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WO2024116127A1 - Venglustat en combinaison avec un inhibiteur fort ou modéré de cyp3a4 - Google Patents

Venglustat en combinaison avec un inhibiteur fort ou modéré de cyp3a4 Download PDF

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Publication number
WO2024116127A1
WO2024116127A1 PCT/IB2023/062098 IB2023062098W WO2024116127A1 WO 2024116127 A1 WO2024116127 A1 WO 2024116127A1 IB 2023062098 W IB2023062098 W IB 2023062098W WO 2024116127 A1 WO2024116127 A1 WO 2024116127A1
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WO
WIPO (PCT)
Prior art keywords
venglustat
pharmaceutically acceptable
acceptable salt
dosage
inhibitor
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/IB2023/062098
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English (en)
Inventor
Nigel Patrick Somerville CRAWFORD
Li Li
Jyoti Sharma
Yan-yan ZHANG
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Genzyme Corp
Original Assignee
Genzyme Corp
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Filing date
Publication date
Application filed by Genzyme Corp filed Critical Genzyme Corp
Priority to EP23821741.8A priority Critical patent/EP4626424A1/fr
Priority to CN202380089614.9A priority patent/CN120417900A/zh
Priority to IL321165A priority patent/IL321165A/en
Priority to KR1020257021380A priority patent/KR20250106321A/ko
Priority to AU2023403087A priority patent/AU2023403087A1/en
Publication of WO2024116127A1 publication Critical patent/WO2024116127A1/fr
Priority to MX2025006345A priority patent/MX2025006345A/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • RESULTS OF TREATMENT USING AN INHIBITOR OF GLUCOSYLCERAMIDE SYNTHASE Provided herein are methods in which patients are administered venglustat in combination with inhibitors of cytochrome CYP3A4, such as itraconazole or fluconazole.
  • the methods may involve making specific adjustments to the venglustat dosage in order to optimise the clinical response of the patient.
  • Venglustat also known as (S)-quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2- ylcarbamate
  • lysosomal storage diseases such as Gaucher disease (See, e.g., WO 2012/129084), proteinopathies such as Alzheimer’s disease and Parkinson’s disease (See, e.g., WO 2016/145046), cystic diseases such as polycystic kidney disease (See, e.g., WO 2014/043068), and ciliopathies such as Bardet-Biedl Syndrome (See, e.g., WO 2020/163337), the contents of each of which applications are hereby incorporated by reference in their entirety.
  • venglustat which is an inhibitor of the enzyme glucosylceramide synthase (GCS)
  • GCS glucosylceramide synthase
  • reducing glycolipid levels e.g., in the case of lysosomal storage diseases
  • reducing protein aggregation e.g., in the case of proteinopathies
  • decreasing apoptosis e.g., in the case of cystic diseases
  • improving the function of ciliary bodies in ciliated epithelial cells e.g., in the case of ciliopathies.
  • Small molecule GCS inhibitors such as venglustat, are primarily intended for oral administration on a regular (e.g., daily) basis.
  • Compounds administered orally may be subject to first-pass metabolic deactivation by the liver, which can reduce their oral bioavailability.
  • oral dosage forms can sometimes require larger dosages to achieve therapeutic efficacy than would be required if the active agent were administered via another route (e.g., intravenously).
  • DDIs drug-drug interactions
  • cytochrome P 450 3A4 CYP3A4
  • the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein said subject is concurrently being administered a strong or moderate inhibitor of CYP3A4.
  • a further aspect provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein said subject is concurrently being administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of venglustat is increased by between about 5% and 25% as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the venglustat or the pharmaceutically acceptable salt thereof is administered in a dosage of about 12 mg per day or a dosage of about 15 mg per day (calculated as the free base).
  • the CYP3A4 inhibitor is a strong inhibitor which increases the plasma exposure of venglustat by between about 60% and 120% as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of between about 4 mg and 15 mg per day (calculated as the free base). In embodiments, the venglustat or the pharmaceutically acceptable salt thereof is administered in a dosage of about 8 mg per day (calculated as the free base).
  • the CYP3A4 inhibitor is a moderate inhibitor which increases the plasma exposure of venglustat by between about 40% and 60% as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or the pharmaceutically acceptable salt thereof is administered in a dosage of between about 12 mg and 15 mg per day (calculated as the free base). In embodiments, the venglustat or the pharmaceutically acceptable salt thereof is administered in a dosage of about 15 mg per day (calculated as the free base).
  • the venglustat is in the form of venglustat free base, a pharmaceutically acceptable salt of venglustat, or a prodrug of venglustat, optionally venglustat L-malate salt.
  • the venglustat or the pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered in combination, e.g., in the same pharmaceutical composition.
  • the venglustat or the pharmaceutically acceptable salt thereof is administered orally and the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally.
  • the disease or disorder is selected from a lysosomal storage disease (e.g., Gaucher disease or Fabry disease), a proteinopathy (e.g., Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease), a cystic disease (e.g., polycystic kidney disease), and a ciliopathy (e.g., Bardet-Biedl syndrome).
  • a lysosomal storage disease e.g., Gaucher disease or Fabry disease
  • a proteinopathy e.g., Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease
  • a cystic disease e.g., polycystic kidney disease
  • a ciliopathy e.g., Bardet-Biedl syndrome
  • the subject has a co-morbidity selected from a fungal infection, a viral infection, a bacterial infection, a mood disorder, and a cancer.
  • the disclosure also provides venglustat or a pharmaceutically acceptable salt thereof (or a combination of venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor, e.g., a composition comprising venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor) for use in a method as defined hereinbefore.
  • the disclosure also provides the use of venglustat or a pharmaceutically acceptable salt thereof (or a combination of venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor, e.g., a composition comprising venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor) in the manufacture of a medicament for use in a method as defined hereinbefore.
  • the disclosure also provides a method for optimizing (e.g., reducing) the dosage of venglustat in a subject being treated with or intended to be treated with venglustat or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor.
  • the disclosure also provides a method for minimising the drug-drug interaction between venglustat and a moderate or strong CYP3A4 inhibitor in a subject suffering from a disease or disorder which is amenable to treatment with venglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with said CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) adjusting the dosage of the venglustat or the pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.
  • the disclosure also provides a method for establishing the correct dosage of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of the venglustat or the pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.
  • the disclosure also provides a method for improving a dosage regimen of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of the venglustat or the pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.
  • the disclosure also provides a method for managing the risk of venglustat/CYP3A4 inhibitor interaction in a subject having a disease or disorder which is amenable to treatment with venglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) initiating treatment in the subject with venglustat or a pharmaceutically acceptable salt thereof at a standard indicated dose; (ii) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (iii) reducing the dosage if the change in plasma exposure is an increase of more than about 25%.
  • the disclosure also provides the use of a strong or moderate CYP3A4 inhibitor in a method for: (a) establishing the correct dosage of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof; (b) improving a dosage regimen of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof; or (c) managing the risk of venglustat/CYP3A4 inhibitor interaction in a subject having a disease or disorder which is amenable to treatment with venglustat or a pharmaceutically acceptable salt thereof, wherein the subject is being administered or is intended to be administered said CYP3A4 inhibitor.
  • the disclosure also provides a method for inhibiting CYP3A4 activity in a subject being treated with venglustat or a pharmaceutically acceptable salt thereof, the method comprising concurrently administering the venglustat or the pharmaceutically acceptable salt thereof with a strong or moderate CYP3A4 inhibitor.
  • the disclosure also provides a method for improving the therapeutic response to venglustat treatment in a subject in need thereof, the method comprising concurrently administering venglustat or a pharmaceutically acceptable salt thereof with a strong or moderate CYP3A4 inhibitor.
  • the disclosure also provides a pharmaceutical composition (e.g., an oral pharmaceutical dosage form) comprising venglustat or a pharmaceutically acceptable salt thereof, in combination with a strong or moderate CYP3A4 inhibitor, and at least one pharmaceutically acceptable excipient.
  • the composition is formulated for oral administration.
  • the composition is a dosage form selected from a capsule (e.g., a hard capsule) and a tablet (e.g., a chewable tablet, an orally disintegrating tablet, a dispersible tablet, or a classic tablet or caplet).
  • a composition as defined hereinbefore for use in a method as defined hereinbefore. Additional features and advantages of the compositions and methods disclosed herein will be apparent from the following detailed description.
  • Fig.1 shows the study design of the clinical study described in Example 4.
  • Fig.2 shows the mean (+SD) plasma concentrations of venglustat following single-dose administration of 15 mg venglustat alone (calculated as free base – open triangles); and following co-administration of 15 mg venglustat with repeated-dose itraconazole (100 mg BID – open circles).
  • Fig.3 shows observed (clinical study) and mean (with 5th and 95th percentile) predicted venglustat plasma concentrations in healthy male subjects following single oral dose of 11.2 mg (Fig.3A), 18.6 mg (Fig.3B), and 112 mg (Fig.3C) venglustat (Cartesian scale).
  • the grey lines represent the predictions from individual trials.
  • the dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black solid lines represent the simulated mean plasma concentration-time profiles.
  • the open circles represent the individual observed concentrations from the clinical study.
  • Fig.4 shows observed (clinical study) and mean (with 5th and 95th percentile) predicted venglustat plasma concentrations in healthy male subjects following single oral dose of 11.2 mg (Fig.4A), 18.6 mg (Fig.4B), and 112 mg (Fig.4C) venglustat (semi-log scale).
  • the grey lines represent the predictions from individual trials.
  • the dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black solid lines represent the simulated mean plasma concentration-time profiles.
  • Fig.5 shows observed (clinical study) and mean (with 5th and 95th percentile) predicted venglustat plasma concentrations in healthy male subjects following repeated QD oral dose of 3.72 mg (Fig.5A), 7.44 mg (Fig.5B), and 14.9 mg (Fig.5C) venglustat (Cartesian scale).
  • the grey lines represent the predictions from individual trials.
  • the dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black solid lines represent the simulated mean plasma concentration-time profiles.
  • the open circles represent the individual observed concentrations from the clinical study.
  • Fig.6 shows observed (clinical study) and mean (with 5th and 95th percentile) predicted venglustat plasma concentrations in healthy male subjects following repeated QD oral dose of 3.72 mg (Fig.6A), 7.44 mg (Fig.6B), and 14.9 mg (Fig.6C) venglustat (semi-log scale).
  • the grey lines represent the predictions from individual trials.
  • the dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black solid lines represent the simulated mean plasma concentration-time profiles.
  • the open circles represent the individual observed concentrations from the clinical study.
  • Fig.7 shows simulated mean (with 5th and 95th percentile) venglustat plasma concentrations plasma concentrations in healthy male subjects following single oral dose of 15 mg of venglustat without (Fig.7A) and with (Fig.7B) co-medication of itraconazole 100 mg BID (Cartesian scale).
  • the simulated profiles are overlayed with individual observed venglustat concentrations (open circles).
  • the black solid line represents simulated mean plasma concentration-time profiles of venglustat without itraconazole interaction
  • the grey solid lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black dashed line represents the simulated mean plasma concentration-time profiles of venglustat with itraconazole interaction
  • the grey dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the open circles represent the individual observed concentrations in the study of Example 4.
  • Fig.8 shows simulated mean (with 5th and 95th percentile) venglustat plasma concentrations plasma concentrations in healthy male subjects following single oral dose of 15 mg of venglustat without (Fig.8A) and with (Fig.8B) co-medication of itraconazole 100 mg BID (semi-log scale).
  • the simulated profiles are overlayed with individual observed venglustat concentrations (open circles).
  • the black solid line represents simulated mean plasma concentration-time profiles of venglustat without itraconazole interaction
  • the grey solid lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black dashed lines represent the simulated mean plasma concentration-time profiles of venglustat with itraconazole interaction
  • the grey dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the open circles represent the individual observed concentrations in the study of Example 4.
  • Fig.9 shows observed (Example 4) and mean (with 5th and 95th percentile) predicted plasma concentrations of itraconazole (Fig.9A) and its primary metabolite hydroxyitraconazole (Fig.
  • Fig.10 shows observed (Example 4) and mean (with 5 th and 95 th percentile) predicted plasma concentrations of itraconazole (Fig.10A) and its primary metabolite hydroxyitraconazole (Fig.10B) in healthy male subjects following itraconazole 100 mg BID (semi-log scale).
  • the grey solid lines represent the predictions from individual trials.
  • the dashed lines represent the 5 th and 95 th percentile of the total virtual population.
  • the black solid lines represent the simulated mean plasma concentration-time profiles.
  • the grey dots (at approximately 125, 160, and 220 hours) represent individual observed concentrations in the study of Example 4.
  • compositions and methods when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass both “consisting essentially of” and “consisting of”.
  • a “subject”, “individual”, or “patient” is used interchangeably herein, and refers to a human.
  • the term “healthy individual” as used herein typically denotes an individual who does not suffer from a condition which is amenable to treatment with venglustat.
  • a healthy individual may be an individual who does not suffer from a lysosomal storage disease such as Gaucher disease, a proteinopathy such as Alzheimer’s disease or Parkinson’s disease, a cystic disease such as polycystic kidney disease, or a ciliopathy such as Bardet-Biedl Syndrome.
  • a healthy individual typically does not have any GBA mutations.
  • a healthy individual may lack mutations in any gene which encodes an enzyme involved in the glycosphingolipid pathway, for example mutations in the genes encoding ceramide synthase, glucosylceramide synthase, galactosylceramide synthase, lactosylceramide synthase, sphingomyelin synthase, ceramidase, glucocerebrosidase, saposin, galactosylceramide ⁇ - galactosidase, acid sphingomyelinase, arylsulphatase A, ⁇ -galactosidase A, ⁇ -hexosaminidase (e.g., Hex A or Hex B), sialidase, GM1- ⁇ -galactosidase, GM2 ganglioside activator protein, glucosyl transferase, and galactosyl transferase.
  • ceramide synthase
  • administering is defined herein as a means of providing an agent (e.g., active ingredient) or a composition containing the agent to a subject in a manner that results in the agent being inside the subject’s body.
  • agent e.g., active ingredient
  • Such an administration can be by any route including, without limitation, oral, dermal, transdermal, transmucosal (e.g., vaginal, rectal, buccal, or sublingual), by injection (e.g., subcutaneous, intravenous, intraperitoneal, intrathecal, intramuscular, intradermal), and by inhalation (e.g., pulmonary, intranasal).
  • Pharmaceutical preparations are, of course, given by forms suitable for each administration route. Administration may also be local or systemic in nature.
  • compositions and methods of the present disclosure are typically directed towards enteral, e.g. oral, administration.
  • enteral e.g. oral
  • “concurrent” and “concurrently” when referring to a therapeutic use means administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are given at the same or different times or whether given by the same or different routes of administrations.
  • the terms “concomitant” and “in conjunction with” as used herein are intended to have an equivalent meaning.
  • Concurrent administration of the two or more active ingredients may be at different times on the same day, or on different dates or at different frequencies.
  • Concurrent administration of the two or more active agents may be intended to treat a single disease or disorder in the patient, but it is typically used herein to refer to the administration of two or more active agents which are effective in treating two or more different diseases or disorders, e.g., wherein each active agent is effective in treating a separate disease or disorder independently of the other active agent(s).
  • the term “simultaneously” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time, typically by the same route of administration.
  • This may refer to administering the two or more active ingredients in a single dosage form or in multiple separate dosage forms which are administered at or about the same time.
  • this may refer to administering to a patient a single oral tablet or capsule comprising two or more active ingredients, or administering two or more oral tablets or capsules comprising between them two or more active ingredients.
  • the two or more active agents will typically be intended to treat two or more different diseases or disorders, e.g., each active agent is effective in treating a separate disease or disorder independently of the other active agent(s).
  • the term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different routes of administration, or administration of two or more active ingredients at different times by the same or different routes of administration.
  • the term “separately” includes administering one active ingredient by injection or inhalation while administering a separate active ingredient orally, when both administrations are taking place at about the same time.
  • the term “separately” includes administering one active ingredient orally at a particular time of day, e.g. in the morning, while administering a separate active ingredient orally at a different time of day, e.g.
  • separate administration would also encompass a dosing regimen under which, for example, one drug is taken on days 1, 3, 5, etc., and another drug is taken on days 2, 4, 6, etc.
  • the two or more active ingredients or drugs will typically be intended to treat two or more different diseases or disorders, e.g., each active agent is effective in treating a separate disease or disorder independently of the other active agent(s).
  • the phrase “at or about the same time” is understood to generally mean two events taking place with less than 30 minutes between them, e.g. less than 20 minutes, or less than 15 minutes, or less than 10 minutes, or less than 5 minutes.
  • “at or about the same time” would include any overlap between such periods of time or the beginning of one such period of time within about 30 minutes of the ending of the previous period of time.
  • “Treating” or “treatment” of a disease includes: (1) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (2) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.
  • “Preventing” or “prevention” of a disease includes causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease.
  • a disease which is “amenable to treatment” with or “treatable by” a particular active agent is a disease which can be treated and/or prevented by the active agent in at least some patients who are suffering from the disease or who are predisposed to the disease.
  • the term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with the disease.
  • the term “suffering” as it relates to the term “prevention” refers to a patient or individual who is predisposed to the disease.
  • a patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease.
  • an “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the severity of the particular disorder being treated, and the form of administration.
  • dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on suitable doses for patient administration.
  • one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with a disease or disorder described herein, ex vivo, in vitro, or in vivo.
  • a “standard indicated dose” refers to the recommended amount of a therapeutic agent for a subject in the absence of variables which may require dose adjustment, e.g., concurrent administration with one or more additional agents as defined herein. Where such variables are present, an “adjusted dose” or “adjusted effective amount” may administered – this may be the same amount or a different amount of the therapeutic agent as compared with a “standard indicated dose” or an “effective amount” for a different (e.g., an average) subject.
  • CYP is an abbreviation for Cytochrome P450 (or Cytochrome Oxidase P450), a family of mammalian enzymes expressed predominantly in the liver which are largely responsible for the oxidative metabolism of many drugs.
  • CYP enzymes There are at least 57 common types of CYP enzymes, and these are group into families.
  • the CYP 3A family includes, among other enzymes, the related CYP3A4 and CYP3A5 enzymes, which collectively account for a large portion of mammalian drug metabolism.
  • CYP3A4 is the predominant cytochrome involved in the metabolism of venglustat and it is responsible for about 80% of venglustat metabolism in human liver microsomes.
  • the term “inhibitor” has its commonly recognized pharmacological meaning.
  • An inhibitor is thus a compound (typically a small molecule) which inhibits, either competitively or non-competitively (e.g., allosterically) the functioning of an enzyme, receptor, or other macromolecular target (e.g., protein).
  • Inhibitors generally operate either by binding to the active site of an enzyme or receptor, blocking access by the normal substrate, or by binding to an allosteric site which results in a conformational change in the enzyme or receptor which reduces the enzyme or receptor’s activity.
  • Competitive inhibitors bind to the active site, and may cause either reversible or irreversible inhibition, the latter often by covalent attachment to the active site.
  • Inhibition of an enzyme in the presence of a compound may also occur indirectly, e.g., if one or more metabolites of the compound are themselves inhibitors (e.g., reversible or irreversible, and/or competitive or non-competitive inhibitors) of the enzyme.
  • the term “CYP3A4 inhibitor” therefore refers to a small molecule compound which inhibits the enzymatic activity of the CYP3A4 enzyme, either competitively or non- competitively, and either reversibly or irreversibly.
  • CYP3A4 inhibitors can be described as strong, moderate, or weak (See, e.g.: “Common Medications Classified as Weak, Moderate and Strong Inhibitors of CYP3A4”, EBM Consult (October 2015), which can be accessed at https://www.ebmconsult.com/articles/medications-inhibitors-cyp3a4-enzyme; and Flockhart “Drug Interactions: Cytochrome P450 Drug Interaction Table”, Indiana University School of Medicine (2007), which can be accessed at https://drug-interactions.medicine.iu.edu).
  • Examples of strong CYP3A4 inhibitors include clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, troleandomycin, voriconazole, ceritinib, and idelalisib.
  • moderate CYP3A4 inhibitors include fluconazole, amiodarone, erythromycin, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan, chamomile, licorice, wild cherry, echinacea angustifolia, fluvoxamine, aprepitant, ciprofloxacin, crizotinib, cyclosporine, dronedarone, imatinib, isavuconazole, and tofisopam.
  • Examples of weak CYP3A4 inhibitors include cimetidine, chlorzoxazone, cilostazol, clotrimazole, fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, and ticagrelor.
  • pharmaceutically acceptable excipient encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • Pharmaceutical compositions also can include stabilizers and preservatives.
  • the term “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • Addition salts can be readily prepared using conventional techniques, e.g., by treating a base compound with a defined amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol.
  • Acids which can be used to prepare pharmaceutically acceptable acid addition salts are those which can form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate [i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • pharmacologically acceptable anions such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate
  • Bases which can be used to prepare the pharmaceutically acceptable base addition salts are those which can form non-toxic base addition salts, e.g., salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N- methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.
  • Addition salts of venglustat are typically acid addition salts.
  • the pharmaceutically acceptable salt of venglustat is venglustat malate, in particular venglustat L-malate.
  • a mass quantity of venglustat referred to herein corresponds, unless explicitly stated otherwise, to a mass of venglustat calculated as free base.
  • a “15 mg dose of venglustat” refers to an amount of 15 mg of venglustat free base, or to an amount of a salt or prodrug of venglustat which provides an equivalent molar quantity (e.g., 20 mg of venglustat malate salt).
  • references to “venglustat” throughout this specification include the pharmaceutically acceptable salts and prodrugs of venglustat, e.g. as described herein.
  • the recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • Venglustat (free base) has a chemical structure according to Formula (I) below, and it may conveniently be provided in the form of a malate addition salt (e.g., prepared as described in the following Examples).
  • F Venglustat is an oral GCS inhibitor under development for the treatment of Fabry disease, Gaucher disease, and GM2 gangliosidosis. Venglustat is primarily metabolized by CYP3A4.
  • Itraconazole is an antifungal medication which has also been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer. It has also been studied for use in conjunction with other chemotherapeutic agents for advanced and metastatic basal cell carcinomas that cannot be treated surgically. Itraconazole can be administered orally, topically, and intravenously. For oral administration, it is typically formulated as a tablet or capsule which may contain about 100 mg of the active per dose. Fluconazole is another antifungal medication.
  • Fluvoxamine is a selective serotonin reuptake inhibitor having antidepressant properties. It is used to treat major depressive disorder and obsessive–compulsive disorder (OCD), as well as other anxiety disorders such as panic disorder, social anxiety disorder, and post-traumatic stress disorder. It is typically administered orally in a dosage starting at 50-100 mg daily which can be increased up to around 300 mg daily, if necessary.
  • OCD obsessive–compulsive disorder
  • PBPK physiologically based pharmacokinetic
  • the present disclosure provides dosage regimens for treatment with venglustat in patients being co-administered CYP3A4 inhibitors.
  • the disclosure provides a validated approach to account for co-administration of a moderate or strong CYP3A4 inhibitor alongside venglustat, thereby enabling safe and effective treatments to be provided in these patient populations.
  • the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein said subject is concurrently being administered a strong or moderate inhibitor of CYP3A4.
  • the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein said subject is concurrently being administered a strong or moderate inhibitor of CYP3A4.
  • a further related aspect provides the use of venglustat in the manufacture of a medicament for use in a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat and concurrently administering a strong or moderate inhibitor of CYP3A4.
  • the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and a strong or moderate inhibitor of CYP3A4.
  • a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and a strong or moderate inhibitor of CYP3A4 for use in a method for treating a disease or disorder in a subject in need thereof.
  • a further related aspect provides the use of venglustat or a pharmaceutically acceptable salt thereof and a strong or moderate inhibitor of CYP3A4 in the manufacture of a medicament for use in a method for treating a disease or disorder in a subject in need thereof.
  • the strong or moderate inhibitor of CYP3A4 is a competitive inhibitor of CYP3A4.
  • one or more metabolites of the strong or moderate inhibitor of CYP3A4 is capable of inhibiting CYP3A4, e.g., such that the strong or moderate inhibitor can increase venglustat exposure through mechanism-based inhibition.
  • the strong or moderate inhibitor of CYP3A4 is a triazole antifungal agent, e.g., itraconazole or fluconazole.
  • the disclosure also provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein said subject is concurrently being administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of venglustat is increased by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • AUC plasma exposure
  • the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject is concurrently being administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of venglustat is increased by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • AUC inhibitor of CYP3A4 inhibitor
  • a further related aspect provides the use of venglustat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject is concurrently being administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of venglustat is increased by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the plasma exposure e.g., AUC
  • the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of venglustat is increased by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • a combination of e.g., a composition comprising
  • venglustat or a pharmaceutically acceptable salt thereof e.g., an inhibitor of CYP3A4
  • the disclosure provides a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4, for use in a method for treating a disease or disorder in a subject in need thereof, whereby the plasma exposure (e.g., AUC) of venglustat is increased by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • a combination of e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4
  • the plasma exposure e.g., AUC
  • a further related aspect provides the use of venglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4 in the manufacture of a medicament for use in a method for treating a disease or disorder in a subject in need thereof, whereby the plasma exposure (e.g., AUC) of venglustat is increased by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the disease or disorder is amenable to treatment with venglustat (or a pharmaceutically acceptable salt thereof). Exemplary diseases and disorders which are treatable by venglustat are described herein.
  • the plasma exposure of venglustat is the AUC of venglustat, e.g., AUC0-12, AUC0-24, AUClast, or AUC ⁇ .
  • the plasma exposure of venglustat is the AUC last of venglustat.
  • the plasma exposure of venglustat is measured experimentally.
  • the plasma exposure of venglustat is estimated by modelling, e.g., by modelling as described herein.
  • the venglustat or the pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered separately, e.g., in separate pharmaceutical compositions, by different modes of administration, and/or at different times (e.g., on different days, or at different times on the same day).
  • the venglustat or the pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered in combination, e.g., in the same pharmaceutical composition.
  • the CYP3A4 inhibitor is a strong inhibitor.
  • the inhibitor increases the plasma exposure of venglustat by at least about 50% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the strong inhibitor increases the plasma exposure of venglustat by at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 92%, 95%, 98%, or 100% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the strong inhibitor increases the plasma exposure of venglustat by between about 50% and 400%, e.g., between about 55% and 300%, between about 60% and 200%, or between about 65% and 150%, as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the strong inhibitor increases the plasma exposure of venglustat by between about 50% and 150% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is an amount of from about 25% to 100% of the standard indicated dose for the disease or disorder being treated (e.g., an amount of from about 50% to 100% of the standard indicated dose).
  • the strong inhibitor increases the plasma exposure of venglustat by between about 60% and 90% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is 100% of the standard indicated dose for the disease or disorder being treated.
  • the strong inhibitor increases the plasma exposure of venglustat by between about 90% and 120% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is an amount of from about 50% to 75% of the standard indicated dose for the disease or disorder being treated.
  • the strong inhibitor increases the plasma exposure of venglustat by between about 60% and 150% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of between about 4 mg and 15 mg per day (calculated as the free base), e.g., a dosage of between about 8 mg and 12 mg per day (calculated as the free base).
  • the CYP3A4 inhibitor is a strong inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 8 mg per day (calculated as the free base), for example in a dosage of from about 7.0 mg to about 9.0 mg per day, e.g., about 7.5 mg or about 8.0 mg (calculated as the free base).
  • a dosage of about 7.5 mg may be obtained, for example, by dividing a 15 mg tablet in half.
  • a dosage of about 8.0 mg may be obtained, for example, by administering two 4 mg unit dosages (e.g., tablets or capsules).
  • the CYP3A4 inhibitor is a strong inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 15 mg per day (calculated as the free base).
  • the strong inhibitor is itraconazole which is administered in a dosage of between about 50 mg and 400 mg per day, e.g., about 200 mg per day (such as a dosage of about 100 mg BID).
  • the CYP3A4 inhibitor is a moderate inhibitor of CYP3A4.
  • the inhibitor increases the plasma exposure of venglustat by between about 5% and 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor. In other embodiments, the inhibitor increases the plasma exposure of venglustat by at least about 25% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the moderate inhibitor increases the plasma exposure of venglustat by between about 25% and 75%, e.g., between about 30% and 65%, between about 35% and 60%, or between about 40% and 55%, as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor.
  • the moderate inhibitor increases the plasma exposure of venglustat by between about 5% and 20% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is 100% of the standard indicated dose for the disease or disorder being treated.
  • the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 15 mg per day (calculated as free base).
  • the moderate inhibitor increases the plasma exposure of venglustat by between about 30% and 65% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is an amount of from about 75% to 100% of the standard indicated dose for the disease or disorder being treated.
  • the moderate inhibitor increases the plasma exposure of venglustat by between about 40% and 60% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is 100% of the standard indicated dose for the disease or disorder being treated.
  • the moderate inhibitor increases the plasma exposure of venglustat by between about 40% and 60% as compared to the exposure resulting from administration of venglustat or a pharmaceutically acceptable salt thereof in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of between about 10 mg and 15 mg per day (calculated as the free base), e.g., in a dosage of about 12 mg per day or about 15 mg per day.
  • the CYP3A4 inhibitor is a moderate inhibitor and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 12 mg per day (calculated as the free base).
  • the CYP3A4 inhibitor is a moderate inhibitor and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 15 mg per day (calculated as the free base).
  • a dosage of about 12 mg may be achieved, for example, by administering three 4 mg unit dosages (e.g., tablets or capsules), or by administering two 6 mg unit dosages (e.g., tablets or capsules).
  • a dosage of about 10 mg may be achieved, for example, by administering one 4 mg unit dosage (e.g., tablet or capsule) and one 6 mg unit dosage (e.g., tablet or capsule).
  • the CYP3A4 inhibitor is fluconazole which is administered in a dosage of between about 100 mg and 500 mg per day, e.g., about 200 mg or about 400 mg per day. In embodiments, the CYP3A4 inhibitor is fluvoxamine which is administered in a dosage of between about 50 mg and 300 mg per day. In other embodiments, the inhibitor of CYP3A4 is not fluvoxamine. In embodiments, the inhibitor of CYP3A4 is not cyclosporine. In embodiments, the inhibitor of CYP3A4 is not fluvoxamine or cyclosporine.
  • the method of the disclosure comprises administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject is concurrently being administered a CYP3A4 inhibitor selected from itraconazole and fluconazole.
  • the method comprises administering to the subject an effective amount of a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor selected from itraconazole and fluconazole.
  • the disclosure provides a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor selected from itraconazole and fluconazole, for use in a method for treating a disease or disorder amenable to treatment with venglustat in a subject in need thereof.
  • a further related aspect provides the use of venglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor selected from itraconazole and fluconazole in the manufacture of a medicament for use in a method for treating a disease or disorder amenable to treatment with venglustat in a subject in need thereof.
  • the venglustat is in the form of venglustat free base, a pharmaceutically acceptable salt of venglustat, or a prodrug of venglustat.
  • the venglustat is in the form of venglustat malate salt, e.g., venglustat L-malate, optionally in crystalline form.
  • the venglustat or pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered simultaneously, optionally in the same pharmaceutical composition (e.g., oral pharmaceutical dosage form).
  • the venglustat or pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered separately.
  • the method comprises administering a separate pharmaceutical composition comprising the CYP3A4 inhibitor (i.e., separate from the pharmaceutical composition or dosage form comprising the venglustat or pharmaceutically acceptable salt thereof).
  • the venglustat or pharmaceutically acceptable salt thereof is administered orally.
  • the CYP3A4 inhibitor is administered orally.
  • the venglustat or pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered orally.
  • the CYP3A4 inhibitor is administered by transdermal, transmucosal, intravenous, intramuscular, subcutaneous, or intranasal administration.
  • the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally.
  • the CYP3A4 inhibitor is administered by transdermal, transmucosal, intravenous, intramuscular, subcutaneous, or intranasal administration and the venglustat or pharmaceutically acceptable salt thereof is administered orally.
  • the venglustat or pharmaceutically acceptable salt thereof is administered orally and the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally.
  • the venglustat or pharmaceutically acceptable salt thereof (and optionally the CYP3A4 inhibitor) is formulated as an oral pharmaceutical composition.
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient as described herein.
  • the pharmaceutical composition further comprises the CYP3A4 inhibitor.
  • the oral pharmaceutical composition is a pill, capsule, caplet, tablet, dragee, powder, granule, film, lozenge, or liquid.
  • the oral pharmaceutical composition is a capsule or tablet, e.g., a tablet.
  • the oral pharmaceutical composition is a formulation as described in international patent application No. PCT/IB2021/056673 (published as WO 2022/018695), the entire content of which is incorporated by reference herein.
  • the formulation is a capsule having the following composition: In redient Amount (Wt %) In embodiments, the capsule contains 15 mg of venglustat (20.16 mg of venglustat malate), the fill mass of the capsule is 165 mg, and the formulation is packaged into a size #3 capsule shell. In other embodiments, the formulation is a tablet having the following composition: S weetener 1.0% In embodiments, the tablet contains 15 mg of venglustat (20.16 mg of venglustat malate), the flavor is apricot flavor, the sweetener is sucralose, and the weight of the tablet is 150 mg. In embodiments, the CYP3A4 inhibitor is itraconazole. In other embodiments, the CYP3A4 inhibitor is fluconazole.
  • the disease or disorder is selected from a lysosomal storage disease, a proteinopathy, a cystic disease, and a ciliopathy.
  • the disease or disorder is a lysosomal storage disease selected from Fabry disease, Gaucher disease (e.g., GD type 1, type 2, or type 3), a GM1-gangliosidosis, a GM2- gangliosidosis (e.g., GM2-activator deficiency, Tay-Sachs disease, Sandhoff disease, or AB Variant), Niemann-Pick disease (e.g., Type C), and Krabbe disease.
  • the disease or disorder is Gaucher disease or Fabry disease.
  • the disease or disorder is type 3 Gaucher Disease (GD3).
  • the disease or disorder is a proteinopathy selected from Alzheimer’s disease, Parkinson’s disease, Lewy Body Dementia, Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, and Huntington’s disease.
  • the proteinopathy is selected from Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In embodiments, the proteinopathy is characterized by tau protein aggregates, alpha-synuclein protein aggregates, and/or amyloid-beta (A ⁇ ) aggregates in the central nervous system.
  • the disease or disorder is a cystic disease selected from polycystic kidney disease, polycystic liver disease, and polycystic ovary disease. In embodiments, the cystic disease is polycystic kidney disease (PKD), e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD).
  • PPD polycystic kidney disease
  • ADPKD autosomal dominant PKD
  • ARPKD autosomal recessive PKD
  • the disease or disorder is a ciliopathy selected from Joubert syndrome, Meckel-Gruber syndrome, Senior-Loken syndrome, Orofaciodigital syndrome type I, Leber’s congenital amaurosis, Bardet-Biedl syndrome (BBS), Alström syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, primary ciliary dyskinesia, and combinations thereof.
  • the ciliopathy is BBS.
  • the subject has a co-morbidity which can be treated with said CYP3A4 inhibitor.
  • the co-morbidity is selected from a fungal infection, a viral infection (e.g., infection with HIV or HCV), a bacterial infection, a mood disorder (e.g., depression or an anxiety disorder), and a cancer.
  • a viral infection e.g., infection with HIV or HCV
  • a bacterial infection e.g., a mood disorder (e.g., depression or an anxiety disorder)
  • a mood disorder e.g., depression or an anxiety disorder
  • a cancer e.g., depression or an anxiety disorder
  • Dose adjustment can increase the plasma exposure (e.g., AUC) of venglustat, for instance by about 50% to about 200%. This may permit an adjusted (e.g., lower) dose of venglustat to be used compared to the standard indicated dose for the disease or disorder being treated.
  • the disclosure provides a method for treating a disease or disorder amenable to treatment with venglustat in a subject in need thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor and concurrently administering an adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in a method for treating a disease or disorder amenable to treatment with venglustat in a subject in need thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor and concurrently administering an adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the use of venglustat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a disease or disorder in a subject, wherein the method comprises concurrent administration of a CYP3A4 inhibitor, and wherein the amount of the venglustat or pharmaceutically acceptable salt thereof in the medicament is an adjusted effective amount.
  • the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In embodiments, the CYP3A4 inhibitor is not fluvoxamine.
  • the disclosure provides a method for treating a disease or disorder amenable to treatment with venglustat in a subject in need thereof, the method comprising administering to the subject a combination of (e.g., a composition comprising) a strong or moderate CYP3A4 inhibitor and venglustat or a pharmaceutically acceptable salt thereof, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in an adjusted effective amount.
  • a combination of e.g., a composition comprising
  • a strong or moderate CYP3A4 inhibitor and venglustat or a pharmaceutically acceptable salt thereof e.g., a composition comprising
  • the present disclosure provides a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and a strong or moderate CYP3A4 inhibitor, for use in a method for treating a disease or disorder amenable to treatment with venglustat in a subject in need thereof, the method comprising administering to the subject an adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof.
  • a composition comprising venglustat or a pharmaceutically acceptable salt thereof and a strong or moderate CYP3A4 inhibitor
  • the present disclosure provides the use of a combination of (e.g., a composition comprising) venglustat or a pharmaceutically acceptable salt thereof and a strong or moderate CYP3A4 inhibitor in the manufacture of a medicament for use in a method of treating a disease or disorder amenable to treatment with venglustat in a subject, wherein the amount of the venglustat or pharmaceutically acceptable salt thereof in the medicament is an adjusted effective amount.
  • the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In embodiments, the CYP3A4 inhibitor is not fluvoxamine.
  • the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of from about 25% to 100% of the standard indicated dose for the disease or disorder being treated (e.g., an amount of from about 50% to 100% of the standard indicated dose). In embodiments, the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is at least about 50% of the standard indicated dose for the disease or disorder being treated, e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the standard indicated dose.
  • the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is less than 100% of the standard indicated dose for the disease or disorder being treated, e.g., less than about 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, or 55% of the standard indicated dose. In embodiments, the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of from about 50% to about 99% of the standard indicated dose for the disease or disorder being treated, e.g., from about 55% to about 95%, from about 60% to about 90%, or from about 65% to about 75% of the standard indicated dose.
  • the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of about 50% of the standard indicated dose for the disease or disorder being treated, e.g., about 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the standard indicated dose.
  • the CYP3A4 inhibitor is a strong inhibitor (e.g., itraconazole) and the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of from about 50% to 100% of the standard indicated dose for the disease or disorder being treated.
  • the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is 100% of the standard indicated dose for the disease or disorder being treated (e.g., a dose of about 15 mg per day). In other embodiments, the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of from about 50% to 100% of the standard indicated dose for the disease or disorder being treated, e.g., from about 50% to about 90%, from about 50% to about 80%, from about 50% to about 70%, or from about 50% to about 60% of the standard indicated dose.
  • the standard indicated dose of venglustat or a pharmaceutically acceptable salt thereof is about 15 mg per day (calculated as the free base) and the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is about 8 mg per day (calculated as the free base), e.g. from about 7.0 mg to about 9.0 mg per day, such as about 7.5 mg or about 8.0 mg (calculated as the free base).
  • a dosage of about 7.5 mg may be obtained, for example, by dividing a 15 mg tablet in half.
  • a dosage of about 8.0 mg may be achieved, for example, by administering two 4 mg unit dosages (e.g., tablets or capsules).
  • the CYP3A4 inhibitor is a moderate inhibitor (e.g., fluconazole) and the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of from about 70% to 100% of the standard indicated dose for the disease or disorder being treated. In embodiments, the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is 100% of the standard indicated dose for the disease or disorder being treated. In other embodiments, the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is an amount of from about 75% to 100% of the standard indicated dose for the disease or disorder being treated, e.g., from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, or from about 95% to 100% of the standard indicated dose.
  • a moderate inhibitor e.g., fluconazole
  • the standard indicated dose of venglustat is about 15 mg per day and the adjusted effective amount of venglustat or a pharmaceutically acceptable salt thereof is from about 10 mg to 15 mg per day, e.g., about 12 mg per day or about 15 mg per day (calculated as the free base).
  • a dosage of about 12 mg may be achieved, for example, by administering three 4 mg unit dosages (e.g., tablets or capsules), or by administering two 6 mg unit dosages (e.g., tablets or capsules).
  • a dosage of about 10 mg may be achieved, for example, by administering one 4 mg unit dosage (e.g., tablet or capsule) and one 6 mg unit dosage (e.g., tablet or capsule).
  • the venglustat or pharmaceutically acceptable salt thereof, and/or the CYP3A4 inhibitor are as defined herein.
  • the subject being treated, and/or the disease or disorder to be treated are as defined herein.
  • the present disclosure provides a method for optimizing (e.g., reducing) the dosage of venglustat in a subject being treated with or intended to be treated with venglustat or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor, e.g., as defined herein.
  • the strong or moderate CYP3A4 inhibitor is administered concurrently with the venglustat or pharmaceutically acceptable salt thereof.
  • the present disclosure provides a strong or moderate CYP3A4 inhibitor, e.g. as defined herein, for use in a method for optimizing (e.g., reducing) the dosage of venglustat in a subject being treated with or intended to be treated with venglustat or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the use of a strong or moderate CYP3A4 inhibitor, e.g. as defined herein, in the manufacture of a medicament for use in a method for optimizing (e.g., reducing) the dosage of venglustat in a subject being treated with or intended to be treated with venglustat or a pharmaceutically acceptable salt thereof.
  • the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.
  • the CYP3A4 inhibitor is selected from itraconazole and fluconazole.
  • the disclosure provides a method for minimising the drug-drug interaction between venglustat and a moderate or strong CYP3A4 inhibitor (e.g., as defined herein) in a subject suffering from a disease or disorder which is amenable to treatment with venglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with said CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) adjusting the dosage of the venglustat or pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25% increase.
  • the determining the change in plasma exposure of venglustat involves measuring the change in plasma exposure after administration of venglustat and/or the CYP3A4 inhibitor, e.g., in one or more healthy subjects. In other embodiments, the determining the change in plasma exposure of venglustat involves predicting the change in plasma exposure, e.g., using a computer implemented model as described herein. In embodiments, the plasma exposure is determined as the AUC as defined herein. In embodiments, the AUC is AUC0-12, AUC0-24, AUClast, or AUC ⁇ . In embodiments, the plasma exposure of venglustat is the AUC last of venglustat. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.
  • the CYP3A4 inhibitor is a strong CYP3A4 inhibitor and/or the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced if the change in plasma exposure is an increase of more than about 50%. In embodiments, the reduced dosage is an adjusted effective amount as defined herein. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor and the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced by an amount of between about 0% and 75% (e.g., between about 0% and 50%) if the change in plasma exposure is an increase of between about 50% and 200%.
  • the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced by an amount of between about 5% and 50%, e.g., between about 10% and 50%, between about 25% and 50%, or between about 40% and 50%. In embodiments, the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced to an amount of between about 4 and 15 mg per day (calculated as free base) if the change in plasma exposure is an increase of between about 50% and 200%, e.g., an amount of between about 7 and 15 mg per day if the change in plasma exposure is an increase of between about 50% and 200%.
  • the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced to an amount of about 8 mg per day (calculated as the free base), e.g., from about 7.0 to about 9.0 mg per day, such as about 7.5 mg or about 8.0 mg (calculated as the free base).
  • a dosage of about 7.5 mg may be obtained, for example, by dividing a 15 mg tablet in half.
  • a dosage of about 8.0 mg may be achieved, for example, by administering two 4 mg unit dosages (e.g., tablets or capsules).
  • the disclosure provides a method for establishing the correct dosage of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of the venglustat or the pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.
  • the disclosure provides a method for improving a dosage regimen of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of the venglustat or the pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.
  • the determining the change in plasma exposure of venglustat involves measuring the change in plasma exposure after administration of venglustat and/or the CYP3A4 inhibitor, e.g., in one or more healthy subjects. In other embodiments, the determining the change in plasma exposure of venglustat involves predicting the change in plasma exposure, e.g., using a computer implemented model as described herein. In embodiments, the plasma exposure is determined as the AUC as defined herein. In embodiments, the AUC is AUC0-12, AUC0-24, AUClast, or AUC ⁇ . In embodiments, the plasma exposure of venglustat is the AUC last of venglustat. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.
  • the CYP3A4 inhibitor is a strong CYP3A4 inhibitor and/or the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced if the change in plasma exposure is an increase of more than about 50%. In embodiments, the reduced dosage is an adjusted effective amount as defined herein. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor and the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced by an amount of between about 0% and 50% if the change in plasma exposure is an increase of between about 50% and 200%.
  • the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced by an amount of between about 5% and 50%, e.g., between about 10% and 50%, between about 25% and 50%, or between about 40% and 50%. In embodiments, the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced to an amount of between about 4 and 15 mg per day (calculated as free base) if the change in plasma exposure is an increase of between about 50% and 200%, e.g., an amount of between about 7 and 15 mg per day if the change in plasma exposure is an increase of between about 50% and 200%.
  • the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced to an amount of about 8 mg per day (calculated as the free base), e.g., from about 7.0 to about 9.0 mg per day, such as about 7.5 mg or about 8.0 mg (calculated as the free base).
  • a dosage of about 7.5 mg may be obtained, for example, by dividing a 15 mg tablet in half.
  • a dosage of about 8.0 mg may be achieved, for example, by administering two 4 mg unit dosages (e.g., tablets or capsules).
  • Another aspect of the disclosure provides a method for managing the risk of venglustat/CYP3A4 inhibitor interaction in a subject having a disease or disorder which is amenable to treatment with venglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) initiating treatment in the subject with venglustat or a pharmaceutically acceptable salt thereof at a standard indicated dose (e.g., a dose as described herein); (ii) determining the change in plasma exposure of venglustat when venglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, as compared to the exposure resulting from administration of venglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (iii) reducing the dosage if the change in plasma exposure is an increase of more than about 25%.
  • a standard indicated dose e.g., a dose as described herein
  • the determining the change in plasma exposure of venglustat involves measuring the change in plasma exposure after administration of venglustat and/or the CYP3A4 inhibitor, e.g., in one or more healthy subjects. In other embodiments, the determining the change in plasma exposure of venglustat involves predicting the change in plasma exposure, e.g., using a computer implemented model as described herein. In embodiments, the plasma exposure is determined as the AUC as defined herein. In embodiments, the AUC is AUC 0-12 , AUC 0-24 , AUC last , or AUC ⁇ . In embodiments, the plasma exposure of venglustat is the AUClast of venglustat.
  • the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor and/or the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced if the change in plasma exposure is an increase of more than about 50%. In embodiments, the reduced dosage is an adjusted effective amount as defined herein. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor and the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced by an amount of between about 0% and 50% if the change in plasma exposure is an increase of between about 50% and 200%.
  • the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced by an amount of between about 5% and 50%, e.g., between about 10% and 50%, between about 25% and 50%, or between about 40% and 50%. In embodiments, the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced to an amount of between about 4 and 15 mg per day (calculated as free base) if the change in plasma exposure is an increase of between about 50% and 200%, e.g., an amount of between about 7 and 15 mg per day if the change in plasma exposure is an increase of between about 50% and 200%.
  • the dosage of the venglustat or the pharmaceutically acceptable salt thereof is reduced to an amount of about 8 mg per day (calculated as the free base), e.g., from about 7.0 to about 9.0 mg per day, such as about 7.5 mg or about 8.0 mg (calculated as the free base).
  • a dosage of about 7.5 mg may be obtained, for example, by dividing a 15 mg tablet in half.
  • a dosage of about 8.0 mg may be achieved, for example, by administering two 4 mg unit dosages (e.g., tablets or capsules).
  • the disclosure provides the use of a strong or moderate CYP3A4 inhibitor in a method for: (a) establishing the correct dosage of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof; (b) improving a dosage regimen of venglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof; or (c) managing the risk of venglustat/CYP3A4 inhibitor interaction in a subject having a disease or disorder which is amenable to treatment with venglustat or a pharmaceutically acceptable salt thereof, wherein the subject is being administered or is intended to be administered said CYP3A4 inhibitor.
  • said method is a method as described herein.
  • the present disclosure provides a method for inhibiting CYP3A4 activity in a subject being treated with venglustat or a pharmaceutically acceptable salt thereof, the method comprising concurrently administering the venglustat or pharmaceutically acceptable salt thereof with a strong or moderate CYP3A4 inhibitor.
  • the present disclosure provides a strong or moderate CYP3A4 inhibitor for use in a method for inhibiting CYP3A4 activity in a subject being treated with venglustat or a pharmaceutically acceptable salt thereof, the method comprising concurrently administering the venglustat or pharmaceutically acceptable salt thereof with the CYP3A4 inhibitor.
  • the present disclosure provides the use of a strong or moderate CYP3A4 inhibitor in the manufacture of a medicament for inhibiting CYP3A4 activity in a subject being treated with venglustat or a pharmaceutically acceptable salt thereof.
  • the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.
  • the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In embodiments, the CYP3A4 inhibitor is not fluvoxamine.
  • the disclosure provides a method for improving the therapeutic response to venglustat treatment in a subject in need thereof, the method comprising concurrently administering venglustat or a pharmaceutically acceptable salt thereof with a strong or moderate CYP3A4 inhibitor.
  • the present disclosure provides a strong or moderate CYP3A4 inhibitor for use in a method for improving the therapeutic response to venglustat treatment in a subject in need thereof.
  • the present disclosure provides the use of a strong or moderate CYP3A4 inhibitor in the manufacture of a medicament for improving the therapeutic response to venglustat treatment in a subject in need thereof.
  • the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.
  • the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In embodiments, the CYP3A4 inhibitor is not fluvoxamine. In embodiments, the venglustat or pharmaceutically acceptable salt thereof and/or the CYP3A4 inhibitor are as defined herein. In embodiments, the concurrent administration of venglustat or a pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor permits a lower dose of the venglustat or pharmaceutically acceptable salt thereof to be used compared to the standard indicated dose for the disease or disorder being treated. In embodiments, the lower dose of the venglustat or a pharmaceutically acceptable salt thereof is an adjusted effective amount as described herein.
  • the concurrent administration of the venglustat or pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor results in an increase in plasma AUC for venglustat of at least about 25% compared to the plasma AUC resulting from administration of the venglustat or pharmaceutically acceptable salt thereof in the absence of the CYP3A4 inhibitor.
  • the subject is being treated for a disease or disorder as defined herein.
  • a change in the plasma exposure of venglustat on concomitant administration of a strong or moderate CYP3A4 inhibitor is determined by a computer implemented method, e.g., as described in the examples which follow.
  • venglustat in the form of a pharmaceutically acceptable salt.
  • Compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids. ⁇ Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g.
  • Acids which can be used to prepare pharmaceutically acceptable salts of venglustat are those which can form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate [i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, a
  • the pharmaceutically acceptable salt is a succinate salt.
  • the pharmaceutically acceptable salt is a 2-hydroxysuccinate salt, e.g., an (S)-2- hydroxysuccinate salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt (i.e., a salt with HCl).
  • the pharmaceutically acceptable salt is a malate salt, e.g., an L-malate salt.
  • the present disclosure also contemplates prodrugs of venglustat.
  • the pharmaceutically acceptable prodrugs disclosed herein are derivatives which can be converted in vivo into venglustat. ⁇ The prodrugs, which may themselves have some activity, become pharmaceutically active in vivo when they undergo, for example, solvolysis under physiological conditions or enzymatic degradation. Methods for preparing prodrugs of venglustat would be apparent to one of skill in the art based on the present disclosure.
  • the carbamate moiety of venglustat is modified.
  • the carbamate moiety may be modified by the addition of water and/or one or two aliphatic alcohols. In this case, the carbon-oxygen double bond of the carbamate moiety adopts what could be considered a hemiacetal or acetal functionality.
  • the carbamate moiety may be modified by the addition of an aliphatic diol such as 1,2-ethanediol.
  • the amino group on the quinuclidine moiety is modified.
  • the amino group may be modified to form an acid derivative or a quaternary ammonium salt.
  • the derivative can be formed, for example, by reacting venglustat with an acetylating agent such as an acid chloride, or with an agent such as an alkyl halide.
  • the present disclosure further embraces hydrates, solvates, and polymorphs of venglustat.
  • the venglustat may be in one or more crystalline forms as described in, e.g., international patent application No.
  • an “isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a pharmaceutical composition e.g., an oral pharmaceutical dosage form
  • the composition may be adapted for use in any of the methods disclosed herein.
  • the pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit.1985).
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.
  • the disclosure provides an oral pharmaceutical dosage form comprising venglustat and a pharmaceutically acceptable excipient, in combination with a CYP3A4 inhibitor (e.g., selected from itraconazole and fluconazole), wherein the dosage form is formulated to provide, when administered orally, an amount of venglustat sufficient to treat a disease or disorder as described according to any of the methods herein.
  • the venglustat is in solid crystal form (e.g., crystalline malate salt Form A of venglustat).
  • the venglustat is in solid amorphous form.
  • the dosage form comprises an amorphous solid dispersion comprising the venglustat and/or the CYP3A4 inhibitor with the pharmaceutically acceptable excipient.
  • the dosage form is a capsule (e.g., a hard capsule) or a tablet (e.g., a chewable tablet, an orally-disintegrating tablet, a dispersible tablet, or a classic tablet or caplet), optionally wherein said dosage form comprises from about 2 to about 30 mg of venglustat (measured as the equivalent amount of free base), e.g., from about 4 mg to about 20 mg, or from about 8 mg to about 12 mg, or about 4 mg, or about 6 mg, or about 8 mg, or about 12 mg, or about 15 mg of venglustat (measured as the equivalent amount of free base).
  • the dosage form is a classic tablet or caplet (e.g., for swallowing), a chewable tablet, an orally disintegrating tablet, or a dispersible tablet.
  • the pharmaceutically acceptable excipient comprises one or more of (a) diluent/filler (e.g., cellulose or microcrystalline cellulose, mannitol, or lactose), (b) binder (e.g., povidone, methylcellulose, ethylcellulose, hydroxypropyl cellulose (such as low- substituted hydroxypropyl cellulose), or hydroxypropyl methylcellulose), (c) disintegrant (e.g., crospovidone, sodium starch glycolate, or croscarmellose sodium), (d) lubricant (e.g., magnesium stearate or sodium stearyl fumarate), (e) a glidant (e.g., silica or talc), (f) sweetener (e.g., sucra
  • the pharmaceutically acceptable excipient comprises one or more hydrophilic water-soluble or water swellable polymers.
  • the polymer is selected from the group consisting of natural or modified cellulosic polymers, or any mixture thereof.
  • any one or more pharmaceutically acceptable excipients are present in an amount of 0.01 to 80% by weight, e.g., 0.1 to 60%, or 0.1 to 40%, or 0.1 to 30%, 0.01 to 15%, or 0.01 to 10%, or 0.1 to 20%, or 0.1 to 15% or 0.1 to 10%, or 0.5 to 10%, or 0.5 to 5%, or 1 to 5%, or 2.5 to 5%, or 1 to 3%, or 0.1 to 1% by weight.
  • the dosage form comprises (a) from 5-95% by weight of diluent(s)/filler(s), e.g., 60-70% or 70-80%, or 65-75%, or 65-70%, or about 68%; (b) from 0.5-5% by weight of lubricant(s), e.g., 1-5%, or 2-4%, or 2-3%, or about 3%; (c) from 2-15% by weight of disintegrant(s), e.g., 4-12%, or 6- 10%, or 7-9%, or about 8%; (d) from 0-12% by weight of binder(s), e.g., 2-10%, or 2-8%, or 3-7%, or 4-6%, or about 5%; (e) from 0-5% by weight of glidant(s), e.g., 0.15-4%, or 1-3%, or 1-2%, or about 1%; and (f) from 0-2% by weight of flavor(s), 0-2% by weight of sweetener(s) and/or 0-
  • the venglustat is present in an amount of from 3% to 20% by weight (measured as free base).
  • the CYP3A4 inhibitor is present in an amount of from 10% to 90% by weight.
  • the dosage form is a tablet comprising a mixture of venglustat (e.g., venglustat malate), the CYP3A4 inhibitor, and one or more pharmaceutically acceptable excipients.
  • the tablet is formed by direct compression of a mixture of venglustat (e.g., venglustat malate), the CYP3A4 inhibitor, and one or more pharmaceutically acceptable excipients.
  • the dosage form is a hard-shelled capsule, e.g., wherein said capsule contains a mixture of venglustat (e.g., venglustat malate), the CYP3A4 inhibitor, and one or more pharmaceutically acceptable excipients.
  • venglustat e.g., venglustat malate
  • CYP3A4 inhibitor e.g., venglustat malate
  • the venglustat, CYP3A4 inhibitor, and other diluents/carriers may be comprised as granules or pellets, or as a powder, said granules, pellets, or powder being contained within the shell of the capsule.
  • the venglustat and/or CYP3A4 inhibitor is present in (a) a mean particle size of 5 to 150 ⁇ m, e.g., 5 to 120 ⁇ m, 5 to 100 ⁇ m, 10 to 100 ⁇ m, 15 to 85 ⁇ m, 20 to 60 ⁇ m, 30 to 40 ⁇ m; and/or (b) a D90 of 120 ⁇ m or less, e.g., 50 to 100 ⁇ m, 70 to 90 ⁇ m, or 60 to 80 ⁇ m; and/or (c) a D10 of 30 ⁇ m or less, e.g.10 to 25 ⁇ m, 10 to 20 ⁇ m or less, or 11 to 14 ⁇ m
  • the venglustat and the CYP 3A4 inhibitor are mixed together to form the oral pharmaceutical dosage form, optionally wherein the dosage form is homogenous with respect to the distribution of the venglustat and the CYP 3A4 inhibitor.
  • the venglustat and the CYP 3A4 inhibitor are released over substantially the same period of time in the gastrointestinal cavity.
  • the venglustat and the CYP 3A4 inhibitor are comprised in separate portions of the composition or dosage form, e.g., in separate compartments, granules or layers.
  • the venglustat and the CYP 3A4 inhibitor are separated by a pharmacologically inert barrier, layer, or shell.
  • the venglustat and the CYP3A4 inhibitor are released over substantially different periods of time in the gastrointestinal cavity or in different regions of the gastrointestinal cavity (e.g., mouth, stomach, duodenum, ileum, or jejunum).
  • the dosage form is formulated for immediate release of the venglustat and/or immediate release of the CYP3A4 inhibitor. In embodiments, the dosage form is formulated for sustained release of the venglustat and/or sustained release of the CYP3A4 inhibitor. In embodiments, the dosage form is formulated for delayed release of the venglustat and/or delayed release of the CYP3A4 inhibitor. In embodiments, the plasma AUC of venglustat after a single oral dose of 15 mg averages at least 3400 ng-h/mL, e.g., 3400 to 6200 ng-h/mL, or 4000 to 5600 ng-h/mL, or 4400 to 5200 ng-h/mL.
  • a pharmaceutical composition or dosage form of the present disclosure can include an agent and another carrier, e.g., compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like.
  • another carrier e.g., compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like.
  • Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume.
  • Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like.
  • amino acid/antibody components which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.
  • Carbohydrate excipients are also intended within the scope of this disclosure, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myoinositol.
  • monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like
  • disaccharides such as lactose, sucrose
  • Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base.
  • Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
  • Additional carriers include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ - cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as “TWEEN 20” and “TWEEN 80”), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).
  • polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ - cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial
  • the present disclosure also provides pharmaceutical compositions, and kits comprising said compositions, which contain venglustat (or a pharmaceutically acceptable salt or prodrug thereof) and a CYP3A4 inhibitor as described herein.
  • the present disclosure further provides a kit comprising a first pharmaceutical composition comprising venglustat or a pharmaceutically acceptable salt thereof, e.g. as described herein, and a second pharmaceutical composition comprising a strong or moderate CYP3A4 inhibitor as described herein.
  • the pharmaceutical compositions can be formulated so as to provide slow, extended, or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres.
  • the pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g., by using an enteric coating.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g., Remington’s).
  • the compounds presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art.
  • solid dosage forms for oral administration e.g., capsules, tablets, pills, dragees, powders, granules, and the like
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose, and/or acacia; (3) humectants, such as glycerol;
  • the pharmaceutical compositions can also comprise buffering agents.
  • Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- actives, and/or dispersing agents.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets and other solid dosage forms such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.
  • the pharmaceutical compositions are administered orally in a liquid form.
  • Liquid dosage forms for oral administration of an active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
  • the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents, and the like.
  • Suspensions in addition to the active ingredient(s) can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g., sorbitol syrup, methyl cellulose, or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g., almond oil, oily esters, or ethyl alcohol); and/or preservative (e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid).
  • a suspending agent e.g., sorbitol syrup, methyl cellulose, or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicle e.g., almond oil, oily esters, or ethyl alcohol
  • preservative e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid
  • the pharmaceutical composition may take the form of tablets or lozenges formulated for buccal administration in a conventional manner.
  • the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, and the like.
  • the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g., intravenous, intramuscular, intra-arterial, subcutaneous, and the like).
  • the presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing, and/or dispersing agent recognized by those of skill in the art.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the pharmaceutical compositions can be in the form of sterile injections.
  • the pharmaceutical compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • a parenterally acceptable liquid vehicle exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer’s solution, and isotonic sodium chloride solution.
  • the pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate.
  • a dissolution enhancing or solubilising agent can be added or the solvent can contain 10-60% w/w of propylene glycol or the like.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions just prior to use.
  • Such pharmaceutical compositions can contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.
  • suitable aqueous and nonaqueous carriers which can be employed in any of the pharmaceutical compositions described herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • delayed absorption of a parenterally-administered active ingredient may be accomplished by dissolving or suspending the compound in an oil vehicle.
  • Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants, or infusion devices.
  • Materials for use in the preparation of microspheres and/or microcapsules include, but are not limited to, biodegradable/bioerodible polymers such as polyglactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L- glutamine), and poly(lactic acid).
  • Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins, or antibodies.
  • Materials for use in implants can be non-biodegradable, e.g., polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(ortho esters).
  • a presently disclosed compound may be formulated as an ointment or cream.
  • Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the disclosure provides a dosage form or pharmaceutical composition as described herein for use in therapy, e.g., for use in a method as defined herein. Having been generally described herein, the follow non-limiting examples are provided to further illustrate the disclosure.
  • Example 1B Preparation of (S)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan- 2-yl)carbamate (venglustat) in free base form
  • Step 1 Dimethylation with methyl iodide
  • a 3N RB flask was equipped with a thermometer, an addition funnel and a nitrogen inlet. The flask was flushed with nitrogen and potassium tert-butoxide (MW 112.21, 75.4 mmol, 8.46 g, 4.0 equiv., white powder) was weighed out and added to the flask via a powder funnel followed by the addition of THF (60 mL).
  • a solution of methyl iodide (MW 141.94, 47.13 mmol, 6.7 g, 2.5 equiv.) in THF (6 mL) was prepared and transferred to the addition funnel.
  • the flask containing the methyl iodide solution was then rinsed with THF (1.5 mL) which was then transferred to the addition funnel already containing the clear colorless solution of methyl iodide in THF.
  • This solution was added carefully dropwise to the dark brown reaction mixture over a period of 30-40 min, keeping the internal temperature below 10°C at all times during the addition. After the addition was complete, the slightly turbid mixture was stirred for an additional 1 h during which time the internal temperature dropped to 0-5°C.
  • reaction mixture was quenched with the slow dropwise addition of 5.0 M aqueous HCl (8 mL) over a period of 5-7 min. The internal temperature was maintained below 20°C during this addition. After the addition, water (14 mL) was added and the mixture was stirred for 2-3 min. The stirring was stopped and the two layers were allowed to separate. The two layers were then transferred to a 250 mL 1N RB flask and the THF was evaporated in vacuo as much as possible to obtain a biphasic layer of THF/product and water. The two layers were allowed to separate. A THF solution of the Step 1 product was used in the next reaction.
  • Step 2 Hydrolysis of the ethyl ester with LiOH monohydrate
  • LiOH.H2O MW 41.96, 75.0 mmol, 3.15 grams, 2.2 equiv.
  • Water 40 mL was added and the mixture was stirred until all the solid dissolved to give a clear colorless solution.
  • This aqueous solution was then added to the 250 mL RB flask containing the solution of the ester in tetrahydrofuran (THF).
  • a condenser was attached to the neck of the flask and a nitrogen inlet was attached at the top of the condenser.
  • the mixture was heated at reflux for 16 hours. After 16 hours, the heating was stopped and the mixture was cooled to room temperature.
  • the THF was evaporated in vacuo to obtain a brown solution.
  • An aliquot of the brown aqueous solution was analyzed by HPLC and LC/MS for complete hydrolysis of the ethyl ester. Water (15 mL) was added and this aqueous basic solution was extracted with TBME (2 x 40 mL) to remove the t-butyl ester.
  • the aqueous basic layer was cooled in an ice-water bath to 0-10°C and acidified with dropwise addition of concentrated HCl to pH ⁇ 1 with stirring.
  • TBME 60 mL
  • the two layers were transferred to a separatory funnel and the TBME layer was separated out.
  • the pale yellow aqueous acidic solution was re-extracted with TBME (40 mL) and the TBME layer was separated and combined with the previous TBME layer. The aqueous acidic layer was discarded.
  • Step 3 Formation of hydroxamic acid with NH 2 OH.HCl
  • the carboxylic acid (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv.) was weighed and transferred to a 25 mL 1N RB flask under nitrogen.
  • NH 2 OH.HCl MW 69.49, 37.7 mmol, 2.62 g, 2.0 equiv.
  • water 1.0 mL was added to the heterogeneous mixture dropwise over a period of 2 minutes and the reaction mixture was stirred at 0-10°C in the ice-water bath for 5 minutes. The cooling bath was removed and the reaction mixture was stirred under nitrogen at room temperature overnight for 20-22 h. The solution became clear as all of the NH2OH.HCl dissolved.
  • Step 3 Conversion of hydroxamic acid to cyclic intermediate (not isolated)
  • the crude hydroxamic acid (MW 280.32, 5.1 g) was transferred to a 250 mL 1N RB flask with a nitrogen inlet. A stir bar was added followed by the addition of acetonitrile (50 mL). The solid was insoluble in acetonitrile. The yellow heterogeneous mixture was stirred for 2-3 minutes under nitrogen and CDI (MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv.) was added in a single portion at room temperature. No exotherm was observed. The solid immediately dissolved and the clear yellow solution was stirred at room temperature for 2-2.5 h.
  • Step 3 continued: Conversion of the isocyanate to the free base
  • the reaction mixture was cooled to 50-60°C and (S)-(+)-quinuclidinol (MW 127.18, 28.28 mmol, 3.6 g, 1.5 equiv.) was added to the mixture as a solid in a single portion.
  • the mixture was re-heated to reflux for 18 h. After 18 h, an aliquot was analyzed by HPLC and LC/MS which showed complete conversion of the isocyanate to the desired product.
  • the reaction mixture was transferred to a separatory funnel and toluene (25 mL) was added. The mixture was washed with water (2 x 40 mL) and the water layers were separated.
  • the combined water layers were re-extracted with toluene (30 mL) and the water layer was discarded.
  • the combined toluene layers were extracted with 1N HCl (2 x 60 mL) and the toluene layer (containing the O-acyl impurity) was discarded.
  • the combined HCl layers were transferred to a 500 mL Erlenmeyer flask equipped with a stir bar. This stirring clear yellow/reddish orange solution was basified to pH 10-12 by the dropwise addition of 50% w/w aqueous NaOH. The desired free base precipitated out of solution as a dirty yellow gummy solid which could trap the stir bar.
  • Step 3 Recrystallization of the crude free base
  • the beige to tan colored crude free base was weighed and re-crystallized from heptane/isopropyl acetate (3:1, 9.0 mL of solvent/g of crude free base).
  • the appropriate amount of heptane/isopropyl acetate was added to the crude free base along with a stir bar and the mixture was heated to reflux for 10 min (free base was initially partially soluble but dissolved to give a clear reddish orange solution when heated to reflux).
  • the heat source was removed and the mixture was allowed to cool to room temperature with stirring when a white precipitate formed.
  • Example 2 Preparation of crystalline forms of (S)-Quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (venglustat) salts Crystalline salts of (S)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2- yl)carbamate may be formed from the free base prepared as described in Example 1B.
  • Example 3 Clinical studies of venglustat in healthy volunteers Several phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics.
  • Study NCT01674036 was split into two parts. The first part (referenced as TDU12766 herein) was a double-blind, randomized, placebo-controlled, sequential ascending single dose study. The second part (referenced as FED12767 herein) was an open-label, randomized, 2- sequence, 2-period, 2-treatment crossover study with a minimum wash-out period; to obtain preliminary information on the pharmacokinetics, tolerability, and safety of venglustat after single oral doses in fed and fasted conditions.
  • Study NCT01710826 was a double-blind, randomized, placebo-controlled study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of an ascending 14-day repeated oral doses of venglustat in healthy male and female subjects (referenced as TDR12768 herein). Details of the study design, drug, assessment, parameters measured, and results are described in detail by Peterschmitt et al. (Clin. Pharmacol. Drug Dev. (2021) 10(1):86–98) and in the corresponding clinicaltrials.gov entries for the two trials cited above. Some of the conclusions are summarised below.
  • Venglustat pharmacokinetics following a single dose In the single ascending ⁇ dose study (TDU12766), across the single oral doses of venglustat malate evaluated (2–150 mg), venglustat was absorbed with a median tmax of 3.00 to 5.50 hours and eliminated with a geometric mean t1/2 of 28.9 hours.
  • mean CL/F ranged from 5.18 to 6.43 L/h across the dose groups. Exposure increased close to dose ⁇ proportionally throughout the dose range: a 75 ⁇ fold dose increase resulted in 97.3 ⁇ , 89.2 ⁇ , and 85.9 ⁇ fold increases in geometric mean Cmax, AUClast, and AUCinf, respectively.
  • Venglustat pharmacokinetics following multiple dosing In the repeated ascending ⁇ dose study (TDR12768) in subjects receiving 5, 10, or 20 mg venglustat malate once daily for 14 days, venglustat was absorbed with a median tmax of 2.00 to 5.00 hours postdose on Days 1 and 14. Steady state appeared to be reached within 5 days of repeated dosing. Venglustat exposure increased close to dose ⁇ proportionally over the dose range of 5–20 mg venglustat malate: this 4 ⁇ fold dose increase resulted in 3.76 ⁇ and 3.69 ⁇ fold increases in geometric mean C max and AUC 0–24 values, respectively, on Day 14.
  • the geometric mean plasma Day 14/Day 1 ratios of 4 ⁇ hydroxycholesterol showed no marked difference between placebo and venglustat ⁇ treated groups, indicating minimal induction of CYP3A4.17 subjects reported a total of 32 mild TEAEs during the study, including 10 TEAEs in the placebo group and 22 TEAEs in the 5 ⁇ , 10 ⁇ , and 20 ⁇ mg dose groups. In the venglustat malate dose groups, the TEAEs reported by the investigator as study drug ⁇ related were constipation, diarrhea, dry mouth, flatulence, pruritus, and fatigue.
  • venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax, 3.00–5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18–6.43 L/h), and pooled geometric mean t 1/2z of 28.9 hours.
  • apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for C max and 2.22 for AUC 0–24 , and no statistically significant effect of dose or sex on accumulation.
  • venglustat showed a favorable safety and tolerability profile with no severe adverse events (SAEs) or deaths. There were several TEAEs in the single dose and multiple dose groups.
  • SAEs severe adverse events
  • Example 4 Clinical study of venglustat co-administered with itraconazole Study Design A Phase I, single-center, open-label, 2-period, single-sequence, non-randomized, drug-drug interaction (DDI) study was conducted to assess the effect of multiple dose itraconazole 100- mg BID on the pharmacokinetics of single-dose venglustat in healthy male subjects under fed conditions with a washout duration of 7 days between treatment periods.
  • DPI drug-drug interaction
  • Treatment Period 1 was 1 day
  • TP2 duration of Treatment Period 2
  • 8 subjects were enrolled in and completed the study.
  • Subjects were males of 20-43 years of age with a mean age of 28.8.
  • Venglustat malate salt form
  • venglustat measured as free base, corresponding to approximately 20 mg of venglustat malate.
  • Blood samples were collected predose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144 and 168 hours following the dose on Day 1.
  • venglustat was determined by HPLC-tandem MS with a lower quantification limit of 0.5 ng/mL. Subjects then proceeded to a 7-day washout period. At the conclusion of the washout period, TP2 began. Subjects were administered itraconazole as a commercial capsule comprising 100 mg of itraconazole twice per day from Day 1 to Day 12 of TP2 (just after eating breakfast and dinner). On Day 6 of TP2, venglustat malate was co-administered to subjects as a hard capsule comprising 15 mg of venglustat (measured as free base) in addition to the itraconazole dose.
  • Blood samples were collected predose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144 and 168 hours post-dose on Day 6, as well as pre-dose on Day 8 and Day 10, and 12-hours post-dose on Day 12. All samples were processed to obtain plasma and plasma concentration of venglustat free base was determined on all Day 6 samples by HPLC-tandem MS with a lower quantification limit of 0.5 ng/mL. The samples from predose through 12 hours post-dose on Day 6, and the Day 8, 10 and 13 samples were also analyzed for itraconazole and hydroxyitraconazole concentration by HPLC-tandem MS with lower quantification limits of 1 ng/mL and 2 ng/mL, respectively.
  • the primary endpoints of the study were to assess the effects of multiple-dose itraconazole (100 mg BID) on the pharmacokinetics of single-dose venglustat (15 mg, measured as free base).
  • the secondary endpoints were to assess the safety and tolerability of single-dose venglustat with and without co-administration of multiple-dose itraconazole and to assess the pharmacokinetics of itraconazole/hydroxyitraconazole.
  • Subjects were also monitored for any adverse events (reported by the subject or observed by investigators), and physical examination and clinical laboratory evaluations were conducted (hematology, biochemistry, urinalysis).
  • Subjects body temperature, body weight, vital signs (heart rate, supine and standing systolic blood pressure, diastolic blood pressure) and 12-lead electrocardiogram are also recorded. Results Overall, venglustat and itraconazole were well-tolerated in all subjects. No serious adverse events, adverse events of special interest, or adverse events leading to study discontinuation were reported. Two subjects reported treatment-emergent adverse events, one during TP1 and one during TP2. Both were mild in nature. One subject reported infrequent bowel movements on Day 4 of TP1, which was considered not related to venglustat. The infrequent bowel movements were treated with a daily dose of 5.5oz prune juice for 5 days.
  • Example 5 Development and verification of a PBPK model for venglustat plasma concentrations The objective of this study was to develop and verify a PBPK model using the available in vitro and in vivo PK information, and to predict venglustat PK for venglustat alone or co- administered with a CYP3A inhibitor in healthy subjects using the PBPK model to support dose recommendations.
  • the venglustat PBPK model was developed based on in vitro / in vivo absorption, distribution, metabolism, and excretion (ADME) data and PK data from Phase 1 clinical studies in healthy subjects (Example 3). Simcyp default “Sim-Healthy Volunteers” population was used for the generation of virtual population.
  • the PBPK model performance was confirmed using observed venglustat single dose and repeated dosing PK data from Phase 1 studies in healthy adult subjects.
  • the simulated results of the drug-drug interaction were verified using results from an in vivo drug interaction study (Example 4) conducted with a known strong CYP3A4 inhibitor, itraconazole, to evaluate the impact of CYP3A inhibition on venglustat exposure.
  • Verification of the PBPK model was carried out by comparing predicted and observed plasma concentration-time profiles of venglustat following a single oral dose of 11.2 mg, 18.6 mg, and 112 ⁇ mg venglustat and following QD oral dose of 3.72 mg, 7.44 mg, and 14.9 mg venglustat for 14 days to healthy subjects.
  • venglustat PK Consistent with the results from an earlier clinical study, food intake had no impact on venglustat PK.
  • the first order absorption parameters (e.g., f a , K a ) of venglustat under fed conditions were kept the same as the ones used in fasting status.
  • the drug distribution of venglustat was reflected by a minimal PBPK model with a single adjustable compartment, which considered both liver and intestinal metabolism, and lumped other tissues together.
  • the transporter impact on venglustat PK was assumed to be minimal. Model performance was confirmed by predicted to observed venglustat exposure ratios of 0.93 to 1.2 after single or repeated oral doses and 1.1 to 1.3 for venglustat alone or when co- administered with itraconazole.
  • Venglustat exposure following co-administration with moderate (fluconazole, and fluvoxamine with CYP2D6 inhibition turned off) and weak (cimetidine with CYP2D6 inhibition turned off) CYP3A inhibitors were predicted to be 1.52-, 1.08-, and 1.08-fold higher compared to venglustat alone, respectively (see Example 5).
  • the first order absorption was assumed in all simulations. Values of the fraction absorbed (f a ) and first order absorption rate constant (K a ) were from an estimate of in vivo permeability, P eff,man , which, in turn, was extrapolated from Caco-2 data using standard assays.
  • the intestinal availability (Fg) was predicted by the Qgut model, which represents a nominal blood flow and is a hybrid parameter reflecting drug absorption rate from the gut lumen, removal of drug from the enterocyte by the enterocytic blood supply and the volume of enterocytes.
  • fu,gut was set at a default value of 1 (assuming that there is insufficient time for plasma protein binding equilibrium or erythrocyte uptake before the drug is removed from the basolateral side of the enterocyte).
  • the calculation of gut intrinsic clearance (CL uG,int ) was based on the assumption the intrinsic clearance per pmol CYP is the same in both gut and liver.
  • Unbound fraction in plasma (f u,p ), blood-to-plasma ratio (B/P) and mean percent unbound to human liver microsome proteins (f u,mic ) were measured for venglustat using standard assays.
  • the clinical data from completed Phase 1 studies were first modelled using population PK (POPPK) method in order to derive PK parameters for PBPK model inputs (e.g., Distribution parameters, V ss and SAC).
  • POPPK population PK
  • the fractional metabolism (f m ) by CYP3A4 and CYP2D6 were based on the in vitro intrinsic metabolic clearance data.
  • CYP3A4 and CYP2D6-mediated intrinsic clearance was calculated using the Simcyp ® built-in retrograde calculator based on f m and oral clearance (CL/F) from the preliminary POPPK model. Based on earlier studies, the contribution of the renal components to the in vivo clearance was estimated to be approximately 30%.
  • the IC50 value of venglustat against human MDR1-mediated transport was determined in house using a standard assay.
  • Clinical PK data for model verification Concentration-time data of venglustat from the Phase 1 single ascending dose and multiple ascending dose clinical trials (Example 3) were used for venglustat model verification in healthy subjects.
  • the venglustat PBPK model was further verified for PK prediction in the absence and presence of itraconazole, a strong CYP3A inhibitor, in healthy subjects using available data from a clinical DDI study (Example 4).
  • a summary of the clinical study design for studies used for venglustat PBPK model verification is provided in Table 3.
  • Table 3 Studies used for venglustat PBPK model verification Dose (mg, N Male/Female Age Dosing regimen measured as (%) (years) free base) 11.2 6 100/0 19-31 Day 1 : Single dose 18.6 6 100/0 24-45 Day 1 : Single dose 112 5 100/0 25-35 Day 1 : Single dose 3.72 9 44.4/55.6 21-41 Repeated dosing, QD for 14 days 7.44 9 55.6/44.4 19-39 Repeated dosing, QD for 14 days 14.9 9 76.7/33.3 23-43 Repeated dosing, QD for 14 days Treatment Period 1: 15 mg venglustat SD on Day 1; Treatment 15 8 100/0 20-43 Period 2: 15 mg venglustat SD on Day 6 Itraconazole 100 mg BID from Day 1 to Day 12 The verification of itraconazole and its primary metabolite PBPK models were performed using their PK data from the study in Example 4.
  • Simulations were conducted with 10 virtual trials at each dose and dosing regimen.
  • Simcyp ® simulates variability in the “Sim-Healthy Volunteers” population using a Monte Carlo approach. Inter-individual physiological variability (height, weight, age, lymphatic flows, etc.) and variation in phenotype, if any, is calculated automatically using databases within the library.
  • the “PK profiles” option was selected for the present analysis. Hence, all calculations (dynamic modeling) are time- and concentration-dependent.
  • the overlay-to-observations option was used to allow the verification of the PBPK model based on the comparison of the concentration-time profiles between observations and predictions.
  • PK parameters e.g., AUC
  • simulations were performed at least 3 half-lives of venglustat in healthy subjects, for groups receiving a single dose. For the groups receiving multiple doses, simulations were performed until the end of the dosing interval of the last dose, as described, e.g., in the clinical studies disclosed herein.
  • Verification of the venglustat PBPK model in healthy subjects consisted of: A. Graphical comparison of mean (5 th and 95 th percentile) predicted plasma concentration (venglustat) and individual observed plasma concentrations from Phase 1 trials (Examples 3 and 4). B.
  • the observed venglustat exposures (Cmax, AUC [single dose], AUC0-24h [repeated dosing]) in the clinical study were compared to those predicted by Simcyp ® .
  • Observed and predicted PK parameters with corresponding mean ratios (predicted/observed) were also computed. These ratios should be within a two-fold interval [0.5-2].
  • C. The performance of the Simcyp ® V17 built-in model for CYP3A inhibitor itraconazole (SVItraconazole_Fed Capsule) and its primary metabolite (SV-OH- Itraconazole) model was verified by comparing the model predicted and observed data from clinical studies in healthy subjects (Example 4).
  • the PBPK model performance for the prediction of venglustat-itraconazole interaction was verified using the following methods: • Visual predictive check comparing the model predicted mean and 90% prediction interval of plasma concentration time profiles to that of the individual observed data of venglustat, itraconazole, and OH-itraconazole; • Comparing PBPK-predicted PK parameters to observed data of itraconazole and OH- itraconazole (steady state C max , C trough , AUC 0-12h ) with corresponding mean ratios (predicted/observed); • Observed and predicted drug interaction ratios of venglustat PK (Cmax ratio, AUClast ratio, and AUC ratio) with corresponding geometric mean ratios (predicted divided by observed) were also computed.
  • the predicted vs. observed values should be within a two-fold interval [0.5-2].
  • the final PBPK model was used to predict the effect of CYP3A4 inhibitors on the steady state PK of venglustat in healthy subjects.
  • Each simulation was conducted with 10 virtual trials of 10 subjects, who are co-administered with the inhibitor, aged from 18 to 65 years old, with a male/female ratio of 50/50, following venglustat repeated dosing to reach steady state.
  • the library virtual population, “Sim-Healthy Volunteers” was implemented for model application. Study design varied dependent on the inhibitor properties and the assumed clinical scenarios. Simulations were run for long enough to reach steady state PK for venglustat and CYP3A inhibitors in healthy subjects, when co-administered.
  • the repeated doses of itraconazole at 100 mg BID was co-administered with venglustat from Day ⁇ 6 to Day 17 in healthy subjects.
  • venglustat exposure when co-administered with strong CYP3A inhibitors (e.g., itraconazole)
  • the repeated doses of itraconazole at 100 mg BID was co-administered with venglustat from Day 6 to Day 17 in healthy subjects.
  • the observed and predicted venglustat concentrations in the healthy male and female subjects after repeated QD doses of venglustat at 3.72 mg, 7.44 mg, and 14.9 mg using the PBPK model are presented in Figure 5 and Figure 6.
  • the observed venglustat PK parameters in the clinical study were compared to those predicted by the PBPK model in Table 5 below.
  • Results – single dose of venglustat in the absence and presence of itraconazole The simulated plasma concentration-time profiles of venglustat after single dose of 15 mg calculated as free base) on Day 6, in the absence and presence of 100 mg itraconazole co- administered BID from day 1 to day 12 are shown in Figures 7 and 8, respectively.
  • Venglustat (15 mg single dose) was administered alone in treatment period 1 (as in Example 4).
  • Example 6 Application of the PBPK model to predict steady-state plasma concentrations of venglustat co-administered with CYP3A inhibitors
  • the verified PBPK model of Example 5 was used to predict venglustat PK with 8 and 15 mg repeated doses in healthy subjects co-administered with other CYP3A inhibitors to guide dose recommendations.
  • PK pharmacokinetics
  • Predictions were made of steady state plasma concentrations of venglustat following repeated oral dosing of venglustat with: (i) fluconazole, a moderate CYP3A4 inhibitor; (ii) fluvoxamine, a moderate CYP3A4 inhibitor; and (iii) cimetidine, a weak CYP3A inhibitor, in healthy subjects.
  • CYP2D6 inhibition was turned off in the model.
  • Model input parameters for fluvoxamine (a moderate CYP3A inhibitor) and cimetidine (a weak CYP3A inhibitor) in the simulations had the default values indicated in the compound library files (SV-Fluvoxamine and SV- Cimetidin, respectively) within the Simcyp Simulator (V17), except for a minor modification of turning off the inhibitory effects on CYP2D6, since both CYP3A and CYP2D6 inhibition had been built in the library models. This allowed for the assessment of the impact of fluvoxamine and cimetidine on venglustat solely via the CYP3A pathway.
  • the fluconazole PBPK model was further verified using clinical data from the literature (Olkkola et al., Anesth. Analg. (1996) 82(3):511-516), regarding the effect of fluconazole on the midazolam exposure.
  • the predicted midazolam Cmax and AUC ratios in healthy subjects following single oral administration of midazolam 7.5 mg on day 1 and on day 6 in the absence and presence of fluconazole are shown in Table 8 below.
  • Table 8 To compare with the observed AUC ratios, which were derived from reported AUC from time 0 to infinity, two independent simulations were conducted to generate the corresponding ratios for midazolam on day 1 and day 6.
  • Predicted values show arithmetic mean, and trial range from 10 simulated trials matching the clinical study design.
  • the ratios of predicted to observed PK parameters were approximately 1.
  • These modified PBPK models were verified for the impact of fluvoxamine/cimetidine on sensitive CYP3A substrates based on published clinical data which studied the effect of fluvoxamine on a sensitive CYP3A substrate (midazolam), as well as the effect of cimetidine on a number of sensitive CYP3A substrates (midazolam, nifedipine, and sildenafil) (See, e.g., Lam et al., J.
  • the observed C max and AUC ratios are expressed as arithmetic mean values. Predicted values show mean, and trial range from 10 simulated trials matching the clinical study design. ⁇ The observed and predicted Cmax or AUC ratios of sildenafil in the presence and absence of cimetidine are presented as the geometric mean with 95% CI in parentheses.
  • the PBPK model was able to adequately predict the DDI potential of fluvoxamine and cimetidine in healthy subjects.
  • the ratio of predicted to observed PK parameters was approximately 1.
  • Plasma PK parameters of venglustat in healthy subjects after repeated dosing at 15 ⁇ mg or 8 mg administered in the absence and presence of itraconazole (strong CYP3A inhibitor), fluconazole (moderate CYP3A inhibitor), fluvoxamine (moderate CYP3A inhibitor), and cimetidine were simulated and the results are shown in Table 10 below.
  • Virtual subjects (age, 18-65; Female, 50%) were generated and randomly assigned to ten different trials of 10 subjects to indicate the variability between groups.
  • the predicted Cmax and AUCtau ratios represent mathematic mean values (with an inhibitor compared to without an inhibitor) of 100 virtual subjects in 10 trials.
  • Co-administration of venglustat with CYP3A inhibitors is predicted to result in higher exposures, with the magnitude of the effect depending to an extent on the potency of the inhibitor.
  • Venglustat steady state AUCtau following co-administration with strong and moderate CYP3A inhibitors were predicted to be 1.69 fold higher with itraconazole, 1.52 fold higher with fluconazole, and 1.08 fold higher with fluvoxamine.
  • the impact of weak CYP3A inhibitor cimetidine on venglustat systemic exposure was considered to be minimal (1.08 fold higher).

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Abstract

L'invention concerne des procédés dans lesquels des patients se voient administrer du venglustat en combinaison avec des inhibiteurs du cytochrome CYP3A4. Les procédés peuvent impliquer la réalisation d'ajustements spécifiques à la dose de venglustat afin d'optimiser la réponse clinique du patient.
PCT/IB2023/062098 2022-12-01 2023-11-30 Venglustat en combinaison avec un inhibiteur fort ou modéré de cyp3a4 Ceased WO2024116127A1 (fr)

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EP23821741.8A EP4626424A1 (fr) 2022-12-01 2023-11-30 Venglustat en combinaison avec un inhibiteur fort ou modéré de cyp3a4
CN202380089614.9A CN120417900A (zh) 2022-12-01 2023-11-30 文鲁司他与cyp3a4的强或中度抑制剂的组合
IL321165A IL321165A (en) 2022-12-01 2023-11-30 Vanglustat in combination with a strong or moderate CYP3A4 inhibitor
KR1020257021380A KR20250106321A (ko) 2022-12-01 2023-11-30 강력하거나 중간 수준인 cyp3a4 억제제와 조합한 벤글루스타트
AU2023403087A AU2023403087A1 (en) 2022-12-01 2023-11-30 Venglustat in combination with a strong or moderate inhibitor of cyp3a4
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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3119742A (en) 1962-12-19 1964-01-28 Smith Kline French Lab Method of preparing sustained release pharmaceutical pellets and product thereof
US3492397A (en) 1967-04-07 1970-01-27 Warner Lambert Pharmaceutical Sustained release dosage in the pellet form and process thereof
US3538214A (en) 1969-04-22 1970-11-03 Merck & Co Inc Controlled release medicinal tablets
US4060598A (en) 1967-06-28 1977-11-29 Boehringer Mannheim G.M.B.H. Tablets coated with aqueous resin dispersions
US4173626A (en) 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
WO2012129084A2 (fr) 2011-03-18 2012-09-27 Genzyme Corporation Inhibiteurs de la glucosylcéramide synthase
WO2014043068A1 (fr) 2012-09-11 2014-03-20 Genzyme Corporation Inhibiteurs de synthase de glucosylcéramide
WO2014152215A1 (fr) 2013-03-15 2014-09-25 Genzyme Corporation Formes de sel de (s)-quinuclidin-3-yl (2-(2-(4-fluorophényl)thiazol-4-yl)propan-2-yl)carbamate
WO2016145046A1 (fr) 2015-03-10 2016-09-15 Genzyme Corporation Procédés de traitement de protéinopathies
WO2020163337A1 (fr) 2019-02-04 2020-08-13 Genzyme Corporation Traitement de ciliopathies à l'aide d'inhibiteurs de la glucosylcéramide synthase (gcs)
WO2021056673A1 (fr) 2019-09-27 2021-04-01 唐旭明 Structure de raccordement pour propulseur latéral pour navire
WO2022018695A1 (fr) 2020-07-24 2022-01-27 Genzyme Corporation Compositions pharmaceutiques comprenant du venglustat

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3119742A (en) 1962-12-19 1964-01-28 Smith Kline French Lab Method of preparing sustained release pharmaceutical pellets and product thereof
US3492397A (en) 1967-04-07 1970-01-27 Warner Lambert Pharmaceutical Sustained release dosage in the pellet form and process thereof
US4060598A (en) 1967-06-28 1977-11-29 Boehringer Mannheim G.M.B.H. Tablets coated with aqueous resin dispersions
US3538214A (en) 1969-04-22 1970-11-03 Merck & Co Inc Controlled release medicinal tablets
US4173626A (en) 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4683195B1 (fr) 1986-01-30 1990-11-27 Cetus Corp
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
WO2012129084A2 (fr) 2011-03-18 2012-09-27 Genzyme Corporation Inhibiteurs de la glucosylcéramide synthase
WO2014043068A1 (fr) 2012-09-11 2014-03-20 Genzyme Corporation Inhibiteurs de synthase de glucosylcéramide
WO2014152215A1 (fr) 2013-03-15 2014-09-25 Genzyme Corporation Formes de sel de (s)-quinuclidin-3-yl (2-(2-(4-fluorophényl)thiazol-4-yl)propan-2-yl)carbamate
WO2016145046A1 (fr) 2015-03-10 2016-09-15 Genzyme Corporation Procédés de traitement de protéinopathies
WO2020163337A1 (fr) 2019-02-04 2020-08-13 Genzyme Corporation Traitement de ciliopathies à l'aide d'inhibiteurs de la glucosylcéramide synthase (gcs)
WO2021056673A1 (fr) 2019-09-27 2021-04-01 唐旭明 Structure de raccordement pour propulseur latéral pour navire
WO2022018695A1 (fr) 2020-07-24 2022-01-27 Genzyme Corporation Compositions pharmaceutiques comprenant du venglustat

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Immobilized Cells and Enzymes", 1984, IRL PRESS, article "Transcription and Translation"
"Methods in Enzymology", 2007, ACADEMIC PRESS, INC., article "Current Protocols in Molecular Biology"
"Remington's Pharmaceutical Sciences", 2000, MACK PUBLISHING CO
"Technology and Application", 2004, CRC PRESS, article "Gene Silencing by RNA Interference"
ANDERSON, NUCLEIC ACID HYBRIDIZATION, 1999
DRESSER G K ET AL: "PHARMACOKINETIC-PHARMACODYNAMIC CONSEQUENCES AND CLINICAL RELEVANCEOF CYTOCHROME P450 3A4 INHIBITION", CLINICAL PHARMACOKINETICS, ADIS INTERNATIONAL LTD., AUCKLAND, NZ, vol. 38, no. 1, 1 January 2000 (2000-01-01), pages 41 - 57, XP000952582, ISSN: 0312-5963, DOI: 10.2165/00003088-200038010-00003 *
FEE ET AL., CLIN. PHARMACOL. THER, vol. 41, no. 1, 1987, pages 80 - 84
FLOCKHART: "Drug Interactions: Cytochrome P450 Drug Interaction Table", 2007, INDIANA UNIVERSITY SCHOOL OF MEDICINE
FRESHNEY: "Culture of Animal Cells: A Manual of Basic Technique", 2005
GENE TRANSFER AND EXPRESSION IN MAMMALIAN CELLS, 2003
HAKKOLA JUKKA ET AL: "Inhibition and induction of CYP enzymes in humans: an update", ARCHIVES OF TOXICOLOGY, SPRINGER, DE, vol. 94, no. 11, 27 October 2020 (2020-10-27), pages 3671 - 3722, XP037285411, ISSN: 0340-5761, [retrieved on 20201027], DOI: 10.1007/S00204-020-02936-7 *
LAM ET AL., J. CLIN. PHARMACOL., vol. 43, no. 11, 2003, pages 1274 - 1282
LI L ET AL: "PBPK MODELING TO ASSESS DRUG-DRUG INTERACTION POTENTIAL OF VENGLUSTAT WITH CYP3A INHIBITORS", CLINICAL PHARMACOLOGY & THERAPEUTICS: CPT, vol. 113, no. S1, 16 February 2023 (2023-02-16), US, pages S74 - S74, XP093127118, ISSN: 1532-6535, DOI: 10.1002/cpt.2835 *
MACPHERSON ET AL., PCR 2: A PRACTICAL APPROACH, 1995
MACPHERSON ET AL.: "PCR 1: A Practical Approach", 1991, IRL PRESS AT OXFORD UNIVERSITY PRESS
MICHAEL R. GREENJOSEPH SAMBROOK: "Molecular Cloning", 2012, COLD SPRING HARBOR LABORATORY PRESS
MOLENAAR-KUIJSTEN LAURA ET AL: "A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs", FRONTIERS IN PHARMACOLOGY, vol. 12, 30 August 2021 (2021-08-30), XP093041056, DOI: 10.3389/fphar.2021.670862 *
NUCLEIC ACID HYBRIDIZATION, 1984
OLIGONUCLEOTIDE SYNTHESIS, 1984
OLKKOLA ET AL., ANESTH. ANALG, vol. 82, no. 3, 1996, pages 511 - 516
PERBAL: "Gene Transfer Vectors for Mammalian Cells", 1984, COLD SPRING HARBOR LABORATORY, article " A Practical Guide to Molecular Cloning"
PETERSCHMITT ET AL., CLIN. PHARMACOL. DRUG DEV, vol. 10, no. 1, 2021, pages 86 - 98
PETERSCHMITT ET AL., CLIN. PHARMACOL. DRUG DEV., vol. 10, no. 1, 2021, pages 86 - 98
PETERSCHMITT ET AL., J. PARKINSONS DIS, vol. 12, 2022, pages 557 - 570
PETERSCHMITT M. JUDITH ET AL: "Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers", CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, vol. 10, no. 1, 1 January 2021 (2021-01-01), GB, pages 86 - 98, XP055818652, ISSN: 2160-763X, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cpdd.865> DOI: 10.1002/cpdd.865 *
SCHWARTZ ET AL., CLIN. PHARMACOL. THER, vol. 43, no. 6, 1988, pages 673 - 80
WILNER ET AL., BR. J. CLIN. PHARMACOL., vol. 53, 2002

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