 71 is the solid pharmaceutical composition of Embodiment 69 or 70, wherein the Q value is between about 70% and 80% at 45 minutes.
  • Embodiment 72 is the solid pharmaceutical composition of Embodiment 71, wherein the Q value is about 75% at 45 minutes.
  • Embodiment 73 is the solid pharmaceutical composition of any one of Embodiments 69-72, wherein the composition is an oral tablet.
  • Embodiment 74 is the solid pharmaceutical composition of any one of Embodiments 69-73, wherein the composition further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
  • Embodiment 75 is the solid pharmaceutical composition of any one of Embodiments 69-74, wherein the composition comprises between about 0.1% and 90% aticaprant by weight.
  • Embodiment 76 is the solid pharmaceutical composition of any one of Embodiments 69-75, wherein the composition comprises between about 10% and 99.9% filler by weight.
  • Embodiment 77 is the solid pharmaceutical composition of any one of Embodiments 69-76, wherein 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.
  • Embodiment 78 is the solid pharmaceutical composition of any one of Embodiments 69-77, wherein the composition wherein the composition 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.
  • Embodiment 79 is a method of treating major depressive disorder (MDD) in a human patient comprising administering to the patient the pharmaceutical composition of any one of Embodiments 1-32 or 38-48, the oral tablet of any of Embodiments 33-37, or the solid pharmaceutical composition of any of Embodiments 69-78.
  • Embodiment 80 is a method of Embodiment 79, wherein the patient has anhedonia.
  • Embodiment 81 is the method of any one of Embodiments 79-80, wherein the pharmaceutical composition, the oral tablet, or the solid pharmaceutical composition comprises about 5 mg aticaprant.
  • Embodiment 82 is the method of any one of Embodiments 79-81, wherein the pharmaceutical composition, the oral tablet, or the solid pharmaceutical composition comprises about 10 mg aticaprant.
  • Embodiment 83 is the method of any one of Embodiments 79-82, wherein the patient had an inadequate response to other antidepressant therapy prior to the treatment with aticaprant.
  • Embodiment 84 is the method of Embodiment 83 wherein the other antidepressant therapy comprised one or more antidepressants.
  • Embodiment 85 is the method of Embodiment 84, wherein the one or more antidepressants comprised a SSRI, SNRI, or a combination thereof.
  • Embodiment 86 is the method of any one of Embodiments 79-85, wherein the aticaprant is S- aticaprant.
  • Embodiment 87 is the method of any one of Embodiments 79-86, further comprising treatment with an effective amount of one or more antidepressants.
  • Embodiment 88 is the method of Embodiment 87, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
  • Embodiment 89 is the method of any one of Embodiments 79-88, wherein the pharmaceutical composition, the oral tablet, or the solid pharmaceutical composition comprising aticaprant is administered once daily.
  • Embodiment 90 is a method of treating major depressive disorder in a human patient, comprising administering a pharmaceutical composition comprising aticaprant and one or more pharmaceutically acceptable excipients to the human patient, wherein the patient had a previous inadequate response to other antidepressant therapy and wherein the pharmaceutical composition is administered orally once daily with or without food.
  • Embodiment 91 is the method of Embodiment 90, wherein the pharmaceutical composition is an oral tablet.
  • Embodiment 92 is the method of Embodiment 90 or 91, wherein the pharmaceutical composition comprises about 5 mg to 10 mg aticaprant, about 5 mg aticaprant, or about 10 mg aticaprant.
  • Embodiment 93 is the method of any one of Embodiments 90-92 wherein the other antidepressant therapy comprised one or more antidepressants.
  • Embodiment 94 is the method of Embodiment 93, wherein the one or more antidepressants comprised a SSRI, SNRI, or a combination thereof.
  • Embodiment 95 is the method of any one of Embodiments 90-94, wherein the aticaprant is S- aticaprant or the aticaprant is crystalline aticaprant.
  • Embodiment 96 is the method of any one of Embodiments 90-95, further comprising treatment with an effective amount of one or more antidepressants.
  • Embodiment 97 is the method of Embodiment 96, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
  • Embodiment 98 is the method of any one of Embodiments 90-97, wherein the patient has anhedonia, optionally moderate to severe anhedonia.
  • Embodiment 99 is the method of any one of Embodiments 90-98, wherein the pharmaceutical composition comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
  • Embodiment is 100 is the method of Embodiment 99, wherein the filler is selected from: microcrystalline cellulose, lactose monohydrate, and silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is silica, colloidal anhydrous; and the lubricant is magnesium stearate.
  • Embodiment 101 is the method of any one of Embodiments 90-100, wherein the pharmaceutical composition comprises between about 0.1% and 90% aticaprant by weight.
  • Embodiment 102 is the method of any one of Embodiments 90-101, wherein the pharmaceutical composition comprises between about 10% and 99.9% filler by weight.
  • Embodiment 103 is the method of any one of Embodiments 90-102, wherein the pharmaceutical composition is a film coated oral tablet, comprising (i) a film coat and (ii) a core tablet, wherein 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.
  • Embodiment 104 is the method of wherein the film coated oral tablet comprises about 97% core tablet by weight and about 3% film coat by weight.
  • Embodiment 105 is the method of any one of Embodiments 90-104, wherein the pharmaceutical composition is an oral tablet 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.
  • 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.
  • Table 7 Additional D8 XRPD methods 4 Min t M th d [00184] PAN [00185] 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.
  • Table 8 HPLC method for chemical purity determinations Parameter Val e J&J Ref: JPI63WOPCT1 T imetable 0 95 5 6 5 95 62 95 5 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.
  • Example 3 Preparation of Pure Aticaprant L/mol of 2-MeTHF. Add 2.39 L/mole n heptane. Stir the contents of the reactor. Adjust temperature to 42 °C and stir for minimum 10 minutes until full dissolution. Filter the solution over a polish filter into a crystallization reactor to remove insoluble matter that might be present. Rinse the polish filter. Stir for minimum 10 minutes at 40 °C. Cool to 20 °C over minimum 1 hour. Stir for minimum 10 minutes at 20 °C. Dose 1.23 L/mol n-heptane over a minimum 30 minutes at 20 °C. Stir for a minimum 10 minutes at 20°C.
  • Table 10 Qualitative and Quantitative Composition of the Aticaprant Tablet Component Quantity (mg/tablet) Quantity (mg/tablet) p p g g [00207] 1. Mix the following, screened components in a blend using a suitable blender: [00208] a. Aticaprant or aticaprant microfine [00209] b. Microcrystalline cellulose [00210] c. Silica, colloidal anhydrous [00211] d. Lactose monohydrate [00212] 2. Screen the blend using a suitable screen. J&J Ref: JPI63WOPCT1 [00213] 3. Add the following screened components to the blend. Mix further using a suitable blender: [00214] a.
  • Example 5 Testing of Tablets Containing Aticaprant
  • 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 0.01 M hydrochloric acid Characteristic Criteria J&J Ref: JPI63WOPCT1 - Reference solutions stored in clear 101% volumetric flasks at ambient conditions, 8 Tblt 1 Tblt 2 Tblt 3 Tblt 4 Tblt 5 Tblt 6 a Risk Based Predictive Stability (RiBPS) study.
  • RhBPS Risk Based Predictive Stability
  • Table 14 Storage Conditions and Testing Frequency for the Accelerated Stability Study / Table 15 ° 0 H J&J Ref: JPI63WOPCT1 14 days -- A A A -- A a A A A 21 days A b A A A A A a A A -- -- [00238]
  • the ICH stability protocol for is presented in Table 16.
  • Table 16 Storage Conditions and Testing Frequency for Stability Study Long Term Storage Conditions Accelerated/Stress Conditions [00239] During the RiBPS study, 3 main degradation products (RRT 0.399, RRT 0.466, and RRT 0.874) showed an increasing trend over the storage period.
  • Aticaprant was evaluated as an adjunctive therapy; therefore, eligible subjects were maintained on their SSRI/SNRI treatment without change throughout the study. At least 50% of recruited subjects had to be anhedonic (as measured by SHAPS total score ⁇ 20).
  • 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: i.
  • Aticaprant To investigate the effect of aticaprant on symptoms of depression using the Clinical Global Impression-Severity (CGI-S), the patient reported Symptoms of Major Depressive Disorder Scale (SMDDS) and the self-assessment of treatment experience (SATE). v. To investigate the effect of aticaprant on symptoms of anxiety using the HAM-A and on core symptoms of anxiety using the HAM-A6 subscale. vi. To assess the plasma PK of aticaprant in subjects with MDD and explore its relationship with efficacy and safety parameters. [00246] Secondary exploratory objectives include: i. To explore the effect of aticaprant on aspects of cognitive and executive function using the CPFQ. ii.
  • 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.
  • Double-Blind Treatment Phase 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. At Visits 3, 4 and 5, the subjects were re-randomized to blind subjects the duration of the placebo lead-in period. During the double-blind phase, the subjects visited the center for out- patient visits every 1 to 2 weeks. See, Table 17.
  • Table 17 Time and Events Schedule Phase Screenin a g Double-blind treatment phase Visit number 1 2 3 4 5 6 7 8 9 1 b 11 0 or EW Week (end of) -5 to 0 0 1 2 3 4 6 7 8 9 11 Day -35 to -2 1 8 1 22 29 43 50 57 64 78 5 Safety assessments Physical and X X X X X neurological J&J Ref: JPI63WOPCT1 examination ASEX X X X X X KSS X X X X X X X Suicidality by C-SSRS X X X X Dosing Randomization Supply new medication X Oral dose medication d 2 until and e including Day 78 Meal after dosing l l l l l l X X X X X Clinical Assessments Structured Interview X j X X X X X X X X X X X X Guide MADRS Structured Interview X X
  • Visits should be conducted ⁇ 3 days of the scheduled day (based on Visit 2, not based on previous visit). b. If a subject discontinues treatment before the end of the double-blind treatment phase, 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. e. When Visit 11 is planned up to 3 days later, continue medication. 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.
  • Withdrawal period Subjects who completed the double-blind treatment period prior to the end of Week 11 entered the withdrawal period where they were treated with placebo for the remaining time of the treatment phase. [00257] C.
  • 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. [00259] When 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. [00261] The first dose was taken in fasting condition on Day 2 of the double-blind phase. The dose of the medication was: • 10 mg aticaprant: 2 capsules of 5 mg aticaprant • Placebo: 2 placebo capsules. [00262] 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: • 5 mg aticaprant: 1 capsule of 5 mg aticaprant • Placebo: 1 placebo capsule.
  • 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.
  • Treatment duration T he 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.
  • Primary analysis set for efficacy 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.
  • Secondary analysis set for efficacy 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.
  • Analysis set for safety 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 efficacy endpoints were presented for both the eITT and the fITT.
  • Level of significance The analysis of primary efficacy endpoint was performed at a significance level of 0.20 (one-sided).
  • the analysis of secondary efficacy J&J Ref JPI63WOPCT1 endpoints was performed at a significance level of 0.20 (two-sided). No adjustment for multiple comparisons was performed.
  • F F.
  • Table 20 Summary of Baseline Psychiatry Rating Scales at the Start of the Lead-in and Treatment Periods; eITT Analysis Set MADRS SHAPS Total Score Total Score N Mean Median N Mean Median (SD) (Range) (SD) (Range) Lead-in Baseline Placebo 61 33.4 (4.25) 34.0 (26; 42) 61 38.0 (6.28) 38.0 (22; 55) Aticaprant 60 32.5 (4.18) 32.0 (25; 45) 60 38.3 (5.66) 38.0 (21; 53) Total 121 32.9 (4.22) 33.0 (25; 45) 121 38.1 (5.96) 38.0 (21; 55) Treatment Baseline Placebo 61 29.2 (5.47) 29.0 (19; 41) 61 36.8 (5.75) 37.0 (23; 50) Aticaprant 60 28.7 (3.58) 28.5 (21; 36) 60 36.4 (5.16) 36.5 (20; 49) Total 121 29.0 (4.61) 29.0 (19; 41) 121 36.6 (5.45) 37.0
  • Negative change to Placebo indicates favorable aticaprant effect. Negative effect size favors aticaprant; positive effect size favors Placebo.
  • the effect size was 0.36 and 0.23, respectively. See, Figs.2 and 3.
  • Full ITT Analysis Set [00291] The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), ranging from 0 to 41. See, Figs.7A and 7B. 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. These results illustrate a statistical superiority over placebo with a durability of effect with the greatest difference seen at week 6. See, Table 23.
  • Table 23 Summary of Baseline Psychiatry Rating Scales at the Start of the Lead-in and Treatment Periods; fITT Analysis Set MADRS SHAPS Total Score Total Score N Mean Median N Mean Median (SD) (Range) (SD) (Range) Lead-in Baseline Placebo 83 32.8 (4.25) 33.0 (26; 42) 83 37.8 (6.01) 38.0 (22; 55) Aticaprant 83 32.4 (4.27) 32.0 (21; 45) 83 37.3 (6.23) 38.0 (14; 53) Total 166 32.6 (4.25) 32.0 (21; 45) 166 37.6 (6.11) 38.0 (14; 55) Treatment Baseline Placebo 83 25.7 (7.73) 26.0 (10; 41) 83 36.3 (5.44) 36.0 (23; 50) Aticaprant 83 24.8 (8.02) 27.0 (0; 36) 83 35.0 (5.85) 36.0 (14; 49) Total 166 25.3 (7.86) 26.5 (0; 41) 166 35.6 (5.67) 3
  • Negative change to Placebo indicates favorable aticaprant effect. Negative effect size favors aticaprant; positive effect size favors Placebo.
  • J&J Ref JPI63WOPCT1
  • Supplementary analysis was conducted using the same MMRM model as described for the primary analysis on all the data collected prior to 15-March-2020 (estimated date of the COVID-19 lockdowns in most of the countries participating in the trial). Seventeen percent of the subjects in fITT and 19% in eITT population had at least one of the MADRS assessment excluded from the model due to COVID-19 impact.
  • the effect size was 0.38 and 0.11, respectively.
  • 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.
  • Negative change to Placebo indicates favorable aticaprant effect. Negative effect size favors aticaprant; positive effect size favors Placebo.
  • Changes in SHAPS total score were analyzed with the same MMRM model used for MADRS total score. The estimated LS Mean difference with 80% 2-sided CI at treatment week 6 between aticaprant and placebo was -0.7 [-1.81, 0.41]. See, Fig.7 and Tables 28 and 29 and Fig.18. The corresponding p-value was 0.419.
  • Table 28 SHAPS Total Score: MMRM Results - Estimated LS Means and Comparison versus Placebo; eITT Analysis Set Change from Baseline Analysis Visit N Mean Mean LSMean LSMean 60% p- (SD) (SD) (SE) Difference Confidence value a Treatment (SE) ⁇ Interval on Treatment Difference Placebo Treatment Week 1 Placebo 61 35.5 -1.3 -0.9 (6.00) (3.17) (0.63) aticaprant 60 34.5 -1.9 -1.7 -0.8 (0.86) [-1.90,0.31] 0.3542 (5.63) (4.30) (0.64) Treatment Week 3 Placebo 59 34.9 -2.2 -1.8 (6.09) (4.65) (0.64) aticaprant 59 33.0 -3.4 -3.2 -1.4 (0.86) [-2.53,-0.31] 0.1005 (6.39) (5.25) (0.64) Treatment Week 4 Placebo 60 33.7 -3.3 -2.9 (5.89) (4.47) (0.63) aticaprant 57 32.0 -4.5 -
  • Table 30 SHAPS Total Score: Mean Changes to Placebo During the Treatment Period; fITT Analysis Set Analysis Visit N Mean Mean 90%CI for Effect Treatment Change from Change to Mean Size Baseline Placebo Change to (SD) (SD pooled) Placebo Treatment Week 1 Placebo 83 -1.5 (3.57) aticaprant 83 -2.0 (4.05) -0.6 (3.82) [-1.5,0.4] -0.15 Treatment Week 3 Placebo 81 -2.2 (5.11) aticaprant 80 -3.2 (5.07) -1.0 (5.09) [-2.4,0.3] -0.20 Treatment Week 4 Placebo 82 -3.0 (4.41) aticaprant 78 -4.2 (5.70) -1.2 (5.08) [-2.5,0.1] -0.23 Treatment Week 5 Placebo 82 -3.8 (4.76) aticaprant 77 -4.3 (5.70) -0.5 (5.24) [-1.8,0.9] -0.09 Treatment Week 6 Placebo 81 -4.2 (4.98) aticaprant 77 -4.7
  • Negative change to Placebo indicates favorable aticaprant effect. Negative effect size favors aticaprant; positive effect size favors Placebo.
  • the MADRS Total Score ranges from 0 to 60, with higher scores indicating greater severity of depression.
  • J&J Ref JPI63WOPCT1 Table 32: MADRS (Montgomery– ⁇ sberg Depression Rating Scale) Total Score: Mean Changes to Placebo During the Treatment Period by Anhedonia Level at Treatment Baseline; fITT Analysis Set Analysis Visit N Mean Change Mean 90% CI Effect Treatment from Baseline Change to for Mean size (SD) Placebo Change to (SD pooled) Placebo Low anhedonia Treatment Week 1 Placebo 49 -1.3 (4.17) aticaprant 52 -2.4 (4.59) -1.0 (4.39) [-2.5,0.4] -0.24 Treatment Week 3 Placebo 47 -3.6 (6.04) aticaprant 49 -4.1 (6.67) -0.5 (6.37) [-2.7,1.7] -0.08 Treatment Week 4 Placebo 48 -4.9 (6.53) aticaprant 48 -6.4 (6.77) -1.5 (6.65) [-3.8,0.8] -0.23 Treatment Week 5 Placebo 48 -6.6 (6.82) aticaprant 45 -7.3 (6.90) -
  • the MADRS Total Score ranges from 0 to 60, with higher scores indicating greater severity of depression. [00315] This data illustrates that segmentation into high vs low anhedonia had a benefit for treating MDD: higher treatment effect for aticaprant. Further, the placebo response was lower in patients with high anhedonia, as compared to low anhedonia.
  • 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 includes the number of subjects evaluable for this endpoint.
  • 'n' number analyzed included all subjects evaluable for specified time point categories.
  • Figs.20-A and 20-B The results illustrate that the treatment effect is larger in patients with more anhedonia at baseline. See, Figs.20-A and 20-B.
  • Fig.20-A i.e., the high anhedonia group
  • 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.
  • J&J Ref JPI63WOPCT1 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.2010, 13, 917-932; Marcus, J. Clin. Psychopharmacol.2008, 28:156–165; Berman, J. Clin. Psychiatry 2007; 68:843–853; Berman, American College of Neuropsychopharmacology, 2008, Annual Meeting Abstracts (Scottsdale, Ariz, Dec 7–11, 2008).
  • Example 7 Single Dose Aticaprant as Adjunctive Antidepressant Therapy
  • 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.
  • Sample Size and Randomization 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 J&J Ref: JPI63WOPCT1 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/SNRI) during the entire study. [00351] Doses and Administration All eligible subjects will receive aticaprant or placebo in addition to their baseline SSRI/SNRI which will be continued during the entire study. Study medication will be taken daily. [00352] 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.
  • 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.
  • J&J Ref JPI63WOPCT1 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.
  • spermatogenesis cycle defined as approximately 3 months
  • 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. • who is sexually active with a woman who is pregnant must use a condom. • must not to donate sperm.
  • a barrier method of contraception e.g., condom with spermicidal foam/gel/film/cream/suppository
  • 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).
  • J&J Ref JPI63WOPCT1 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.
  • Type 1 or Type 2 diabetes mellitus Subjects with Type 1 or Type 2 diabetes mellitus who are controlled (hemoglobin A1c ⁇ 8.0% and glucose ⁇ 150 mg/dL at screening) 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 FT4 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.
  • Diagnosis of acquired immunodeficiency syndrome Human immunodeficiency virus testing is not required.
  • J&J Ref JPI63WOPCT1
  • Key Secondary To assess efficacy of aticaprant compared with placebo in adult subjects with MDD ANH+ as adjunctive therapy to an antidepressant on patient- reported assessment of anhedonia outcomes: • Change from baseline to Day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.
  • Other Secondary To assess the efficacy of aticaprant compared with placebo in adult subjects with MDD ANH+ as adjunctive therapy on the following: • Proportion of responders at Day 43 ( ⁇ 50% reduction in MADRS total score). • Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ⁇ 12 at Day 43.
  • 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: • AEs including AESI.
  • An AE can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product.
  • TEAEs were AEs with onset during the treatment phase that has worsened since baseline.
  • the full safety analysis set included all enrolled subjects who received at least 1 dose of study medication in the treatment period.
  • 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: • MAOIs within 4 weeks before screening until the first follow-up visit. • Antipsychotic drugs from at least 14 days before Day 1 until the first follow-up visit.
  • Hypnotic drugs or food supplements from at least 7 days prior to Day 1 until the first follow-up visit, including but not limited to benzodiazepines, non- J&J Ref: JPI63WOPCT1 benzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and ramelteon), sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin / agomelatine.
  • benzodiazepines non- J&J Ref: JPI63WOPCT1 benzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and ramelteon)
  • sedating antihistamines including over-the
  • Non-SSRI/SNRI antidepressants e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe
  • TMS or DCS or electrical stimulation use prior to screening is not exclusionary.
  • T3 thyroid hormone or other thyroid function supplementation prescribed for depression. These medications are allowed when given to control pre-existing thyroid disease/disorder.
  • Ketamine or esketamine within 5 years prior to and during the study (up to 2 doses are allowed in lifetime prior to screening).
  • Psychedelics e.g., psilocybin.
  • Memantine • Other investigational drugs within 30 days prior to and during the study.
  • J&J Ref JPI63WOPCT1
  • 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 [00364]
  • 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.
  • 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 8 weeks, • and a follow-up phase of 1-2 weeks.
  • Approximately 624 subjects randomized in a 2:1:1 ratio to placebo, aticaprant 5 mg, and aticaprant 10 mg) will be enrolled in the study. This enrolment is targeted to achieve a minimum of 556 adult subjects with MDD with prominent anhedonia and approximately 68 elderly subjects ( ⁇ 65 years) with MDD with prominent anhedonia.
  • 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
  • Symptoms of anhedonia based on clinical assessment and confirmed by a positive response for anhedonia (MDE symptoms Item 2) on the SCID-CT at screening and baseline (Day 1 prior to randomization). 6. SHAPS total score of ⁇ 38 at screening and baseline (Day 1 prior to randomization) corresponding to prominent (high level) of anhedonia. 7. Inadequate response to at least 1 but no more than 2 antidepressants (SSRI/SNRI), administered at an adequate dose and duration in the current episode of depression. 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.
  • SSRI or SNRI for depressive symptoms, in any formulation and available in the participating country citalopram, duloxetine, escitalopram, J&J Ref: JPI63WOPCT1 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.
  • J&J Ref JPI63WOPCT1 •
  • a man 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;
  • a condom who is sexually active with a woman who is pregnant must use a condom;
  • c must not donate sperm.
  • 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).
  • 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.
  • J&J Ref JPI63WOPCT1 test for abnormal ALT and AST is permitted during the screening period provided there is an alternative explanation for the out of range value.
  • 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 J&J Ref: JPI63WOPCT1 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 FT4 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.
  • Requires chronic use of a PPIs A history of chronic NSAID or aspirin use. (Low dose aspirin e.g., in cardiovascular disease prevention is allowed).
  • 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.
  • Diagnosis of acquired immunodeficiency syndrome Human immunodeficiency virus testing is not required for this study. 35.
  • J&J Ref JPI63WOPCT1
  • Other Secondary Assess the efficacy of aticaprant compared with placebo as adjunctive therapy to an antidepressant (SSRI or SNRI) in adult subjects with MDD with prominent anhedonia: • Proportion of responders at Day 43 and Day 57 ( ⁇ 50% reduction in MADRS total score). • Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ⁇ 12 at Day 43 and Day 57. • Change from baseline to Day 43 and Day 57 in MADRS-6 • Change from baseline to Day 43 and Day 57 in Patient Health Questionnaire, 9- Item (PHQ-9) total score.
  • 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: • AEs including AESI • Vital signs • ECG • Laboratory Values J&J Ref: JPI63WOPCT1 • Weight/BMI • Suicidality assessment using the C-SSRS • Withdrawal symptoms assessment using the PWC-20 [00378] Other Objectives (exploratory): • To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers in relation to clinical response on depression symptoms and anhedonia upon monotherapy with aticaprant.
  • Prohibited therapies [00382] 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: • MAOIs within 4 weeks before screening until the first follow-up visit. • Antipsychotic drugs from at least 14 days before Day 1 until the first follow-up visit.
  • Hypnotic drugs or food supplements from at least 7 days prior to Day 1 until the first follow-up visit, including but not limited to benzodiazepines, non- benzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and ramelteon), sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin.
  • benzodiazepines non- benzodiazepine hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and ramelteon)
  • sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and
  • Non-SSRI/SNRI antidepressants e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe
  • TMS or DCS or electrical stimulation use prior to screening is not exclusionary.
  • T3 thyroid hormone or other thyroid function supplementation prescribed for depression. These medications are allowed when given to control pre-existing thyroid disease/disorder.
  • Ketamine or esketamine within 5 years prior to and during the study (up to 2 doses are allowed in lifetime prior to screening).
  • Psychedelics e.g., psilocybin.
  • Memantine • Other investigational drugs within 30 days prior to and during the study.
  • Example 9 [00383] This is a Phase 1, open-label, single dose, multicenter, 4-part study in healthy adult participants.
  • 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.
  • J&J Ref JPI63WOPCT1
  • Potential participants will be screened from Day -28 to Day -2 to determine participants’ eligibility for study participation. For Part 1, qualified participants will be admitted on Day -1 of each treatment period and will remain in-house for the total duration of the treatment (Day -1 until Day 5, with single-dose treatment on Day 1 and 96 hours of PK), whereas for Part 2, PK sampling will be done up to 120 hours (Day 6).
  • Part 1 The 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.
  • J&J Ref JPI63WOPCT1
  • Part 2 [00395] The 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.
  • 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.
  • participants 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.
  • Parts 1 and 2 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. J&J Ref: JPI63WOPCT1 [00404] Parts 1 and 2, of the study will start at any time, irrespective of other parts of the study. [00405] For Parts 1 and 2, 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).
  • Table 57 Part 1 Schedule of Activities P hase Screening Open-Label (washout of 7 days between each administration of d i i F P 1 P i d 14 + 1 2h J&J Ref: JPI63WOPCT1 s equence c High-fat breakfast d X Oral dose aticaprant e X X Open-Label (washout of 7 days between each End-of-Study (Day 10 Phase administration of study intervention) For to Day 14) or Early Part 1: Periods 1-4 Withdrawal Study Day Day 2 Day 3 Day Day 5 4
  • 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 J&J Ref: JPI63WOPCT1 treatment period (for Part 1) and prior to discharge on Day 6 of each treatment period (for Part 2), and at end-of-study or early withdrawal.
  • J&J Ref JPI63WOPCT1 treatment period
  • Day 6 of each treatment period for Part 2
  • Eligible participants can be enrolled in more than one part of study if sufficient wash-out period is completed between periods by participants. [00426] Screening for eligible participants will be performed within 28 days before administration of the study intervention. [00427] (i) Inclusion Criteria [00428] Each potential participant must satisfy all of the following criteria to be enrolled in the study: [00429] For All Participants Age • Healthy male and female participants between 18 and 55 years of age, inclusive. 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 J&J Ref: JPI63WOPCT1 clinical unit on Day -1 of the first treatment period.
  • 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 o 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.
  • J&J Ref JPI63WOPCT1 .
  • 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 male participant who is sexually active with a woman who is pregnant must use a condom.
  • Clinically relevant 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 J&J Ref: JPI63WOPCT1 behavior on Day -1 prior to the start of the treatment should be excluded.
  • Prior/Concomitant Therapy • Contraindications to the use of aticaprant or similar class of drugs (not limited to drugs such as mu-antagonists, kappa-antagonists) per local prescribing information. • Participant requires chronic use of a PPIs. • History of chronic NSAID or aspirin use. (Low dose aspirin e.g., in cardiovascular disease prevention is allowed). • Taken any disallowed therapies, Concomitant Therapy before the planned first 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 J&J Ref: JPI63WOPCT1 surgery, or has surgery planned during the time the participant is expected to participate in the study. • History of substance or alcohol use disorder according to DSM-5 criteria within 6 months before Screening or positive test result(s) for alcohol, nicotine metabolites or drugs of abuse (including barbiturates, opioids [including methadone], cocaine, cannabinoids, amphetamines, methamphetamines, hallucinogens such as PCP and LSD, and benzodiazepines) at Screening or Day - 1 of each treatment period.
  • nicotine metabolites or drugs of abuse including barbiturates, opioids [including methadone], cocaine, cannabinoids, amphetamines, methamphetamines, hallucinogens such as PCP and LSD, and benzodiazepines
  • [00439] Drinks, on average, more than 8 cups of tea/coffee/cocoa/cola or other caffeinated beverages per day. [00440] • Clinically significant acute illness within 7 days prior to study intervention administration. [00441] • History of clinically significant drug and/or food allergies. [00442] (iii) Meals and Dietary Restrictions [00443] 1. Participants may not consume any food or beverages containing, grapefruit juice, Seville oranges (including any orange marmalade), or quinine (e.g., tonic water) from 48 hours (72 hours in the case of grapefruit juice and Seville oranges) before the first dose of study intervention until the last dose of study intervention. [00444] 2.
  • methylxanthine-containing products e.g., chocolate bars or beverages, energy drinks if it contains methylxanthine, coffee, teas, or colas
  • caffeine i.e., no more than approximately 500 mg/day, as contained in 5 cups of tea or coffee or 8 cans of cola
  • Strenuous exercise may affect study specified assessments and safety laboratory results; for this reason, strenuous exercise should be avoided within 48 hours before all planned study visits and during stays in the CRC. Prior exercise will be allowed if the participant’s serum creatinine concentration is within the normal range. Minor abnormalities, which are not considered to be of clinical relevance, are acceptable. [00453] 2. Participants will be advised not to donate blood for at least 3 months after completion of the study or to participate in an investigational drug study for at least 1 month after completion of the study. [00454] B. Study Intervention J&J Ref: JPI63WOPCT1 [00455] All 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. [00456] For each participant, all doses must be administered at approximately the same time. [00457] Participants receiving study intervention in the fasted condition will fast overnight for at least 10 hours. [00458] 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. [00459] 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.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • prescription or nonprescription medication including vitamins and herbal supplements
  • other than the study intervention are prohibited, except for paracetamol.
  • 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.
  • 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.
  • Table 59 Volume of Blood to be Collected From Each Participant (Part 1) e e ) a J&J Ref: JPI63WOPCT1 a . Calculated as number of samples multiplied by amount of blood per sample. b . c. Repeat or unscheduled samples may be taken. Note: An indwelling intravenous cannula may be used for blood sample collection. If a mandarin (obturator) is used, blood loss due to discard is not expected.
  • Table 60 Volume of Blood to be Collected From Each Participant (Part 2) T ype of Sample Volume per No. of Approximate S ample (mL) Samples per Total Volume of c. Repeat or unscheduled samples may be taken. Note: An indwelling intravenous cannula may be used for blood sample collection. If a mandarin (obturator) is used, blood loss due to discard is not expected. [00473] (i) Vital Signs [00474] Body temperature, pulse/heart rate, respiratory rate, blood pressure will be assessed. [00475] 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.
  • Electrocardiograms [00477] 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.
  • C-SSRS Columbia Suicide Severity Rating Scale
  • J&J Ref JPI63WOPCT1
  • 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.
  • Plasma and CSF samples will be used to evaluate the PK of aticaprant. [00485] Evaluations [00486] Blood samples (4 mL each) for determination of aticaprant plasma concentrations will be collected at the time points indicated in Tables 59-60. [00487] Analytical Procedures [00488] During the study, serial blood samples (4 mL each) for determination of aticaprant plasma concentrations, will be collected at the time points as indicated in Tables 59-60. [00489] 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
  • B) coefficient of determination (r 2 adj) is at least 0.90. [00496] If requirement (B) is not met, t1/2, ⁇ z, and AUC ⁇ will be reported as approximations. [00497] Actual sampling times will be checked for major aberrations. In case a major aberration occurs for an actual sampling time of>20.00% deviation from the scheduled time, this plasma concentration will be excluded from descriptive statistics in the plasma concentration table. [00498] Sample Size Determination [00499] The intra-participant coefficient of variation (CV) for PK parameters (AUC ⁇ and Cmax) 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
  • Populations for Analysis Sets [00502] Populations for Analysis Sets [00503] For purposes of analysis, the following populations are defined: Population Description Enrolled All participants who sign the consent and not screen failures. [00505] 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. [00506] Initial Participant Characteristics [00507] For all participants who received at least one dose of study intervention, descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be performed for age, BMI, weight, and height. Sex and race will be listed and tabulated.
  • Reasons for exclusion of a participant or a sample from the analysis include, but are not limited, to the following: [00512] • Predose aticaprant plasma concentrations higher than 5% of Cmax [00513] • Vomiting (within 3 hours post-dose under fasting conditions and 8 hours post-dose under fed conditions) after study intervention administration for immediate-release products.
  • J&J Ref JPI63WOPCT1
  • %AUC ⁇ ,ex exceeds 20% for a given participant, that participant will be excluded from the statistical analysis of AUC ⁇
  • Too few data greater than 10% missing values per each participant
  • Noncompliance with study procedures affecting pharmacokinetics e.g., comedication
  • graphical representations of the results will include (but are not limited to) the following graphs for aticaprant: [00520] • Log-linear and linear-linear plasma concentration-time profiles for each individual [00521] • Log-linear and linear-linear plasma concentration-time profiles for the mean values per intervention [00522] • Log-linear and linear-linear plasma concentration-time profiles for the median values per intervention [00523] • Log-linear and linear-linear overlay plots of the individual plasma concentration-time profiles for each intervention [00524] • A graphical comparison of the individual and mean ( ⁇ SD) primary PK parameters of aticaprant for each intervention [00525] For dose proportionality, graphical representations of the results will include (but are not limited to) the following graphs for aticaprant: [00526] • Log-linear and linear-linear plasma concentration-time profiles for each individual, for all dose levels.
  • the primary parameters of interest for the statistical analysis will be the log-transformed estimated AUCs, AUClast, AUC ⁇ , and Cmax.
  • 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.
  • 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 J&J Ref: JPI63WOPCT1 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.
  • Treatment A 2 ⁇ 5 mg oral capsule administered in the morning, after at least 10-hour overnight fasting (Reference)
  • Treatment B 1 ⁇ 10 mg Formulation Concept 1 administered in the morning, after at least 10-hour overnight fasting (Test) [00542]
  • Dose-Proportionality may be observed between 1 ⁇ 10 mg unmilled API tablet vs.1 ⁇ 5 mg unmilled API tablet Table 68: Dose-proportionality testing (10 mg Tablet vs.5 mg tablet) - Summarized statistical results for Estimated Ratio of Means and 90% Confidence Interval: Treatment B/Treatment A- ATICPARANT-For completers (Dose proportionality); Pharmacokinetics Data Analysis Set N Geometric Means an ) back-transformed using anti-logarithm.
  • Treatment B 1 ⁇ 10 mg Formulation Concept 1 administered in the morning, after at least 10-hour overnight fasting (Reference)
  • Treatment C 1 ⁇ 5 mg Formulation Concept 1 administered in the morning, after at least 10-hour overnight fasting (Test) 5 mg dose normalized to 10 mg [00544]
  • Food-Effect [00545] Food effect (high-fat diet) was observed for 10 mg unmilled API tablet ( ⁇ 44% increase in AUC) with delayed Tmax to ⁇ 3 hours in presence of high-fat diet vs.1.5 hours in the absence of high-fat diet.
  • J&J Ref JPI63WOPCT1
  • Treatment B 1 ⁇ 10 mg Formulation Concept 1 administered in the morning, after at least 10-hour overnight fasting (Reference)
  • 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 (Test)
  • Table 70 Summarized PK Parameters of Aticaprant in Part 2 9) 0- ) ) b ) b ) c ) b
  • J&J Ref JPI63WOPCT1
  • Treatment H 1 ⁇ 10 mg Formulation Concept 2 administered in the morning approximately 30 minutes aft er the start of a standardized high-fat breakfast following at least 10-hour overnight fasting Participant 100029, Treatment F (incomplete profile) and 100031 (vomiting) hence excluded
  • Table 71 Statistical comparison results of the relative bioavailability of a 1 ⁇ 10 mg milled API tablet (test) with 2 ⁇ 5 mg API in capsule formulation (reference).
  • Treatment E 2 ⁇ 5 mg oral capsule administered in the morning, after at least 10-hour overnight fasting (Reference)
  • Treatment F 1 ⁇ 10 mg Formulation Concept 2 administered in the morning, after at least 10- hour overnight fasting (Test).
  • Table 72 Statistical comparison results of the dose-proportionality between 1 ⁇ 10 mg milled API tablet (reference) and 1 ⁇ 5 mg milled API tablet formulation (test).
  • Intra-participant CV(%) 100* (sqrt(exp(MSE)-1).
  • 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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