WO2023170550A1 - Polymorph forms of aticaprant for use in treating major depressive disorder - Google Patents

Polymorph forms of aticaprant for use in treating major depressive disorder Download PDF

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Publication number
WO2023170550A1
WO2023170550A1 PCT/IB2023/052088 IB2023052088W WO2023170550A1 WO 2023170550 A1 WO2023170550 A1 WO 2023170550A1 IB 2023052088 W IB2023052088 W IB 2023052088W WO 2023170550 A1 WO2023170550 A1 WO 2023170550A1
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Prior art keywords
aticaprant
crystalline form
amorphous
treatment
anhedonia
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PCT/IB2023/052088
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English (en)
French (fr)
Inventor
Philippe Fernandes
Mark Schmidt
Vanina Popova
Adam SAVITZ
Rama Melkote
Wayne C. Drevets
Srihari Gopal
Darrel Pemberton
Chakradhar Lagishetty
Iva Kezic
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Janssen Pharmaceuticals Inc
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Janssen Pharmaceuticals Inc
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Priority to JP2024553358A priority Critical patent/JP2025508051A/ja
Application filed by Janssen Pharmaceuticals Inc filed Critical Janssen Pharmaceuticals Inc
Priority to KR1020247033176A priority patent/KR20240156409A/ko
Priority to AU2023232536A priority patent/AU2023232536A1/en
Priority to IL315409A priority patent/IL315409A/en
Priority to CA3254365A priority patent/CA3254365A1/en
Priority to CN202380038808.6A priority patent/CN119156211A/zh
Priority to EP23712343.5A priority patent/EP4489747A1/en
Publication of WO2023170550A1 publication Critical patent/WO2023170550A1/en
Priority to JOJO/P/2024/0197A priority patent/JOP20240197A1/ar
Priority to CONC2024/0012158A priority patent/CO2024012158A2/es
Priority to MX2024010980A priority patent/MX2024010980A/es
Anticipated expiration legal-status Critical
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
    • A61K9/48—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • KOR antagonists may be effective for the treatment of patients with mood disorders, perhaps by modulating the negative affective state associated with stress response.
  • Anhedonia is one of the core symptoms of depression. At least mild symptoms of anhedonia are present in about 90% of patients suffering from major depressive disorder (MDD). Only about 50% of patients with MDD show a meaningful response (>50% improvement to a first line antidepressant treatment), leaving many patients with substantial persistent impairment.
  • Therapeutic strategies such as switching antidepressants and using adjuvant drug treatments can improve response, however almost 40% of patients remain symptomatic and fail to achieve full remission.
  • the disclosure provides crystalline Form I of aticaprant. [0006] In other aspects, the disclosure provides crystalline Form II of aticaprant. [0007] In further aspects, the disclosure provides crystalline Form III of aticaprant. [0008] In yet other aspects, the disclosure provides an amorphous form of aticaprant. [0009] In still further aspects, the disclosure provides pharmaceutical compositions comprising a crystalline form of aticaprant as described herein or the amorphous form of aticaprant. The crystalline form of aticaprant may be Form I, Form II, or Form III.
  • the disclosure provides methods of treating major depressive disorder in a human patient, comprising administering to the human patient in need thereof an effective amount of a crystalline form of aticaprant as described herein or the amorphous form of aticaprant.
  • the crystalline form of aticaprant may be Form I, Form II, or Form III.
  • the disclosure provides a crystalline form of aticaprant as described herein for use in the treatment of major depressive disorder in a human patient.
  • the crystalline form of aticaprant may be Form I, Form II, or Form III.
  • the disclosure provides an amorphous form of aticaprant for use in the treatment of major depressive disorder in a human patient.
  • the disclosure provides uses of the crystalline form of aticaprant as described herein or the amorphous form of aticaprant in the manufacture of a medicament for the treatment of major depressive disorder in a human patient.
  • the crystalline form of aticaprant may be Form I, Form II, or Form III.
  • the disclosure provides packages or pharmaceutical products comprising (i) a crystalline form of aticaprant as described herein, the amorphous form of aticaprant, or a combination thereof, and (ii) instructions for treating major depressive disorder in a human patient.
  • the crystalline form of aticaprant may be Form I, Form II, or Form III.
  • Fig.1 is the x-ray powder diffraction (XRPD) pattern of aticaprant Form III (transmission mode).
  • Fig.2 are XRPD patterns of amorphous aticaprant. The top pattern results from 1,4-dioxane, the middle pattern results from t-butanol, and the bottom pattern results from THF/H2O.
  • Fig.3 is the modulated differential scanning calorimetry (mDSC) thermogram of amorphous aticaprant.
  • Fig.4 is the differential scanning calorimetry (DSC) thermogram of Form III of aticaprant.
  • Fig.5 is the DSC thermogram of the sample from Fig.3 heated from -40 to 131 °C/10 °C/min.
  • Fig.6 is the XRPD pattern of crystalline Form I of aticaprant.
  • Fig.7 is the DSC thermogram of crystalline Form I of aticaprant.
  • Fig.8 is the XRPD pattern of crystalline Form II of aticaprant (1 g scale).
  • Fig.9 is the mDSC thermogram of crystalline Form II of aticaprant (1 g scale).
  • Fig.10 is the gravimetric vapor sorption (GVS) isotherm plot of crystalline Form II of aticaprant (1 g scale).
  • VGS gravimetric vapor sorption
  • Fig.11 is the GVS kinetics plot of crystalline Form II of aticaprant (1 g scale).
  • Fig.12 is the mDSC thermogram of crystalline Form III of aticaprant.
  • Fig.13 is a schematic showing the decision tree for the treatment of gums/oils in the solubility screen.
  • Fig.14 is the trial design of Example 1.
  • Fig.15 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.16 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.17 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.18 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.19 is a line graph showing MADRS total score: mean values ( ⁇ SE) over time for the eITT analysis set.
  • Fig.20-A is a line graph showing MADRS total score: mean values ( ⁇ SE) over time for the full intent-to-treat (fITT) analysis set.
  • Fig.20-B is an excerpt from Fig.20-A for treatment weeks 0-6.
  • Fig.21 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.22 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.23 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.24 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.25 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.26 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.27 is a line graph showing SHAPS total score: mean values ( ⁇ SE) over time for the eITT analysis set.
  • Fig.28 is a line graph showing SHAPS total score: mean values ( ⁇ SE) over time for the fITT analysis set.
  • Fig.29 illustrates the MADRS change from baseline by anhedonia severity.
  • Fig.30-A is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS ⁇ 38.
  • Fig.30-B is a line graph showing MADRS change from baseline for patients with low anhedonia, i.e., SHAPS ⁇ 38.
  • Fig.31 is bar graph showing the comparison of MADRS in patients having low and high anhedonia.
  • Fig.32 is a line graph showing the ASEX total score mean change from baseline.
  • Fig.33 is a bar graph showing ASEX item level change total score mean change from baseline.
  • Fig.34 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.35 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 [0050] 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). [0051] The disclosure provides novel crystalline and amorphous forms of aticaprant.
  • crystalline forms i.e., Forms I, II, and III
  • crystalline Form I is anhydrous.
  • crystalline Form II is anhydrous.
  • crystalline Form III is anhydrous.
  • 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.
  • amorphous refers to a solid form of a chemical moiety that is present in a non-crystalline state.
  • An amorphous solid is a crystal having no characteristic shape or form. That is, amorphous forms lacks long-range structural order. Characterization of amorphous form may be performed by those skilled in the art including, without limitation, XRPD, TGA, infrared spectroscopy, Raman spectroscopy, solid state NMR, DSC, scanning electron microscopy, dynamic solvent sorption, laser diffraction, dissolution, MET analysis, densitometry, viscometry, high pressure liquid chromatography (HPLC), inverse gas chromatography, or combinations thereof.
  • an amorphous sample comprises no other forms, i.e., the sample is 100% w/w amorphous.
  • An amorphous sample may also contain solids that are crystalline.
  • an amorphous form may contain solids such that the sample is at least about 99% w/w amorphous, at least about 95% w/w amorphous, at least about 90% w/w amorphous, at least about 85% w/w amorphous, at least about 80% w/w amorphous, or the like.
  • the term “crystalline” refers to solid state form of a chemical moiety wherein the atoms, molecules, or ions are assembled in a highly ordered structure that extends in all directions.
  • crystalline includes all crystalline forms of Compound I, including salts thereof. Characterization of crystalline forms may be performed by those skilled in the art including, without limitation, XRPD or DSC. Typically, the XRPD pattern contains sharp intensity peaks. This contrasts to the XRPD pattern of an amorphous form that often contains a broad, peak, without no identifying peaks. A crystalline form may be completely crystalline or partially crystalline. In some aspects, a crystalline sample may be 100% w/w crystalline. A crystalline sample may also contain solids that are amorphous.
  • a crystalline form may contain solids such that the sample is at least about 99% w/w crystalline, at least about 95% w/w amorphous, at least about 90% w/w crystalline, at least about 85% w/w crystalline, at least about 80% w/w crystalline, or the like.
  • the term “anhydrous” or “anhydrate” as used herein refers to a crystalline or amorphous form 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%, 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°.
  • 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 disclosure also provides crystalline Form I of aticaprant. Crystalline Form I of aticaprant may be characterized by a number of techniques including, without limitation, x-ray diffraction and differential scanning calorimetry.
  • crystalline Form I of aticaprant is characterized by x-ray diffraction.
  • Crystalline Form I of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°.
  • crystalline Form I of aticaprant is characterized by x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°.
  • crystalline Form I of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 13.9°, 17.3°, 17.4°, 18.0°, and 24.0°.
  • crystalline Form I of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° and one or more additional peaks at 2 ⁇ ( ⁇ 0.2) of 3.8°, 7.7°, 10.1°, 19.7°, 21.8°, 22.4°, 23.1°, and 25.3°.
  • crystalline Form I of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° and one or more additional peaks at 2 ⁇ ( ⁇ 0.2) of 3.8°, 6.9°, 7.7°, 10.1°, 11.6°, 14.1°, 14.7°, 15.5°, 18.8°, 19.4°, 19.7°, 20.5°, 21.8°, 22.4°, 23.1°, 24.7°, 25.3°, 28.2°, and 29.5°.
  • crystalline Form I of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° and one or more additional peaks at 2 ⁇ ( ⁇ 0.2) of 3.8°, 6.9°, 7.7°, 10.1°, 11.6°, 12.5°, 14.1°, 14.7°, 15.5°, 18.8°, 19.4°, 19.7°, 20.5°, 21.8°, 22.4°, 23.1°, 24.7°, 26.6°, 25.3°, 27.0°, 28.2°, 28.9°, 29.5°, and 30.3°.
  • crystalline Form I of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0° and one or more additional peaks as shown in Table 1.
  • crystalline Form I of aticaprant is characterized by the x-ray diffraction pattern peaks in Table 2. In other embodiments, crystalline Form I of aticaprant is characterized by the x-ray diffraction pattern peaks in Table 3. In further embodiments, crystalline Form I of aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to Fig.6. [0061] Crystalline Form I of aticaprant may also be characterized by differential scanning calorimetry. In some embodiments, crystalline Form I of aticaprant is characterized by a differential scanning calorimetry thermogram comprising a Tonset at about 92.9°C.
  • crystalline Form I of aticaprant is characterized by a differential scanning calorimetry thermogram comprising a peak temperature (T m ) at about 101.7°C.
  • crystalline Form I of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.7.
  • the disclosure also provides crystalline Form II of aticaprant.
  • Crystalline Form II of aticaprant may be characterized by a number of techniques including, without limitation, x- ray diffraction and differential scanning calorimetry.
  • crystalline Form II of aticaprant is characterized by x-ray diffraction.
  • crystalline Form II 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.
  • crystalline Form II 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 at 2 ⁇ ( ⁇ 0.2) of 12.9°, 14.6°, 20.8°, 22.7°, and 23.5°.
  • crystalline Form II 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 at 2 ⁇ ( ⁇ 0.2) of 11.9°, 12.9°, 14.6°, 17.4°, 20.8°, 22.7°, 23.5°, 25.5°, and 28.4°.
  • crystalline Form II 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 at 2 ⁇ ( ⁇ 0.2) of 6.2°, 9.3°, 11.9°, 12.9°, 14.6°, 16.7°, 17.4°, 20.8°, 22.7°, 23.5°, 25.5°, 27.6°, 28.4°, and 29.5°.
  • crystalline Form II 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 4.
  • crystalline Form II of aticaprant is characterized by the x-ray diffraction pattern peaks in Table 5. 12.9 20.8 25.5
  • crystalline Form II of aticaprant is characterized by the x-ray diffraction pattern peaks in Table 6.
  • crystalline Form II of aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to Fig.8.
  • Crystalline Form II of aticaprant may also be characterized by differential scanning calorimetry.
  • crystalline Form II of aticaprant is characterized by a differential scanning calorimetry thermogram comprising one or both endotherms at about 74.7°C and about 96.2°C.
  • crystalline Form II of aticaprant is characterized by a differential scanning calorimetry thermogram comprising a peak temperature (Tm) at 102.4°C.
  • crystalline Form II of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.9.
  • the disclosure further provides 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. In some embodiments, crystalline Form III of aticaprant is characterized by x-ray diffraction. In other embodiments, crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°.
  • crystalline Form III of aticaprant is characterized by four or more x- ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 8.2°, 9.7°, 12.0°, 13.5°, 15.1°, 16.4°, 19.4°, 28.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, 28.8°, and 30.0°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 3.1°, 19.0°, 24.0°, 24.3°, or 26.2 and one or more additional peaks of Table 7.
  • crystalline Form III of aticaprant is characterized the x-ray diffraction pattern peaks in Table 8.
  • crystalline Form III of aticaprant is characterized the x-ray diffraction pattern peaks in Table 9.
  • crystalline Form III of aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to Fig.1.
  • Crystalline Form III of aticaprant may also be characterized by differential scanning calorimetry.
  • the differential scanning calorimetry thermogram comprises a peak temperature (Tm) at about 121°C.
  • crystalline Form III of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to Fig. 4.
  • the disclosure also provides an amorphous form of aticaprant.
  • the amorphous form is characterized by a differential scanning calorimetry thermogram comprising a glass transition temperature (T g ) of about 45.5°C.
  • the amorphous form of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to Fig. 3.
  • the amorphous form of aticaprant is characterized by a differential scanning calorimetry thermogram comprising a T onset of about 43.8°CIn
  • the amorphous form of aticaprant is characterized by an mDSC thermogram that corresponds to Fig.12.
  • Treatment Methods are provided for treating patients having a more severe type of depression, i.e., major depressive disorder. In some embodiments, the patient is experiencing moderate to severe anhedonia.
  • antidepressants are known to have a variety of side effects such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among others. Thus, patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side-effects.
  • the methods described herein are effective in managing the patient’s depression and anhedonia using crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 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 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • Reduction of anhedonia after initiating treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant may be measured relative to the anhedonia of the patient as measured before treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, i.e., a baseline anhedonia measurement.
  • the treating clinician is able to calculate the change of anhedonia from the baseline to the real time anhedonia measurement at any point after treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • a baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day before treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the patient’s change of anhedonia will depend on several factors including, without limitation, anhedonia severity, patient’s sensitivity to crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, other pharmaceutical agents being administered, among others.
  • the patient’s anhedonia is reduced after about 3 weeks of treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the patient’s anhedonia is reduced after about 3 weeks of treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant. In further embodiments, the patient’s anhedonia is reduced after about 3 weeks to about 6 weeks, and, in certain embodiments, through week 6, of treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 terms “subject” and “patient” refer to a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, the term “adult” as used herein refers to a human that is about 18 years of age or older.
  • 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 11. Table 11 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 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.
  • Decreased concentration Nearly every day; may be indecisiveness; may be subjective or observed by others 9.
  • Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning 2. Episode not attributable to physiological effects of a substance or another medical condition 3. Episode not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders 4. No history of manic or hypomanic episode [0081]
  • Major depressive disorder may be categorized as mild, moderate, or severe.
  • the MDD is mild. In other embodiments, the MDD is moderate. In further embodiments, the MDD is severe. As used herein, “mild MDD” applies to a patient having few, if any, symptoms in excess of those required to make the diagnosis, the intensity of the symptoms is distressing but manageable, and the symptoms result in minor impairment in social or occupational functioning.
  • the mild MDD may be a single episode (ICD-10 F32.0) or a recurrent episode (ICD-10 F33.0).
  • Mode MDD applies to a patient having a number of symptoms, intensity of symptoms, and/or functional impairment are between those specified for “mild” and “severe.”
  • the moderate MDD may be a single episode (ICD-10 F32.1) or a recurrent episode (ICD-10 F33.1).
  • severe MDD applies to a patient where the number of symptoms is substantially in excess of that required to make the diagnosis, the intensity of symptoms is seriously distressing and unmanageable, and the symptoms markedly interfere with social and occupational functioning, and urgent symptom control is necessary.
  • the severe MDD may be a single episode (ICD-10 F32.2) or a recurrent episode (ICD-10 F33.2).
  • MDD is classified according to the DSM-5 definition of Table 12.
  • Table 12 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. No hx of mania or hypomania [0082] Several scales are known in the art that may be utilized to diagnose or monitor patients with MDD.
  • MADRS Montgomery– ⁇ sberg Depression Rating Scale
  • CGI-S Clinical Global Impression – Severity
  • SSDDS Symptoms of Major Depressive Disorder Scale
  • SATE Self-Assessment of Treatment Experience
  • MGH Massachusetts General Hospital
  • ATRQ Antidepressant Treatment Response Questionnaire
  • MADRS is utilized to diagnose and/or monitor the patient.
  • MADRS is a 10-item rating scale that is used in antidepressant studies. It is clinician- administered and designed to be used in subjects with MDD to measure the overall severity of depressive symptoms.
  • the MADRS scale is validated, reliable, and acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression.
  • MADRS is administered using the Structured Interview Guide for the MADRS (SIGMA).
  • 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.
  • the MADRS evaluates apparent sadness, reported sadness, inner tension, sleep appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • CGI-S is utilized to diagnose and/or monitor the patient’s depression.
  • CGI-S is a scale that rates the severity of the subject’s illness at the time of assessment, relative to the clinician’s past experience with subjects who have the same diagnosis and improvement with treatment.
  • CGI-S provides an overall clinician-determined summary measure of severity of subject’s illness that considers all available information, including knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, and impact of symptoms on subject’s ability to function.
  • CGI-S evaluates severity of psychopathology on scale of 0 to 7.
  • SMDDS is utilized to diagnose and/or monitor the patient’s depression.
  • SMDDS is a subjective rating of the patient.
  • the SMDDS is a 16-item PRO measure. Each item is rated by the subject according to a 5-point Likert scale. Subjects respond to each question using a rating scale between 0 (“Not at all” or “Never”) to 4 (“Extremely” or “Always”).
  • 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 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.
  • 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.
  • Typical antipsychotics include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like.
  • phenothiazines e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin
  • thioxanthenes e.g., thiothixene, flupentixol
  • antidepressant medication includes natural products such as Kava-Kava, St.
  • the antidepressant medication includes neuropeptides such as thyrotropin-releasing hormone and the like or compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like.
  • the antidepressant medication is a hormone such as triiodothyronine, and the like.
  • the antidepressant medication is SSRI, SNRI, or a combination thereof.
  • the antidepressant is a SSRI that is escitalopram, sertraline, paroxetine, fluoxetine or citalopram.
  • the antidepressant medication is a SNRI that is venlafaxine, duloxetine, vortioxeine or desvenlafaxine.
  • the non-pharmacologic treatment for use herein may be selected by one skilled in the art. 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.
  • the patient was receiving treatment with other antidepressant therapy prior to receiving crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant in combination with one or more antidepressant(s), wherein crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is administered adjunctively with an antidepressant(s) not previously administered to the patient, i.e., a new antidepressant.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is administered in a regimen with an antidepressant(s) previously administered to the patient.
  • 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is dosed as described herein.
  • a patient is under concurrent treatment with both an antidepressant and crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, where both are administered by their prescribed dosing regimens.
  • the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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. [0099] Crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant and the antidepressant(s) may be administered via the same or different routes of administration.
  • Suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in) intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is administered orally.
  • Treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant as described herein has several advantages over the treatments in the art.
  • the patient does not experience many of the side effects that are associated with other antidepressants, i.e., antidepressants other than crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • antidepressants other than crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the patient does not experience weight gain during the treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • weight gain refers to an increase in the weight of patient, relative to the weight of the patient before taking crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant or the weight of the patient that is assessed at the time of the initial administration of the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the patient may actually see a decrease in overall weight, relative to the weight of the patient before taking crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the patient’s weight is stable, i.e., does not increase or decrease.
  • the patient does not experience a clinically relevant weight gain which is characterized as a weight increase of ⁇ 7%.
  • the patient does not experience a decrease in sexual functioning during the treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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. In yet other embodiments, the sexual functioning comprises orgasm satisfaction. Desirably, the patient’s sexual functioning is assessed at the time of initial administration of the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the patient’s sexual functioning while taking crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant can be compared to the patient’s sexual functioning before administration of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • ASEX Arizona Sexual Experience Scale
  • the ASEX is used to investigate whether crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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). [00103] 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 information regarding the impact of adjunctive treatment on aspects of cognitive and executive function including attention, memory and mental acuity. Subjects with MDD are often reported to have difficulties with functioning in this area.
  • the KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from “extremely alert” (1) to “very sleepy, great effort to keep awake, fighting sleep” (9).
  • the TEPS includes 18 items, 2 subscales designed to distinguish between anticipatory and consummatory pleasure.
  • the term “aticaprant” refers to 3- fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, i.e., the following . and is also known as JNJ-67953964, CERC-501, and LY-2456302.
  • “aticaprant” refers to the (S)-enantiomer of aticaprant, i.e., the following compound: . also known as (S)-aticaprant or (S)-3-fluoro-4-4-2-(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: .
  • the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant contains less than about 10% by weight, based on the weight of the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, of the (R)-enantiomer of aticaprant.
  • the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, of the (R)-enantiomer of aticaprant.
  • the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant contains about 0.001 to about 10% by weight, based on the weight of the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, of the (R)-enantiomer of aticaprant.
  • the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1%, about 0.001 to about 0.5%, about 0.001 to about 0.1%, about 0.1 to about 5%, about 0.1 to about 1%, about 0.1 to about 5%, or about 0.5 to about 5% by weight, based on the weight of the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, of the (R)-enantiomer of aticaprant.
  • the methods described herein include administering an effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is utilized in an effective amount as determined by the attending physician.
  • other antidepressant(s) is utilized in an effective amount either separately or in combination with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 a crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant free base basis.
  • the amounts indicate that amount of the crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).
  • the effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is less than about 60 mg.
  • the effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.
  • the effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is about 1 to about 50 mg, about 5 to about 50 mg, about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, about 40 to about 50 mg, about 1 to about 45 mg, about 2 to about 45 mg, about 5 to about 45 mg, about 10 to about 45 mg, about 20 to about 45 mg, about 30 to about 45 mg, about 30 to about 40 mg, about 30 to about 35 mg, about 1 to about 40 mg, about 5 to about 40 mg, about 10 to about 40 mg, about 20 to about 40 mg, about 30 to about 40 mg, about 1 to about 35 mg, about 2 to about 35 mg, about 5 to about 35 mg, about 10 to about 35 mg, about 20 to about 35 mg, about 25 to about 35 mg, about 30 to about 35 mg, about 1 to about 30, about 2 to about 30 mg, about 5 to about 30 mg, about 10 to about 30 mg, about 10
  • the effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is about 5 to about 15 mg. In still further embodiments, the effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is about 10 mg.
  • compositions are 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 I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • 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.
  • compositions for use herein, the composition further comprises one or more buffers, preservatives, penetration agents, wetting agents, surfactants, solubilizing agents, thickening agents, colorant agents, antioxidants, emulsifying agents, isotonizing agents, suspending agents, and/or viscosity increasing agents.
  • pharmaceutical compositions comprises one or more buffers and/or buffer systems (i.e. conjugate acid-base-pairs).
  • buffer shall mean any solid or liquid composition (preferably an aqueous, liquid composition) which when added to an aqueous formulation adjusts the pH of said formulation.
  • a buffer may adjust the pH of the aqueous formulation in any direction (toward more acidic, more basic or more neutral pH).
  • the buffer is pharmaceutically acceptable.
  • Suitable examples of buffers which may be used in the aqueous formulations described herein include, but are not limited to citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, and the like.
  • the pharmaceutical compositions herein may contain a preservative.
  • the terms “antimicrobial preservative” and “preservative” refer to any substance that is added to pharmaceutical compositions in order to preserve them against microbial degradation or microbial growth.
  • microbial growth typically plays an essential role, i.e., the preservative serves the main purpose of avoiding microbial contamination. It may also be desirable to avoid any effect of the microbes on the active ingredients and excipients, respectively, i.e., to avoid microbial degradation.
  • preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate.
  • the terms “penetration agent”, “penetration enhancer”, and “penetrant” refer to any substance that increases or facilitates absorption and / or bioavailability of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the penetration agent increases or facilitates absorption and / or bioavailability of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, following administration.
  • Suitable examples include, but are not limited to tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid, lecithines, and the like; and chitosan (and salts), and surface active ingredients such as benzalkonium chloride, sodium dodecyl sulfate, sodium docusate, polysorbates, laureth-9, oxtoxynol, sodium deoxycholate, polyarginine, and the like.
  • the penetration agent is selected to meet one or more of the following general requirements: (a) It is effective at increasing absorption of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, preferably in a temporary and/or reversible manner; (b) It is pharmacologically inert; (c) It is non-allergic, non-toxic and / or non-irritating; (d) It is highly potent (effective in small amounts); (e) It is compatible with the other components of the pharmaceutical composition; (f) It is odorless, colorless and / or tasteless; (g) It is accepted by regulatory agencies; and (h) It is inexpensive and available in high purity.
  • compositions for use herein may further contain one or more additional excipients for example, wetting agents, surfactant components, solubilizing agents, thickening agents, colorant agents, antioxidant components, and the like.
  • additional excipients for example, wetting agents, surfactant components, solubilizing agents, thickening agents, colorant agents, antioxidant components, and the like.
  • a suitable antioxidant component include, but are not limited to one or more of the following: sulfites; ascorbic acid; ascorbates, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylene diamine tetraacetic acid or its sodium or calcium salts; tocopherol; gallates, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof.
  • the antioxidant component provides long term stability to the liquid compositions.
  • Solubilizing and emulsifying agents can be included to facilitate more uniform dispersion of the active ingredient or other excipient that is not generally soluble in the liquid carrier.
  • a suitable emulsifying agent include, but are not limited to, for example, gelatin, cholesterol, acacia, tragacanth, pectin, methyl cellulose, carbomer, and mixtures thereof.
  • solubilizing agents examples include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.
  • the solubilizing or emulsifying agent may be present in an amount sufficient to dissolve or disperse the active ingredient, i.e., crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in the carrier.
  • a suitable isotonizing agent may include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof.
  • Suspending agents or viscosity increasing agents may also be added to the pharmaceutical compositions. Suitable examples include, but are not limited to, hydroxypropyl methylcellulose, sodium carmellose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and the like.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant may be administered once daily, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the patient had an inadequate response to other antidepressant therapy prior to treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the disclosure relates to crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, for use as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the disclosure also relates to the use of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • antidepressant therapy can be in particular selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
  • crystalline Form I of 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, for use as described herein, comprising administration of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, for use as described herein, comprising administration of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in combination with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in the manufacture of a medicament, as described herein, wherein the treatment comprises administration of an effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in combination with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in combination with an effective amount of one or more antidepressants.
  • one or more antidepressants can be selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
  • the disclosure relates to crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, for use as described herein.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is S-aticaprant.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in particular S-aticaprant, for use as described herein is administered orally.
  • the disclosure relates to crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is S-aticaprant.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is to be administered, more in particular, about 10 mg.
  • crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is to be administered orally.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant is in particular S-aticaprant.
  • the instructions for treatment direct administration of about 2 to about 35 mg crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, more in particular, about 10 mg.
  • the instructions for treatment direct crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in particular S-aticaprant, is for oral administration.
  • the instructions for treatment direct crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, in particular S-aticaprant, is for once daily administration.
  • administration of crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant does not result in weight gain during treatment, including clinically relevant weight gain.
  • the disclosure relates to crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, for use as described herein, wherein the patient does not experience weight gain during the treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant.
  • the disclosure relates to a use as defined herein, wherein the patient does not experience weight gain during the treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, for use as described herein, wherein the patient does not experience a decrease in sexual functioning during the treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Hamilton Pleasure Scale
  • the disclosure relates to the use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • SHAPS Hamilton Pleasure Scale
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Hamilton Pleasure Scale
  • 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 crystalline Form I of aticaprant, crystalline Form II of aticaprant, crystalline Form III of aticaprant, or amorphous 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.
  • SHAPS Hamilton Pleasure Scale
  • Embodiments The invention provides also the following non-limiting embodiments: Embodiment 1 is a crystalline Form I of aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°, wherein aticaprant has the following structure: .
  • Embodiment 2 is the crystalline Form I of aticaprant that is characterized by an x-ray powder diffraction pattern that corresponds to Fig.6.
  • Embodiment 3 is the crystalline Form I of aticaprant of Embodiment 1 or 2 that is characterized by a differential scanning calorimetry thermogram comprising one endotherm at about 92.9°C.
  • Embodiment 4 is the crystalline Form I of aticaprant of any one of Embodiments 1-3 that is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.7.
  • Embodiment 5 is the crystalline Form I of aticaprant of any one of Embodiments 1-4 that is anhydrous.
  • Embodiment 6 is the crystalline Form II of aticaprant that 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°, wherein aticaprant has the following structure: .
  • Embodiment 7 is the crystalline Form II of aticaprant of Embodiment 6 that is characterized by an x-ray powder diffraction pattern that corresponds to Fig. 8.
  • Embodiment 8 is the crystalline Form II of aticaprant of Embodiment 6 or 7 that is characterized by a differential scanning calorimetry thermogram comprising one or both endotherms at about 74.7°C and about 96.2°C.
  • Embodiment 9 is the crystalline Form II of aticaprant of any one of Embodiments 6-8 that is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.9.
  • Embodiment 10 is the crystalline Form II of aticaprant of any one of Embodiments 6-9 that is anhydrous.
  • Embodiment 11 is a crystalline Form III of aticaprant that 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°, wherein aticaprant has the following structure: .
  • Embodiment 12 The crystalline Form III of aticaprant of Embodiment 11 that is characterized by an x-ray powder diffraction pattern that corresponds to Fig. 1.
  • Embodiment 13 is the crystalline Form III of aticaprant of Embodiment 11 or 12 that is characterized by a peak temperature (T m ) at about 121°C.
  • Embodiment 14 is the crystalline Form III of aticaprant of any one of Embodiments 11-13 that is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.4.
  • Embodiment 15 is the crystalline Form III of aticaprant of any one of Embodiments 11-14 that is anhydrous.
  • Embodiment 16 is an amorphous form of aticaprant, wherein aticaprant has the following structure: .
  • Embodiment 17 is the amorphous form of Embodiment 16 that is characterized by a differential scanning calorimetry thermogram comprising a T g of about 45.5°C.
  • Embodiment 18 is the amorphous form of aticaprant of Embodiment 16 or 17 that is characterized by a differential scanning calorimetry thermogram that corresponds to Fig.3.
  • Embodiment 19 is a pharmaceutical composition comprising the crystalline form of aticaprant of any one of Embodiments 1-15 or the amorphous form of aticaprant of any one of Embodiments 16-18.
  • Embodiment 20 is a method of treating major depressive disorder in a human patient with crystalline aticaprant.
  • Embodiment 21 is a method of treating major depressive disorder in human patient, comprising administering crystalline aticaprant to the human patient, wherein the patient had a previous inadequate response to other antidepressant therapy.
  • Embodiment 22 is a method of treating major depressive disorder in a human patient, comprising administering to the human patient in need thereof an effective amount of a crystalline form of aticaprant of any one of Embodiments 1-15 or an amorphous form of aticaprant of any one of Embodiments 16-18.
  • Embodiment 23 is the method of Embodiment 22, wherein the treatment comprises administration of an effective amount of the crystalline form of aticaprant or amorphous form of aticaprant.
  • Embodiment 24 is the method of Embodiment 22 or 23, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 25 is the method of any one of Embodiment 21, 23, or 24, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 26 is the method of any one of Embodiments 20-25, further comprising adjunctive treatment with an effective amount of one or more antidepressants.
  • Embodiment 27 is the method of any one of Embodiments 20-26, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 28 is the method of any one of Embodiments 20-27, wherein the crystalline form of aticaprant is the crystalline form of S-aticaprant or the amorphous form of aticaprant is the amorphous form of S-aticaprant.
  • Embodiment 29 is the method of any one of Embodiments 20-28, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 2 to about 35 mg.
  • Embodiment 30 is the method of Embodiment 29, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 10 mg.
  • Embodiment 31 is the method of any one of Embodiments 20-30, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered orally.
  • Embodiment 32 is the method of any one of Embodiments 20-31, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered once daily.
  • Embodiment 33 is the method of any one of Embodiments 20-32, wherein the patient has anhedonia.
  • Embodiment 34 is the method of any one of Embodiments 20-33, wherein the patient has moderate anhedonia.
  • Embodiment 35 is the method of any one of Embodiments 20-33, wherein the patient has severe anhedonia.
  • Embodiment 36 is the method of any one of Embodiments 22-35, wherein the patient does not experience weight gain during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 37 is the method of Embodiment 36, wherein patient's body weight is assessed at the time of the initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 38 is the method of any one of Embodiments 20-37, wherein the patient does not experience a decrease in sexual functioning during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 39 is the method of Embodiment 38, wherein the sexual functioning of the patient is assessed at the time of initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 40 is the method of Embodiment 38 or 39, wherein the sexual functioning comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.
  • Embodiment 41 is the method of any one of Embodiments 38-40, wherein sexual functioning is assessed by the Arizona Sexual Experience Scale.
  • Embodiment 42 is the method of any one of Embodiments 33-35, 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 the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 43 is the method of any one of Embodiments 33-35 and 42, wherein 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.
  • Embodiment 44 is the method of Embodiment 42 or 43, wherein the anhedonia scale is the Snaith Hamilton Pleasure Scale.
  • Embodiment 45 is crystalline form of aticaprant for treating major depressive disorder in a human patient.
  • Embodiment 46 is crystalline form of aticaprant of any one of Embodiments 1-15 for treating major depressive disorder in human patient, wherein the patient had a previous inadequate response to other antidepressant therapy.
  • Embodiment 47 is crystalline form of aticaprant of any one of Embodiments 1-15 for treating major depressive disorder in a human patient.
  • Embodiment 48 is crystalline form of aticaprant of Embodiment 47, wherein the treatment comprises administration of an effective amount of the crystalline form of aticaprant or amorphous form of aticaprant.
  • Embodiment 49 is crystalline form of aticaprant of Embodiment 47 or 48, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 50 is crystalline form of aticaprant of any one of Embodiments 46 or 49, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, serotonin- norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 51 is crystalline form of aticaprant of any one of Embodiments 45-50, further comprising adjunctive treatment with an effective amount of one or more antidepressants.
  • Embodiment 52 is crystalline form of aticaprant of any one of Embodiments 45-51, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 53 is crystalline form of aticaprant of any one of Embodiments 45-52, wherein the crystalline form of aticaprant is the crystalline form of S-aticaprant or the amorphous form of aticaprant is the amorphous form of S-aticaprant.
  • Embodiment 54 is crystalline form of aticaprant of any one of Embodiments 45-53, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 2 to about 35 mg.
  • Embodiment 55 is crystalline form of aticaprant of Embodiments 54, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 10 mg.
  • Embodiment 56 crystalline form of aticaprant of any one of Embodiments 45-55, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered orally.
  • Embodiment 57 is crystalline form of aticaprant of any one of Embodiments 45-56, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered once daily.
  • Embodiment 58 is crystalline form of aticaprant of any one of Embodiments 45-57, wherein the patient has anhedonia.
  • Embodiment 59 is crystalline form of aticaprant of any one of Embodiments 45-58, wherein the patient has moderate anhedonia.
  • Embodiment 60 is crystalline form of aticaprant of any one of Embodiments 45-58, wherein the patient has severe anhedonia.
  • Embodiment 61 is crystalline form of aticaprant of any one of Embodiments 47-60, wherein the patient does not experience weight gain during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 62 is crystalline form of aticaprant of Embodiment 61, wherein patient's body weight is assessed at the time of the initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 63 is crystalline form of aticaprant of any one of Embodiments 45-62, wherein the patient does not experience a decrease in sexual functioning during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 64 is crystalline form of aticaprant of Embodiment 63, wherein the sexual functioning of the patient is assessed at the time of initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 65 is a crystalline form of aticaprant of Embodiment 63 or 64, wherein the sexual functioning comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.
  • Embodiment 66 is a crystalline form of aticaprant of any one of Embodiments 63-65, wherein sexual functioning is assessed by the Arizona Sexual Experience Scale.
  • Embodiment 67 is the crystalline form of aticaprant of any one of Embodiments 58-60, 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 the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 68 is the crystalline form of aticaprant of any one of Embodiments 58-60 and 67, wherein 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.
  • Embodiment 69 is the crystalline form of aticaprant of Embodiment 67 or 68, wherein the anhedonia scale is the Snaith Hamilton Pleasure Scale.
  • Embodiment 70 is the amorphous form of aticaprant for treating major depressive disorder in a human patient.
  • Embodiment 71 is the amorphous form of aticaprant of any one of Embodiments 16-18 for treating major depressive disorder in human patient, wherein the patient had a previous inadequate response to other antidepressant therapy.
  • Embodiment 72 is the amorphous form of aticaprant of any one of Embodiments 16-18 for treating major depressive disorder in a human patient.
  • Embodiment 73 is the amorphous form of aticaprant of Embodiment 72, wherein the treatment comprises administration of an effective amount of the crystalline form of aticaprant or amorphous form of aticaprant.
  • Embodiment 74 is the amorphous form of aticaprant of Embodiment 72 or 73, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 75 is the amorphous form of aticaprant of any one of Embodiments 71 or 74, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, serotonin- norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 76 is the amorphous form of aticaprant of any one of Embodiments 70-75, further comprising adjunctive treatment with an effective amount of one or more antidepressants.
  • Embodiment 77 is the amorphous form of aticaprant of any one of Embodiments 70-76, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin- norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 78 is the amorphous form of aticaprant of any one of Embodiments 70-77, wherein the crystalline form of aticaprant is the crystalline form of S-aticaprant or the amorphous form of aticaprant is the amorphous form of S-aticaprant.
  • Embodiment 79 is the amorphous form of aticaprant of any one of Embodiments 70-78, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 2 to about 35 mg.
  • Embodiment 80 is the amorphous form of aticaprant of Embodiment 79, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 10 mg.
  • Embodiment 81 is the amorphous form of aticaprant of any one of Embodiments 70-80, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered orally.
  • Embodiment 82 is the amorphous form of aticaprant of any one of Embodiments 70-81, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered once daily.
  • Embodiment 83 is the amorphous form of aticaprant of any one of Embodiments 70-82, wherein the patient has anhedonia.
  • Embodiment 84 is the amorphous form of aticaprant of any one of Embodiments 70-83, wherein the patient has moderate anhedonia.
  • Embodiment 85 is the amorphous form of aticaprant of any one of Embodiments 70-84, wherein the patient has severe anhedonia.
  • Embodiment 86 is the amorphous form of aticaprant of any one of Embodiments 72-85, wherein the patient does not experience weight gain during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 87 is the amorphous form of aticaprant of Embodiment 86, wherein patient's body weight is assessed at the time of the initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 88 is the amorphous form of aticaprant of any one of Embodiments 70-87, wherein the patient does not experience a decrease in sexual functioning during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 89 is the amorphous form of aticaprant of Embodiment 88, wherein the sexual functioning of the patient is assessed at the time of initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 90 is the amorphous form of aticaprant of Embodiment 88 or 89, wherein the sexual functioning comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.
  • Embodiment 91 is the amorphous form of aticaprant of any one of Embodiments 88-90, wherein sexual functioning is assessed by the Arizona Sexual Experience Scale.
  • Embodiment 92 is the amorphous form of aticaprant of any one of Embodiments 83-85, 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 the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 93 is the amorphous form of aticaprant of any one of Embodiments 83-85 and 92, wherein 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.
  • Embodiment 94 is the amorphous form of aticaprant of Embodiment 92 or 93, wherein the anhedonia scale is the Snaith Hamilton Pleasure Scale.
  • Embodiment 95 is the use of a crystalline form of aticaprant or amorphous form of aticaprant in the manufacture of a medicament for treating major depressive disorder in a human patient.
  • Embodiment 96 is the use of the crystalline form of aticaprant of any one of Embodiments 1-15 or the amorphous form of aticaprant of any one of Embodiments 16-18 in the preparation of a medicament for treating major depressive disorder in human patient, wherein the patient had a previous inadequate response to other antidepressant therapy.
  • Embodiment 97 is the use of the crystalline form of aticaprant of any one of Embodiments 1-15 or the amorphous form of aticaprant of any one of Embodiments 16-18 in the preparation of a medicament for treating major depressive disorder in a human patient.
  • Embodiment 98 is the use of Embodiment 97, wherein the treatment comprises administration of an effective amount of the crystalline form of aticaprant or amorphous form of aticaprant.
  • Embodiment 99 is the use of Embodiment 97 or 98, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 100 is the use of any one of Embodiment 96 or 99, wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 101 is the use of any one of Embodiments 95-100, further comprising adjunctive treatment with an effective amount of one or more antidepressants.
  • Embodiment 102 is the use of any one of Embodiments 95-101, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
  • Embodiment 103 is the amorphous form of aticaprant of any one of Embodiments 95-102, wherein the crystalline form of aticaprant is the crystalline form of S-aticaprant or the amorphous form of aticaprant is the amorphous form of S-aticaprant.
  • Embodiment 104 is the amorphous form of aticaprant of any one of Embodiments 95-103, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 2 to about 35 mg.
  • Embodiment 105 is the amorphous form of aticaprant of Embodiment 104, wherein the effective amount of the crystalline form of aticaprant or the amorphous form of aticaprant is about 10 mg.
  • Embodiment 106 is the amorphous form of aticaprant of any one of Embodiments 95-105, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered orally.
  • Embodiment 107 is the amorphous form of aticaprant of any one of Embodiments 95-106, wherein the crystalline form of aticaprant or the amorphous form of aticaprant is administered once daily.
  • Embodiment 108 is the amorphous form of aticaprant of any one of Embodiments 95-107, wherein the patient has anhedonia.
  • Embodiment 109 is the amorphous form of aticaprant of any one of Embodiments 95-83, wherein the patient has moderate anhedonia.
  • Embodiment 110 is the amorphous form of aticaprant of any one of Embodiments 95-84, wherein the patient has severe anhedonia.
  • Embodiment 111 is the amorphous form of aticaprant of any one of Embodiments 77-85, wherein the patient does not experience weight gain during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 112 is the amorphous form of aticaprant of Embodiment 111, wherein patient's body weight is assessed at the time of the initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 113 is the amorphous form of aticaprant of any one of Embodiments 95-112, wherein the patient does not experience a decrease in sexual functioning during the treatment with the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 114 is the amorphous form of aticaprant of Embodiment 113, wherein the sexual functioning of the patient is assessed at the time of initial administration of the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 115 is the amorphous form of aticaprant of Embodiment 113 or 114, wherein the sexual functioning comprises sexual drive, sexual arousal, vaginal lubrication, erection, orgasm achievement, or orgasm satisfaction.
  • Embodiment 116 is the amorphous form of aticaprant of any one of Embodiments 113-114, wherein sexual functioning is assessed by the Arizona Sexual Experience Scale.
  • Embodiment 117 is the amorphous form of aticaprant of any one of Embodiments 108-110, 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 the crystalline form of aticaprant or the amorphous form of aticaprant.
  • Embodiment 118 is the amorphous form of aticaprant of any one of Embodiments 108-110 and 117, wherein 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.
  • Embodiment 119 is the amorphous form of aticaprant of Embodiment 117 or 118, wherein the anhedonia scale is the Snaith Hamilton Pleasure Scale.
  • Embodiment 120 is a package or pharmaceutical product comprising (i) the crystalline form of aticaprant of any one of Embodiments 1-15, the amorphous form of aticaprant of any one of Embodiments 16-18, or a combination thereof, and (ii) instructions for treating major depressive disorder in a human patient having anhedonia.
  • Example 1 Instrument and Methodology Details
  • A. X-ray Powder Diffraction (XRPD) [00130] Bruker AXS D8 Advance [00131] 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.
  • Samples were prepared and analyzed in either a metal or Millipore 96 well- plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1–2 mg) were used as received. The Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum. [00138] The scan mode for the metal plate used the gonio scan axis, whereas a 2 ⁇ scan was utilized for the Millipore plate.
  • Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every 60 seconds.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
  • TA Instruments Discovery DSC [00149] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 275 °C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.
  • D. Thermo-Gravimetric Analysis (TGA) [00152] TA Instruments Q500 [00153] TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. Typically, 1-5 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 mL/min was maintained over the sample.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
  • TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 position auto-sampler. Typically, 1-5 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 25 mL/min was maintained over the sample. [00157] The instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis. [00158] E. Polarized Light Microscopy (PLM) [00159] Leica LM/DM Polarized Light Microscope [00160] Samples were analyzed on a Leica LM/DM polarized light microscope with a digital video camera for image capture.
  • PLM Polarized Light Microscopy
  • G. Gravimetric Vapor Sorption (GVS) Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyzer, controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 °C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 mL/min. The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0–100 %RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by a microbalance (accuracy ⁇ 0.005 mg).
  • a microbalance accuracy ⁇ 0.005 mg.
  • 5-30 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions).
  • a moisture sorption isotherm was performed as outlined below (2 scans per complete cycle).
  • the standard isotherm was performed at 25 °C at 10 %RH intervals over a 0–90 %RH range.
  • a double cycle (4 scans) was carried out. Data analysis was carried out within Microsoft Excel using the DVS Analysis Suite. See, Table 15.
  • POLAG an alternative to liquid-assisted grinding, is a mechanochemical method that uses polymers in association with grinding for promoting and/or accelerating mechanochemical reactions.
  • Planetary Mill Procedure Aticaprant and the relevant polymer were placed in sample vials and two stainless steel grinding beads (3 mm diameter) were added. The mixtures were ground for 2 hours at 500 rpm using a planetary Fritsch Mill (Pulverisette 6) with an Automaxion adapter. After grinding all samples were initially analyzed by XRPD.
  • Example 3 - Generation and Characterization of Amorphous Aticaprant [00202] Both freeze drying and fast evaporation techniques were utilized to generate amorphous aticaprant. [00203] A.
  • Form III of aticaprant (20 mg) was weighed into 3 HPLC vials. Each vial was treated with 10 vol (250 ⁇ L) of the relevant solvent at 25 °C and shaken. The sample in t-BuOH was placed at 90 °C for a few seconds, where a solution was obtained. The solutions were filtered using a 0.45 ⁇ m PTFE membrane Acrodisc filter, before being flash frozen in an acetone/dry ice bath for 5 minutes. The samples were then freeze-dried overnight. The resulting solids were characterized by XRPD. [00205] Form III was shown to be soluble in 70% THF/H 2 O at RT (biphasic), and in t- BuOH at 90 °C.
  • BDE Blow-Down Evaporation
  • T g was determined to be 45.5 °C by mDSC. See, Table 19 for the characterization of amorphous aticaprant.
  • Example 4 - Polymorph Screens [00211] A. Solubility Assessment [00212] Form III of aticaprant (20 mg) was dispensed into amber HPLC vials with a magnetic stirrer bar. Each vial was treated with the relevant solvent (5 vol) at RT and stirred at 300 rpm for 10 mins. If suspensions were still observed, Form III of aticaprant (20 mg) was dispensed into amber HPLC vials (x 49) with a magnetic stirrer bar. Each vial was treated with the relevant solvent (5 vol) at RT and stirred at 300 rpm for 10 mins.
  • Form III of aticaprant was obtained from water, DMSO (after maturation of the gum formed at 25/50 °C for 8 days), diethyl ether (crystalline), DCM (crystalline), heptane, 3-methyl-1-butanol, water/methanol (20%), nitromethane, chloroform (crystalline) and cyclohexane.
  • B. Low Temperature Polymorphism Screen [00216] The low temperature polymorph screen was carried out using amorphous aticaprant at 5 °C. Amorphous aticaprant (30 mg), generated by BDE in section “Blow-Down Evaporation (BDE) Procedure” noted above, was used. Each vial was treated with the solvent noted in Table 21 in a given volume to produce a slurry at 5 °C and stirred at 500 rpm for 10 mins. For clear solutions at 10 mins that converted to slurries, a small aliquot was taken and analyzed by XRPD. Any samples remaining as clear solutions were set aside and cooled to RT overnight, and later treated with antisolvent. Results of the low-temperature polymorph screen can be found in Table 21.
  • Form III was obtained from antisolvent addition of heptane to a number of solvent systems.
  • D. Temperature Cycling Polymorph Screen 25/50 °C was carried out on amorphous aticaprant. Samples were treated with the solvent (2.5-5 vol, depending on solubility) in Table 23. Initial observations were made before the samples were placed on a platform shaker incubator programmed at 4 h cycles at 25/50 °C. Observations were made after one day and 7 days, and any solids were analyzed by XRPD. Samples remaining as solutions were treated with cold antisolvent (either n-heptane or water), before being placed back in the maturation chamber.
  • cold antisolvent either n-heptane or water
  • Table 24 Stock solutions of Form III of aticaprant in DMSO and t- BuOH [00230] The solutions were then split into the relevant number of vials to give 30 mg per HPLC vial. Samples in DMSO and t-BuOH were placed in the freezer for ca.1 h, after which were removed and treated with the relevant antisolvent in 5:1 antisolvent/solvent ratio. The antisolvent was added slowly to the frozen solution. Samples were then left to stand at RT. The results of the solvent deposition screen can be found in Table 25. [00231] Solutions that had not produced solids after 6 days were removed from the refrigerator and lids were removed to evaporate the solvent.
  • a solid was also produced in the sample in t- BuOH/cyclohexane after being left to evaporate for 6 days, shown to be Form II by XRPD.
  • the t-BuOH sample was isolated via vacuum filtration, and left to dry for 2 h under vacuum. After this time, it was covered and left overnight.
  • F. Solvent Interfacial Crystallization Screen [00233] Solvent interfacial screening was carried out by utilizing immiscible solvent/antisolvent combinations. Stock solutions of Form III of aticaprant were initially made. See, Table 26. The solutions were then split into vials to give 30 mg per vial. The samples were treated with the relevant antisolvent in 5:1 antisolvent/solvent ratio. Samples were then left to stand at RT.
  • Form I Characterization of Form I, Form II, and Form III
  • Form I was obtained in the screens from ethyl acetate and MEK (both through solvent evaporation). It also was obtained from addition of heptane antisolvent to solutions in ethyl acetate and diethyl ether.
  • the sample from the solubility assessment in ethyl acetate was isolated and characterized by XRPD, 1 H NMR, and DSC (Fig.7), and static storage at elevated temperature and humidity. The results are shown Table 30.
  • DSC shows a broad endotherm, at 92.9 °C (57.4 J/g). After static storage, the sample was shown to remain as Form I.
  • Form II is likely an anhydrous form, which remains stable after storage at elevated temperature and humidity.
  • Form II was obtained from the static storage of amorphous Aticaprant for 1 week at 40 °C/75% RH, and was also observed several times in the screens from amorphous.
  • Form II is anhydrous, and exhibits low hygroscopicity, and remains stable through both GVS analysis and static storage at elevated temperature and humidity conditions (40 °C/75% RH and 25°C/97% RH).
  • Form III [00242] Form III exhibits desirable solid-state characteristics and appears to be the most stable form.
  • Form III of aticaprant was found to be crystalline by XRPD.
  • 1 H NMR showed that the material was consistent with the proposed structure, with the presence of residual ethyl acetate.
  • Ion chromatography showed that there were no cations/anions present, and HPLC showed 99.8% purity.
  • the DSC (heating from 20 to 131 °C at 10°C/min) showed a peak temperature at 121°C. See, Fig.12.
  • Example 6 Scale Up of Form I [00251]
  • Form III of aticaprant (0.5 g) was weighed into a large vial. The solid was dissolved in ethyl acetate (2.5 mL/5 vol). The solution was left to evaporate (vial lid loosened) overnight. The next morning, a solution remained. The sample was placed in the vacuum oven for ca. 1 h to further concentrate the solution. After this time, a white precipitate had begun to form. The suspension was left at RT overnight, after which a white solid was obtained.
  • the solid was dissolved in DMSO (13.3 mL/13.3 vol), and the solution was placed in the freezer for ca.30 mins. To the frozen solution was slowly added water (added around sides of bottle with rotation to minimize perturbation of the solid, in 10 mL aliquots), until a total of 50 mL water had been added. A white suspension was formed on top of the frozen solvent layer almost immediately. The suspension was left to stand for four days. After this time, the sample appeared more uniform, (no longer two layers), slight white ppt on top, and gummy solid on bottom of container. The sample was placed for maturation overnight (25/50 °C - 4 h cycles).
  • agglomerates comprised of smaller particles ( ⁇ 10 ⁇ m in size), as well as the presence of plates in the agglomerates (ca.60 ⁇ m in length), and larger, ridged particles ( ⁇ 120 ⁇ m in length).
  • Form II remained stable after static storage at elevated temperature and humidity conditions for 1 week.
  • 1 H NMR of the isolated solid showed the presence of residual DMSO (0.08 mol. eq).
  • TGA showed a small mass loss ambient – 108 °C (0.95%/ ⁇ 0.05 mol. eq. DMSO), along with additional mass loss from 108-255 °C, attributed to the onset of decomposition onset.
  • the XRPD is shown in Fig. 8.
  • DSC analysis showed an endotherm at 74.7 °C (4.7 J/g), overlapping with a second, sharper endotherm at 96.2 °C (onset, 51.3 J/g). See, Fig.9.
  • GVS analysis showed that Form II is slightly hygroscopic. A mass uptake of 0.26 % is observed from 40-90% RH in the first cycles, with a mass loss of 0.57%. Similar mass water uptake (0.25%) is observed in the second sorption cycle, with all the water being lost again in the second desorption cycle, with a slight hysteresis observed. See, Figs. 10-11. XRPD analysis post-GVS shows the sample to remain as Form II. HPLC analysis shows a purity of 99.7%.
  • Microscopy analysis by SEM/PLM shows the presence of irregular particles.
  • Particle size ranges from ⁇ 10 ⁇ m and up to ca. 200 ⁇ m.
  • Large agglomerates are present comprised of smaller particles ( ⁇ 10 ⁇ m in size), plates also present in the agglomerates (ca.60 ⁇ m in length), as well as larger ridged particles ( ⁇ 120 ⁇ m in length).
  • Static storage at elevated temperature and humidity conditions 40 °C/75% RH and 25°C/97% RH shows the sample to remain as Form II. See, Table 36.
  • Example 8 [00263] This was a multi-center, placebo-controlled, randomized, double-blind study in subjects with MDD who have had an inadequate response to SSRI/SNRI treatment.
  • 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. [00267] 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. 14. [00272] Subjects were screened within 35 to 2 days prior to Day 1 to ascertain their eligibility per the inclusion and exclusion criteria.
  • TES Time and Events Schedule
  • EW visit should be completed.
  • 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. [00277] 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. [00278] C. Dosage and Administration [00279] 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. [00280] When Visit 11 was planned up to 3 days later, the subject continued medication until Visit 11. [00281] The capsules were swallowed whole and not chewed, divided, dissolved or crushed. After having taken the medication, subjects did not to eat or drink for at least 30 minutes.
  • the first dose was taken in fasting condition on Day 2 of the double-blind phase.
  • the dose of the medication was: • 10 mg aticaprant: 2 capsules of 5 mg aticaprant • Placebo: 2 placebo capsules.
  • 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 endpoints was performed at a significance level of 0.20 (two-sided). No adjustment for multiple comparisons was performed. [00306] F.
  • the effect size was 0.36 and 0.23, respectively. See, Figs.15 and 16.
  • Full ITT Analysis Set [00312] The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), ranging from 0 to 41. See, Figs.20-A and 20-B.
  • the mean changes from treatment baseline in MADRS total score at Treatment Week 6 for fITT were smaller than for eITT: -9.7 (8.02) for aticaprant and -6.6 (8.57) for placebo.
  • the observed effect size was 0.36.
  • LSMeans difference estimate was -3.0 (80% 1-sided CI upper limit of -1.88) for eITT and -3.4 (80% 1-sided CI upper limit of -2.51) for fITT.
  • (ii) Secondary Endpoints [00317] MADRS Remission Rates over Treatment Period [00318] At Treatment Week 6 the percentage of subjects with MADRS remission (MADRS total score ⁇ 10) in the eITT population was 16.9% for aticaprant and 16.9% for placebo. Treatment week 6 remission rates in fITT population were 31.2% for aticaprant and 22.2% for placebo.
  • C max is defined as maximum plasma concentration of aticaprant.
  • the eITT population included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period.
  • 'N' number of subjects analyzed includes the number of subjects evaluable for this endpoint.
  • 'n' number analyzed included all subjects evaluable for specified time point categories.
  • 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.
  • greater improvement in items related to anhedonia and dysphoria in subgroup with high anhedonia vs low anhedonia See, Fig. 31.
  • Sexual pleasure is an important component of hedonic tone.
  • the brain reward circuitry is controlled by several areas: nucleus accumbens, ventral tegmental area and the amygdala. It is hypothesized that treatment with kappa opioid receptors may restore the normal homeostatic balance in patients with overactivation. Treatment with aticaprant could potentially improve symptoms of anhedonia. Other symptoms associated with the reward circuitry includes: sexual pleasure, lack of interest and lack of enjoyment.

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